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CHRISTINE ADAMEC THE ENCYCLOPEDIA OF ENDOCRINE DISEASES AND DISORDERS

THE ENCYCLOPEDIA OF ENDOCRINE DISEASES AND DISORDERS

William Petit Jr., M.D. Christine Adamec The Encyclopedia of Endocrine Diseases and Disorders

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Library of Congress Cataloging-in-Publication Data

Petit, William. The encyclopedia of endocrine diseases and disorders / William Petit Jr., Christine Adamec. p. ; cm. Includes bibliographical references and index. ISBN 0-8160-5135-6 (hc : alk. paper) 1. Endocrine glands—Diseases—Encyclopedias. [DNLM: 1. Endocrine Diseases—Encyclopedias—English. WK 13 P489ea 2005] I. Adamec, Christine A., 1949– II. Title. RC649.P48 2005 616.4’003—dc22 2004004916

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This book is printed on acid-free paper. CONTENTS

Foreword vii Acknowledgments ix Introduction xi Entries A–Z 1 Appendixes 247 Bibliography 289 Index 303

FOREWORD s an endocrinologist, I am very familiar with Other, less common endocrine diseases and dis- Athe importance of the endocrine glands to orders also have an impact. Some patients face can- human functioning. These glands work continu- cer of their endocrine glands, such as cancer of the ously to maintain the health of all individuals as we pancreas, thyroid, ovaries, testes, and the other move through each and every day of our lives. In organs that comprise the endocrine system. These fact, when one or more of the endocrine glands cancers are not as commonly diagnosed as are can- malfunction, the person’s entire system is often cers of the lung, breast, prostate, or colon. thrown into disarray. For example, if a person However, they are equally as devastating to those develops Hashimoto’s thyroiditis, an autoimmune who experience them. disorder that causes hypothyroidism, the person’s Some people develop very rare diseases of the once-normal thyroid levels will drop. He or she endocrine system. One such disease, gigantism, may become lethargic and show a variety of symp- causes extremely tall height due to a malfunction toms. These range from annoying to severe and of the pituitary gland. Other individuals have affect many activities of daily living. Due to lethar- unusually short stature, or dwarfism, often due to gy, the patient’s physical activity level will usually genetic mutations they have inherited from their decrease. Thus the patient may gain weight, even parents and sometimes from deficiencies of growth though he or she eats about the same amount of hormone. food as they had before becoming hypothyroid. In this volume, we have attempted to cover the The individual with hypothyroidism may also gamut of endocrine diseases and disorders, ranging appear apathetic and depressed, sometimes leading from the more common diseases, such as thyroid the patient to seek treatment for these symptoms disease and diabetes, to the rarer medical problems. rather than for the underlying cause. Our goal is to provide readers with a broad There are many other examples of endocrine overview of the endocrine system, illustrating how diseases that manifest profound effects on those the endocrine glands function when they work who live with these illnesses, especially if their normally as well as describing what happens when endocrine disorder is not identified and treated. For the endocrine glands malfunction and discussing example, diabetes mellitus has a major health what can be done in the case of the latter. impact on millions of people. Sadly, many people We must also point out that although doctors who have diabetes, and particularly Type 2 diabetes cannot cure all diseases and disorders, many ill- which usually can be treated with oral medica- nesses that were not treated years ago—because tions, are undiagnosed and untreated. These peo- the medical tools were not available at that time— ple risk suffering severe complications from their can now be treated by endocrinologists. For exam- long-term untreated illness. ple, if infertility is caused by an endocrine disorder,

vii viii The Encyclopedia of Endocrine Diseases and Disorders the problem can often be identified and treated, obese) increased from one in 200 Americans in enabling an anxious couple to become transformed 1986 to one in 50 by the year 2000. into happy parents. In addition, over the same time period, the If the illness is potentially fatal, such as cancer, number of people who were obese (with a BMI of many treatments are available that can help 30 or greater) increased from one in 10 to one in patients resolve their cancer or extend their life for five Americans—another dramatic change. Clearly, many years. We doctors still do not have all the obesity is a major problem in the United States. It answers, of course, but we are learning more all is also one that needs to be addressed by both the time. Continuing research will enable us to dis- patients and their doctors. cover much more about endocrine diseases and Patients also bear other responsibilities in man- disorders and how to treat them more effectively. aging their health. For example, they should have In the meantime, we also know that patients annual checkups and should see their doctors more can take many actions to increase the probability of frequently if they are ill. Doctors are not mind their good health. For example, eating a healthy readers. They need to see their patients regularly. diet and exercising regularly will not only help Doctors also need to be given complete and many patients avert the scourge of obesity but will accurate information by their patients. When also significantly reduce their risk of developing patients withhold information from their doctors, diseases such as diabetes or hypertension. such as facts about smoking habits, intake of alco- Such healthy habits are very important. Recent hol, and use of alternative remedies, they may be studies have shown that the prevalence of both compromising their health. obesity and severe obesity has greatly increased. In summary, when doctors and patients work For example, a study reported in a 2003 issue of together in a healthy partnership, many endocrine Archives of Internal Medicine reported that the preva- diseases and disorders, as well as many other med- lence of people with a body mass index (BMI) of 40 ical problems, can often be successfully resolved or or greater and who were about 100 pounds or managed. more overweight (and thus considered severely —William Petit Jr., M.D. ACKNOWLEDGMENTS

r. Petit and Christine Adamec would both like hypercalcemia during his years at the Clinical Dto thank the following individuals: Marie Research Center at Yale University, involved with Mercer, reference librarian at the DeGroodt Public the Diabetes Control and Complications Trial Library in Palm Bay, Florida, for her assistance in (DCCT). He would also like to thank the nurses of locating hard-to-find journal articles and books. In Hunter 5. addition, they would like to thank Mary Jordan, Dr. Petit would also like to thank the following: interlibrary loan librarian at the Central Library his team members in his offices, including Doreen Facility in Cocoa, Florida, for her research assis- Rackliffe, PA-C, Doreen Akehurst, Milagros Cruz, tance. Thanks also to Stuart Moss, librarian at the Cheryl Dunphy, Mona Huggard, and Michelle Nathan Kline Institute for Psychiatric Research in Rodriguez; his team members at the Joslin Diabetes Orangeburg, New York, for helping to locate docu- Center at New Britain General Hospital, including ments that were difficult to find. Mary Armetta, Sue Bennett, Lynne Blais, Linda Dr. Petit would like to thank his wife, Jennifer Ciarcia, Carole Demarest, Lynn Diaz, Tracy Dube, Hawke-Petit, and his daughters, Hayley Elizabeth Cindy Edwards, Jen Kostak, Linda Krikawa, Marc and Michaela Rose, for allowing him to monopo- Levesque, Karen McAvoy, Terri McInnis, Pat lize the computer to trade electronic mails and files O’Connell, Denise Otero, Robin Romero, Kate with his coauthor. He would like to thank his coau- Simoneau, Ursula Szczepanski, and Sue Zailskas; thor, Mrs. Adamec, for her unwavering support and his physician colleagues at New Britain and hard work and for continuing to push him as General Hospital in New Britain, Connecticut, he continued his usual clinical and speaking duties, including Jim Bernene, M.D., Latha Dulipsingh, leaving only nights and weekends to write. M.D., Joe Khawaja, M.D., Tom Lane, M.D., Ray Dr. Petit would also like to thank all his patients LeFranc, M.D., Joe Rosenblatt, M.D., and Mubashir over the years who continue to teach him clinical Shah, M.D. endocrinology. These include, among many others, Christine Adamec would like to thank her hus- his first patient with diabetes mellitus and pancre- band, John Adamec, for his support and patience atic cancer when Dr. Petit was a third-year student; throughout the project. a patient in his clinic in Rochester, New York, with Special thanks to James Chambers, editor in a very rare combination of empty sella syndrome chief, Arts & Humanities, Facts On File, Inc., for his and isolated adrenocorticotropic hormone (ACTH) support of this project. deficiency; and his patients with immobilization

INTRODUCTION

ndocrinology is the study of normal and abnor- By using sophisticated and complex feedback Emal hormonal function. The endocrine glands loop systems that are somewhat comparable to the are vitally important organs that are necessary to sensors of a thermostat and yet are also far more sustain all human functions as well as life itself. complicated than the most sophisticated computer, The glands that comprise the endocrine system the endocrine glands and the other systems of the affect the ability to become pregnant and success- body work together. They sense and respond to the fully carry the pregnancy, the ability to breast-feed numerous minor and major changes in the per- an infant, and the ability of a child to grow and son’s daily environment and the resulting bodily develop normally, including sexual differentiation. needs. On a minute-to-minute and a day-by-day basis, the If a person is in danger, for example, the adrenal endocrine system helps to regulate an individual’s glands increase the production of adrenaline (also basic functions, such as heart rate, blood pressure, known as epinephrine), so that the individual is cognitive processes, appetite, energy storage and more alert and ready either to take action or to utilization levels, tissue growth and rejuvenation, seek escape. (This is also known as the fight-or- sleep, sexuality, bone health, fertility, overall body flight reaction.) The person’s blood pressure and metabolism, masculinity and femininity, and virtu- heart rate both increase, enabling the individual to ally every aspect of continued life. respond with an attack or by running away. When The endocrine glands comprise an elegant and the perceived danger is over, the endocrine glands complex system. This system is basically the brain signal the body to move to a lower and normal that orchestrates and monitors numerous vital level of alertness. Adrenaline levels drop, and the bodily functions through the release of a cascade of person’s heart rate and blood pressure stabilize to hormones. These hormones send chemical mes- normal. In addition, the generalized feeling of fear, sages to other parts of the body, enabling actions to panic, or anxiety subsides as the catecholamines start or end as well as to speed up or slow down. that were released are metabolized and return back Some important hormones that are released to their basal levels. exert their primary effect on other hormones, and This is only one example of the numerous feed- they, in turn, either trigger or inhibit the release of back loops that are constantly operating in the yet other hormones. For example, the hypothala- human body, internal sentinels that are always on mus releases growth hormone-releasing hormone, duty, ready to react to an individual’s particular which triggers the pituitary to release growth hor- needs. Of course, most modern situations do not mone. The effects of growth hormone are mediated actually require any physical battles to occur throughout the body by insulin-like growth factor 1 between people. However, contemporary humans (IGF-1). The hypothalamus can also release a com- still have the same basic physical anatomy and the pound that inhibits the release of prolactin. same endocrine system as people had during the

xi xii The Encyclopedia of Endocrine Diseases and Disorders earliest times when they needed to survive by creas is directly affected by, and also affects, the either standing up to threats and fighting or by digestive system. In other words, eating food and running away from them as fast as possible. the type of food that is eaten will trigger changes to the pancreas and the digestive system. While the person travels to her job, the endocrine The Endocrine System glands are still actively functioning, with some Works Around the Clock glands on standby alert. For example, if another car The endocrine system is comprised of the following suddenly darts into the driver’s path, the surge of key organs: the hypothalamus, the pituitary gland, adrenaline released by the adrenal glands (as well as the pineal gland, the thyroid gland, the parathy- by the sympathetic nervous system) will often roids, the thymus gland, the pancreas, the adrenal enable the driver to react quickly and, one hopes, to glands, the ovaries, and the testes. All these glands allow her to avert a car crash. After the danger sub- are actively involved in both major and minor daily sides, the individual’s adrenaline levels will drop life processes. Researchers have also found that back down again as they are no longer needed to certain organs that were previously not believed to keep her at such a high level of alertness. have endocrine functions do, in fact, secrete hor- When an individual arrives at work, her mones. Examples include atrial natriutetic factor endocrine glands continue to pump out hormones, from the left atrium in the heart, leptin from the fat regulating her blood pressure, blood sugar, calcium cells, and angiotensin from the blood vessels. transfers from her bones to the blood, and so on. For example, before people wake up in the Assuming that she is a healthy woman, her thyroid morning, the blood levels of many hormones, gland enables her to have normal energy levels. including cortisol, begin to rise, facilitating the Her pancreas maintains a normal blood sugar level, awakening. Cortisol is secreted by the adrenal unless she has diabetes and needs to take medica- glands. Its effect is to help to maintain normal tions on a regular basis to attain a normal or near- blood pressure and blood glucose levels, to main- normal rate of blood sugar. The endocrine glands tain a normal level of electrolytes, and also to help continue their vigilance with a constant uncon- people to maintain their vigilance and alertness. scious and involuntary monitoring of the body Later in the day and during sleep, the cortisol lev- throughout the day. They adjust the output of hor- els will drop to lower yet appropriate levels. mones as needed. If it is a slow and easy day for the Another hormone, growth hormone, is released owner of the endocrine glands, they generally need in a pulsatile fashion while people sleep. This hor- not be as active as when she has difficult physical mone mediates growth as well as helps to repair the (or emotional) problems that need to be resolved. often microscopic damage that has occurred to the tissues, whether a person is eight or 88 years old. Endocrine Glands Both cortisol and growth hormone operate in part on a biological cycle, sometimes known as the Over the Life Span circadian cycle. They are affected by whether the Endocrine glands affect people over the entire person is asleep or awake. Other hormones are course of their lives. They enable women to released fairly continuously, such as thyroid hor- achieve pregnancies (or to suffer from problems mone and parathyroid hormone. with infertility), to breast-feed their babies (or to After the individual awakes and consumes her have difficulty with breast-feeding), to respond to breakfast, the pancreas works to keep her blood crises, and to sleep well or poorly. For example, sugar stable and within a very tight range by pro- from the age of puberty until about the age of 50, ducing insulin as needed. How much insulin is a woman’s ovaries will produce increased and fluc- needed, though, varies with whether she eats a tuating levels of estrogen and progesterone hor- bran muffin, a Danish, a piece of fruit or, as occurs mones, which will affect many aspects of her life. in some cases, skips breakfast altogether, depleting Estrogen levels will vary during the menstrual her energy stores for the morning. Thus, the pan- cycle. Prior to menstruation, some women develop Introduction xiii bloating, headaches, and other symptoms until the return to normal again, although she is at risk for onset of their periods. The ovaries also produce developing gestational diabetes at every subse- eggs that will enable a woman to ovulate and also quent pregnancy. All women with gestational dia- often to achieve a pregnancy if she has unprotect- betes should have an oral glucose tolerance test six ed sex with a fertile man. weeks after giving birth. Women who have had Similarly, the testosterone that is produced by the gestational diabetes also have an increased risk of man’s testes (also known as the testicles) increases developing diabetes mellitus later in life, usually the male libido and contributes to the man’s ability to during middle age. have an erection, enabling intercourse. Testosterone, Women who have had Type 1 or Type 2 diabetes in conjunction with follicle-stimulating hormone prior to their pregnancy will need to monitor their (FSH) and other hormones, allows the development glucose levels closely and carefully watch their diet of spermatozoa. Testosterone and other hormones and exercise levels. In addition, they may need to also later facilitate the release of sperm into the man’s change their dosages and/or the medications that ejaculate, which can then combine with a fertile they take during pregnancy. Women who formerly woman’s egg to create a pregnancy. Low levels of took oral agents for their Type 2 diabetes may need testosterone may result in problems with a male’s to take insulin during the pregnancy. Postpartum sexual development, libido, and erectile function as levels will also need to be checked. well as his fertility. Some pregnant women develop abnormalities of Of course, fertility is affected by many different their thyroid levels, becoming hypothyroid or hyper- factors, and the key one is age. Fertility declines thyroid, although hypothyroidism is more common. with age. Women over age 35 are significantly less The thyroid levels may normalize after delivery or fertile than women who are younger. Fertility also they could also worsen considerably. Pregnant declines for men as they age, although it does not women with even minor thyroid abnormalities appear to decline as precipitously or at as young an should consult with an endocrinologist about their age in men as in women. Elderly men can father own health and the health of their infants. children, although this is not common. After menopause, a woman’s estrogen levels If a woman becomes pregnant, her endocrine drop. Some women experience difficult symptoms, glands will adapt to that major body change as well. such as hot flashes, insomnia, and mood swings. Once the woman becomes pregnant, the body sens- Some women decide to combat these symptoms by es this change and, consequently, ovulation ceases. using hormone replacement therapy (HRT), which Prolactin levels may begin to rise during pregnancy. is a combination of estrogen and progesterone. They particularly increase after childbirth, enabling Those who have had a hysterectomy can safely use the woman to breast-feed her child. The dopamine only estrogen replacement therapy (ERT). Studies that normally inhibits the release of prolactin is not have shown that HRT may be dangerous for some released and thus breast milk can be produced. women, particularly those with a family history of Most women are healthy during their pregnan- breast cancer. ERT has been associated with an cies, but some women experience endocrine diffi- increased risk for developing ovarian cancer. Each culties. For example, a small percentage of women woman who is considering using hormones (HRT) develop gestational diabetes that is triggered by the after menopause must consider the pros and cons of pregnancy. Gestational diabetes is controlled by their use and discuss the issue with her gynecologist. diet, exercise, and insulin, depending on the sever- Testosterone levels in men also decline with ity of the gestational diabetes. Women with gesta- aging, although few men use testosterone on a reg- tional diabetes will need to test their blood and ular basis as a hormone therapy in the same way monitor their diet closely. They will also need to that menopausal women use HRT. Perhaps in the consult with an endocrinologist as well as with future, testosterone use will become a more stan- their obstetrician. dard and accepted medical practice for men, and Once the woman with gestational diabetes has they will take their TRT (testosterone replacement delivered the baby, her glucose levels will usually therapy) every day, along with their morning coffee. xiv The Encyclopedia of Endocrine Diseases and Disorders

The Endocrine Glands Affect When Problems Occur with the Every Other System in the Body Endocrine System The endocrine glands affect all other systems in the Sometimes the functioning of one or more of the body. The parathyroid glands, for example, are endocrine glands goes awry. If the highly complex integral to the health and maintenance of the system of feedback loops that tells the body when skeletal system. They utilize both calcium and vita- and how much of certain hormones should be min D to help with the process of maintaining secreted seriously malfunctions, diseases and occa- healthy bones. Illnesses such as osteoporosis or sionally even death can result. Yet many different Paget’s disease impair the normal production of life-threatening malfunctions of the endocrine sys- bone tissue. Patients with hypoparathyroidism, a tem are often manageable when competent and rare disease of the parathyroid glands that is caused caring physicians treat the person. by damage or trauma to the parathyroid glands, For example, diabetes mellitus is a common dis- develop hypocalcemia, and they need to take sup- order of the endocrine system, affecting an esti- plements of calcium and vitamin D. Malnourished mated 18 million individuals in the United States. children with rickets also have abnormally miner- Type 1 diabetes, which affects about 1 million peo- alized bones, with bowed legs and other abnormal ple in the United States, is an autoimmune disor- features of the skeleton. der of the endocrine system caused by the The digestive system is also impacted by the destruction of beta cells in the pancreas. The beta endocrine system in many ways, affecting the indi- cells within the pancreas make insulin, and with- vidual’s overall metabolism, the degree of appetite, out insulin, people die. Fortunately, people who and the speed and efficiency of digestion. For have Type 1 diabetes can inject insulin, enabling example, diabetes mellitus can slow down the most people with this type of diabetes to live long stomach emptying and thus slow digestion (a con- and healthy lives. However, even with insulin dition called gastroparesis). injections, people with Type 1 diabetes must still Some diseases greatly affect an individual’s make many accommodations in order to maintain appetite and feeling of fullness (satiety). The best their health and to help avoid the many complica- example of this effect is Prader-Willi syndrome, an tions that can occur with diabetes, such as diabet- endocrine disorder that causes patients to have ic nephropathy (a kidney disease), diabetic enormous appetites. The parents or caregivers of neuropathy (a nerve disease), and diabetic children with Prader-Willi syndrome will literally retinopathy (an eye disease) as well as heart lock up the refrigerator because the children with attack, strokes, and other health risks. Prader-Willi syndrome will eat themselves sick. One major accommodation that people with Such children and adults have severe and con- both Type 1 and Type 2 diabetes must make is to tinuing problems with obesity, and researchers are perform daily blood testing of their glucose levels, seeking a way to help them. The key to resolving with subsequent adjustments of their medication Prader-Willi syndrome may also help many people and diet based on the blood test findings. For exam- without the disorder but who nonetheless have ple, if their blood sugar is low (hypoglycemia), these problems with chronic obesity. patients need to ingest some glucose in the form of In the circulatory system, the blood and heart a glucose tablet or fruit. If no better choices are are kept healthy by a normal metabolic rate main- available to them, then sugary food or fluids can tained by the thyroid gland. The nervous system provide the needed blood sugar boost. and the brain are also affected by the endocrine Type 2 diabetes is a far more common problem glands, particularly by the thyroid gland. The skin than Type 1 diabetes. In those with Type 2 diabetes, is affected by the endocrine system. Excessive lev- the beta cells of the pancreas produce some insulin, els of androgens (male hormones) in a woman can although inadequate levels to maintain normal cause severe acne, excessive hair growth (hir- blood glucose levels (euglycemia). These patients sutism), depression, and infertility. These problems, need to take oral medications and also test their once identified, are usually treatable. blood at least several times each day so they can Introduction xv make needed adjustments to their diet, exercise endocrine clinic for children at Johns Hopkins in plans, and medications. 1935. Other clinics were created, and the specialty Having too much circulating hormone is also evolved further in the mid 1950s and 1960s. By possible, whether the hormone is testosterone, 2002, there were 65 training programs in the estrogen, thyroxine, or any other hormone that the United States for pediatric endocrinologists. endocrine glands produce. For example, all females The American Board of Pediatrics has an produce a small amount of testosterone. However, endocrinology board that certifies the training and if too much testosterone is generated by the competence of pediatric endocrinologists in ovaries, this leads to a virilizing effect, causing the endocrinological diseases, including diabetes. woman’s breasts to flatten, increased body hair to According to a 2004 article in Pediatric Research, 927 grow on the chest and face, and infertility. pediatric endocrinologists have been certified by Fortunately physicians can seek the cause of this the board since 1978. condition and then act to treat it. Although most children and adolescents do not experience any disorders of the endocrine system, Endocrine Disorders and Development in their endocrine systems do affect normal life changes Children and Adolescents as they grow. Such life changes include the onset of Adults are not the only people affected by puberty and, in a female, the onset of menstruation endocrine diseases; children and adolescents are (menarche), the growth of breasts (thelarche), the susceptible as well. For example, if a child or an appearance of underarm hair (adrenarche) and pubic adolescent develops a tumor of the pituitary that hair (pubarche), and so forth. Boys experience typi- secretes excess growth hormone, he or she may cal male signs of puberty, such as facial and body hair develop gigantism, causing the child or adolescent and maturing changes in the testes and penis, as to grow to very tall heights. Occasionally, the child described by Dr. Tanner in 1962 and subsequently can exceed seven feet in height. Conversely, a defi- called Tanner stages. ciency of growth hormone, due to a malfunction of The amazing transformation of a child into a man either the pituitary or the hypothalamus, will lead or woman is a major achievement orchestrated by to growth failure. As a result, the person will be sig- the endocrine system, as is the decline of the hor- nificantly shorter than his or her peers. mones, no longer needed after the childbearing years Yet these are also conditions that physicians have are over. In some cases, however, children develop begun to correct by administering specific medica- disorders that may cause either an early puberty tions or growth hormone treatments. Although (precocious puberty) or a delayed puberty or anoth- such treatments may help children tremendously, er growth disorder. Pediatric endocrinologists should both physically and psychologically, these treat- be consulted to evaluate and treat such illnesses. ments continue to be controversial among some physicians. Some experts do not want to alter Endocrine Disorders and the Elderly nature and their philosophical view is that, for As individuals age into their senior years, they face example, if a person is biologically destined to be an increased risk for developing certain endocrine very tall, then he or she should be very tall. Others disorders. These include thyroid disease, particular- argue that height will affect a person for the rest of ly hypothyroidism, and bone disorders such as his or her life and thus they feel that it is a parent’s osteoporosis and osteopenia. Elderly individuals right to choose to do what is in the best interests of also face a greater risk of developing some danger- the child, including actions to limit height. ous and often fatal forms of cancer, particularly Children and adolescents with suspected or tumors of the ovary and the pancreas. Older diagnosed endocrine disorders should be treated by individuals are also more likely to develop below- pediatric endocrinologists, physicians who special- normal levels of calcium in the blood (hypocal- ize in both pediatrics and endocrinology. The father cemia), a condition that is treatable with both of pediatric endocrinology is regarded by many as calcium and vitamin D supplements. Lawson Wilkins, a physician in Baltimore, In addition, seniors face an increased risk of Maryland, who is said to have established the first developing Type 2 diabetes. They urgently need xvi The Encyclopedia of Endocrine Diseases and Disorders treatment to help avoid the many complications that Psychological Effects of can occur with untreated diabetes mellitus, such as Endocrine Disorders diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy as well as heart attack and stroke. Endocrine disease can have a profound impact on Elderly men are prone to developing erectile dys- the emotional and mental health of those afflicted. function (ED), often a treatable condition. For example, people who are hyperthyroid can sometimes seem almost manic in their behavior, while those who are hypothyroid may appear Genetics and the Endocrine System depressed and lethargic. Psychiatric drugs will not Sometimes genetic diseases or other influences resolve these problems. Only a proper diagnosis impair a person’s normal sexuality. For example, in can lead to effective treatment. Turner syndrome, a medical problem found only in Ironically, sometimes the treatment for existing females, one of the X chromosomes is either miss- psychiatric illnesses can result in endocrine disor- ing or impaired. Thus the female does not develop ders. For example, lithium is a medication that is normally. As a result, women with this disorder often given to treat individuals with bipolar disor- experience a broad variety of medical problems. der (manic depression). Lithium can induce a form With Klinefelter syndrome, a genetic condition of diabetes insipidus (nephrogenic DI) as well as inherited only by males, the male has two or more induce hypercalcemia, hyperparathyroidism, X chromosomes in addition to the Y chromosome. hyperthyroidism, hypothyroidism, and thyroiditis. This condition causes small testes and infertility. As a result, patients who are exhibiting new Many other endocrine diseases and disorders psychiatric symptoms should be screened for an have an underlying genetic element. For example, endocrine disorder. In addition, if patients have the children of parents with diabetes mellitus have both psychiatric problems and endocrine diseases, an increased risk for development of diabetes. psychiatrists and endocrinologists should work Autoimmune disorders, such as thyroid diseases, together to provide the best treatment for the often have a familial link. An example of just a few patient. other endocrine diseases with a strong genetic component include adrenal leukodystrophy, Cancer and the Endocrine System Carney complex, congenital adrenal hyperplasia, Graves’ disease, and McCune-Albright syndrome. Sometimes cancer strikes the endocrine organs. Of course, having a genetic predisposition to The prognosis for patients who develop such can- develop an endocrine disease or disorder does not cers ranges from good, with forms of cancer such as mean that a person is doomed to develop the ill- testicular cancer and thyroid cancer, to very poor, ness. Instead, it means that the risk for developing as with ovarian cancer or pancreatic cancer. The such a disorder is increased when a family member reason for the high death rates among most people (such as a parent or sibling) has that disorder, com- diagnosed with ovarian cancer or pancreatic cancer pared with other individuals whose family mem- is that symptoms usually do not appear until the bers do not have the disorder. disease has spread to other organs and is no longer Most doctors take careful family medical histo- curable. ries from patients because they want to take note Researchers are actively seeking better ways to of potential health problems. That way, they can be diagnose and treat cancers of the ovaries and the vigilant about the problem and administer periodic pancreas. Research breakthroughs with earlier tests, as appropriate. For example, if a person has diagnoses and better treatments are anticipated in parents with diabetes mellitus, the physician is the years ahead. As of this writing, for example, likely to watch for diabetes in this person, particu- scientists are evaluating a test that may indicate a larly if the person begins to exhibit any symptoms marker for early ovarian cancer. If the test works, of the disease. the disease would be far more treatable than at Introduction xvii later stages, when the disease is now usually dis- stimulates the release of thyroid-stimulating hor- covered. mone (TSH). Growth hormone-releasing hormone Yet there is considerable hope for the future, (GHRH) stimulates the release of growth hormone even in cases of ovarian cancer and pancreatic can- (GH). Gonadotropin-releasing hormone (GNRH) cer, as research continues. Of importance is that as stimulates the release of both luteinizing hormone recently as the 1970s, a diagnosis of testicular can- (LH) and follicle-stimulating hormone (FSH). cer was essentially a death sentence for the men Dopamine inhibits the release of prolactin (PRL). who developed the disease. However, research and Desmopressin acetate (DDAVP) is relayed via neu- advances that have occurred since then have made rons to the posterior pituitary gland to help regulate most cases of testicular cancer not only treatable fluid and also salt and water balance in the body. but also frequently curable. In addition, the hypothalamus also includes centers that directly affect the libido, the individual’s appetite (the desire to eat), as well as the feeling of Zeroing in on the Endocrine Glands fullness after eating (satiety). Malfunctions of the Each gland of the endocrine system has at least one hypothalamus can sometimes be minor, but they (and usually more than one) distinctively impor- can also become severe and even life threatening. tant function. In a healthy person, the glands in The hypothalamus and the pituitary glands the endocrine system work together smoothly. together control the overall growth and develop- Sometimes, though, medical problems and condi- ment of a child, but they continue to be important tions occur that can impair the endocrine system as for people of all ages. Even elderly people secrete well as the overall harmony of the body. The indi- small levels of growth hormone. vidual glands themselves may malfunction due to The hypothalamus also helps to maintain both a disease, an autoimmune disorder, or another rea- normal body temperature and blood pressure. son. In addition, external factors may impair the When the hypothalamus or pituitary glands endocrine glands, such as when a person is in a car malfunction, they can cause extremely large or crash or other accident and the pituitary or other extremely small size in children and adults. Andre glands are damaged. the Giant was an example of a person whose pitu- In addition to the known hormones that are itary gland caused him to develop gigantism as a released by the endocrine glands, more than 40 dif- child. If the pituitary gland malfunctions in a simi- ferent hormones are produced within the gastroin- lar way in an adult, as with acromegaly, it will not testinal tract. Many of their functions are still cause increased height because the bones are unknown. Other organs such as the heart (specifi- already fused and completed (longitudinal cally, the left atrium) produce hormones such as growth). However, the cartilage and tissue can still peptides. grow and can also overgrow. This results in a much The following are some examples of the glands distorted personal appearance, causing a person to in the endocrine system as well as potential med- suffer from facial or other physical deformities. ical problems that may occur in these glands. These Acromegaly is treatable with surgery, radiation topics are also discussed in the entries throughout therapy, and medications. this encyclopedia. A malfunctioning pituitary gland may result in a person with a moon-faced appearance who suffers The Hypothalamus and the Pituitary Gland from obesity, hypertension, and diabetes. Harvey The hypothalamus is a complex gland. It controls Williams Cushing discovered this medical problem, the function of the pituitary gland and also directly stemming from excessive ACTH secretion from the affects the release of the seven pituitary hormones. pituitary, in 1932. It was subsequently named Corticotropin-releasing hormone (CRH) factor stim- Cushing’s disease. ulates the release of adrenocorticotropic hormone An excess of cortisol (hypercortisolism) can also (ACTH). Thyrotropin-releasing hormone (TRH) initiate from a cause other than the pituitary gland, xviii The Encyclopedia of Endocrine Diseases and Disorders

Your endocrine system is a collection of glands that produce hormones that regulate your body’s growth, metabolism, and sexual development and function. The hormones are released into the bloodstream and transported to tissues and organs throughout your body. The table below describes the function of these glands.

Adrenal glands Divided into 2 regions; secrete hormones that influence the body’s metabolism, blood chemicals, and body characteristics, as well as influence the part of the nervous system that is involved in the response and defense against stress Hypothalamus Activates and controls the part of the nervous system that controls involuntary body functions, the hormonal system, and many body functions, such as regulating sleep and stimulating appetite Ovaries and testicles Secrete hormones that influence female and male characteristics, respectively Pancreas Secretes a hormone (insulin) that controls the use of glucose by the body Parathyroid glands Secrete a hormone that maintains the calcium level in the blood Pineal body Involved with daily biological cycles Pituitary gland Produces a number of different hormones that influence various other endocrine glands Thymus gland Plays a role in the body’s immune system Thyroid gland Produces hormones that stimulate body heat production, bone growth, and the body’s metabolism (CREDIT: American Medical Association) Introduction xix and in such a case, the disease is known as but surgery or radioactive iodine may also be Cushing’s syndrome rather than Cushing’s disease. required to manage this illness. Both Cushing’s syndrome and Cushing’s disease Thyroid surgery has been used on patients since include the same array of medical problems: obesi- the late 19th century when surgeon Theodor ty, diabetes, hypertension, and other illnesses. Kocher developed procedures to remove the thyroid gland to treat patients who had tumors and The Thyroid Gland goiters. Kocher received the Nobel Prize in 1909 for The thyroid gland is a very important butterfly- his successful work with the thyroid gland. shaped organ situated in the neck. It controls the However, doctors also found that removing too basic metabolism of the body and affects an indi- much thyroid tissue left patients very ill. Kocher vidual’s energy levels, sleep cycles, hair growth, himself noted that the total thyroidectomy caused skin texture, and even fertility. Hypothyroidism, or patients to suffer serious consequences. an underactive thyroid gland, is a type of thyroid In 1891, British physician George Murray isolat- malfunction that results in patients becoming ed thyroid extracts from sheep. He provided them lethargic and apathetic. The individual may also to a severely hypothyroid patient who subsequent- suffer from widespread aches and body pains. ly improved and took the thyroid supplements for Sometimes the patient may be misdiagnosed with 28 more years. In 1927, researchers first synthe- another medical problem altogether, such as arthri- sized thyroid hormones and found that the syn- tis or fibromyalgia. thetic form of thyroid was as effective as the Simple blood tests, along with clinical observa- thyroid hormone extracted from animals. tions of a patient and a thorough evaluation of the Today, most people in the United States who patient’s signs and symptoms, can usually deter- need thyroid hormones take levothyroxine, a syn- mine whether the patient’s thyroid levels are with- thetic form of thyroid hormone. In fact, Synthroid, in the normal range. In the mid-20th century, a form of levothyroxine, is one of the top 10 best- doctors determined that a patient had abnormal selling medications of all types in the United States. thyroid levels by measuring the patient’s basal Some people suffer from autoimmune thyroid metabolic rate (BMR) upon awakening using spe- diseases in which the body mistakenly perceives cial hospital equipment that measured oxygen con- the thyroid gland as if it were a bacterial invasion. sumption. The BMR test, however, was proven to In such cases, the immune system actively seeks to be an extremely inefficient and imprecise way to destroy the thyroid gland. ascertain the presence of thyroid disease. Another In one syndrome, the antibodies actually stimu- test, the radioactive iodine uptake scan, used late the gland to enlarge and to become overactive. equipment to determine the biological activity of The symptomatology of hyperactivity, an enlarged the gland as well as its size and contour. thyroid gland and bulbous eyes, was first identified In the mid-20th century, researchers also devel- by Irish physician Robert James Graves in 1835 and oped a blood test to measure thyroid hormone in was subsequently named after him. Graves’ disease the blood, using protein-bound iodine (PBI) meas- is an autoimmune hyperthyroid disorder that has urements to diagnose thyroid disease. In the latter been experienced by many people, including for- part of the 20th century, the more sophisticated mer President George H. W. Bush and his wife thyroid-stimulating hormone (TSH) blood test was Barbara Bush, as well as by the late John F. developed. As of this writing, the TSH test is still Kennedy Jr. The comedian Marty Feldman, recog- considered the gold standard for diagnosing most nizable by his very bulging eyes, also had Graves’ thyroid diseases. disease. For most patients, Graves’ disease is treat- The thyroid gland can go into overdrive, becom- able with medications and surgery. ing hyperthyroid or overactive. The gland may Hashimoto’s thyroiditis, an autoimmune disorder enlarge and develop a goiter, which is sometimes that was first described by Japanese physician Dr. H. visible even to a layperson. Medications can often Hashimoto in 1912, is the most common cause of dampen the overactive effect of hyperthyroidism, hypothyroidism in the United States. It may initially xx The Encyclopedia of Endocrine Diseases and Disorders cause individuals to become transiently hyperthy- person’s body is unable to use the insulin because roid. Then, as the gland is further destroyed by the of insulin resistance. Such patients have Type 2 disease, patients develop hypothyroidism. diabetes, which is a major endocrine disease affect- In rare cases, infants are born with congenital ing millions of people in the United States and hypothyroidism, which would, if left untreated, other countries. cause severe developmental delays and retardation. People who are alcoholics often experience Fortunately, all newborn infants in the United damage to their pancreas caused by excessive States are screened for thyroid disease. If it is drinking and poor nutrition. This may lead to pan- detected, they are immediately treated with iodine, creatitis, a severely painful and dangerous inflam- thyroid drugs, or other medications and are care- mation of the pancreas. fully followed by their pediatricians. Pancreatic cancer is another malfunction of the The thyroid may also develop cancer. Fortunately, pancreas. As of this writing, few people survive this in many cases it is a slow-growing cancer that is iden- deadly form of cancer, because it is rarely tifiable and treatable. Sometimes the thyroid gland detectable in its early stages. As a result, once the develops nodules, which may be solid, cystic, or a characteristic jaundice (yellowing of the skin) of combination of solid and cystic. Thyroid nodules are pancreatic cancer is clearly visible, death typically often biopsied for cancer, although they are often follows. (The presence of jaundice alone does not benign. always indicate that a person has pancreatic cancer. Hepatitis and other diseases may also cause jaun- The Pancreas dice. However, whenever a person of any age is The pancreas is a critical organ that maintains and jaundiced, physicians should actively seek to iden- fuels the body in the process of digestion and the tify the cause so that treatment may begin.) assimilation of nutrients. Its functions are essential The pancreas is an unusual organ in that it is to life. If the pancreas fails, the insulin and the both an endocrine gland and an exocrine gland. An digestive enzymes that it normally produces must endocrine gland is ductless, while an exocrine be replaced for the person to survive. This is gland contains ducts. Depending on which func- achieved through medication or, in the most tion is being considered, the pancreas is an extreme case, through a pancreatic transplant from endocrine gland or an exocrine gland. For exam- a recently deceased person. In many cases, it is ple, the islets cells of the pancreas produce insulin, achieved through the administration of insulin. which is an endocrine function. However, the pan- Insulin was discovered in 1921 by Canadian creas also produces digestive enzymes, which is an doctor Frederick Banting and then–medical student exocrine function. Even people with diabetes who Charles Best, who first tested insulin on diabetic depend on insulin have pancreases that produce dogs. When the dogs’ health improved, Banting digestive enzymes. and Best went on to test insulin on diabetic children and adults, with success. The Parathyroid Glands Before this discovery of insulin, every person Although most people have never heard of the with Type 1 diabetes died from the disease. They parathyroid glands, they are very important glands. often succumbed in their childhood, teens, or early The parathyroids are tiny glands that are embedded adulthood. Insulin has been synthesized and con- in and around the thyroid gland. They are directly siderably improved upon since then. However, this responsible for regulating the flow of calcium from remarkable early discovery has enabled millions of the blood and into the bones and then back again people worldwide to lead normal lives. People with as needed throughout the day and night. The Type 1 diabetes today stay alive only because they parathyroid glands directly affect the healthy func- inject insulin. tioning of an individual’s bones, kidneys, and gut. In some cases, the pancreas produces a subnor- Calcium is necessary for life. Without it, a per- mal amount of insulin or even an amount that son will eventually go into seizures (tetany) and, if would usually be sufficient for survival, but the the condition continues uncorrected, will die. Introduction xxi

Fortunately, severe hypocalcemia is rare. When it middle-aged females. Tumors called pheochromo- does occur (such as with the accidental removal of cytomas can also occur in the adrenal medulla. or injury to the parathyroids during thyroid surgery), it is nearly always easily treatable with intra- The Pineal Gland venous calcium followed by maintenance doses of The pineal gland is a somewhat mysterious gland oral calcium and vitamin D after the patient recov- with functions that are yet to be fully explored. ers from the surgery. Scientists do know that the pineal gland produces Having too much calcium is also possible, a con- natural melatonin, which is the hormone that dition called hypercalcemia. This can lead to kidney helps people to fall asleep. It is also involved in the stones, malaise, decreased cognitive function, daily sleep/wake cycles. Some experts suspect that osteoporosis, and a host of other serious medical melatonin may be more important than has been problems. Hypercalcemia often stems from either previously realized, and they have begun studying hyperparathyroidism or cancer. the relationship of melatonin to other hormones The parathyroid glands can also become cancer- such as testosterone. ous. Some early studies indicate that low levels of melatonin are linked to low levels of testosterone. The Adrenal Glands By increasing testosterone levels (by administering The adrenal glands are two glands located adjacent testosterone to males with low blood levels of this to the kidneys and close to the pancreas. They are hormone), researchers have found that melatonin organs essential to healthy growth and development levels will also increase. In addition, if administer- and also sustain normal life. The adrenal glands pro- ing supplements of melatonin to raise a man’s duce adrenaline, cortisol, and aldosterone as well as melatonin levels, his testosterone levels will appar- androgens, and deficiencies of these hormones can ently increase as well. Further studies may bring lead to serious diseases. Hypofunctioning adrenal important new information about melatonin and glands can lead to Addison’s disease, while hyper- the pineal gland. functioning leads to Cushing’s syndrome and adrenal hyperplasia. The adrenal glands also affect the The Ovaries overall metabolism of the body. The ovaries are the source of female sexual charac- Addison’s disease, a malfunction of the adre- teristics as well as of female fertility. The ovaries nal glands causing inadequate levels of circulat- produce hormones, such as estrogen, that lead to ing cortisol, is a dangerous and sometimes female sexual characteristics, such as soft skin and life-threatening condition that requires lifelong hair, healthy breasts, and a functioning reproduc- monitoring by physicians and the patients them- tive system. Estrogen was isolated as a hormone by selves. Thomas Addison first described this disor- researchers in the early 20th century, as was testos- der of the adrenal glands, which caused skin terone. The ovaries also release an egg each month darkening and was life threatening, to the South that can unite with a sperm to create an ovum and, London Medical Society in 1855. The disease was ultimately, a pregnancy. subsequently named after him, although Dr. Because many women throughout time have Addison reportedly received no acknowledgment wished to avoid or delay pregnancy, many for his important discovery within his lifetime. women and their partners were extremely Cushing’s syndrome and Addison’s disease are pleased when the first oral contraceptive was both diseases that, once identified, are treatable. developed and sold in the United States in 1960. Patients and their physicians must continue to be This drug was based on studies by such alert to changes in cortisol levels and treat them researchers as Gregory Pincus, who showed that accordingly. progesterone prevented ovulation. The adrenal glands can also develop a cancerous When ovaries malfunction, they can become tumor. Adrenocortical carcinoma is a rare and high- extremely disruptive, causing pain, excessive men- ly malignant tumor, more commonly found among strual bleeding (or the lack of menstrual periods, xxii The Encyclopedia of Endocrine Diseases and Disorders which is known as amenorrhea), infertility, occur, and it is diagnosed most frequently among extreme hair growth, and other medical problems. men in their 20s–40s. Fortunately, testicular cancer Polycystic ovary syndrome (PCOS) is a medical is usually detectable and treatable, and the survival condition that causes great distress to some rate is high. In addition, if the man loses one of his women. It may cause moderate to extreme hairi- two testes, he will usually retain normal sexual ness (hirsutism), anovulation (failure to ovulate), function and will remain fertile. infertility, and other serious medical problems. If PCOS is left untreated, women may develop Type 2 The Thymus diabetes and cardiovascular diseases. The thymus is a very small endocrine organ locat- Another disease of the ovaries is ovarian cancer, ed in the chest. As far as is known, it does little a disease that is extremely dangerous and one that except contribute to some immune functions. is not usually detected until it is inoperable, as with Future research may reveal a more important role pancreatic cancer. Researchers have recently devel- for the thymus than is currently known. oped a blood test for early ovarian cancer, and experts are evaluating this test as of this writing. It may have the potential to save the lives of thou- Newer Hormones and sands of women each year by allowing ovarian Endocrine Discoveries cancer to be treated in the early stages. As research continues, scientists are discovering Sometimes women develop ovarian cysts, which many more key hormones that are directly linked are fluid-filled and usually benign growths on the to the endocrine system. For example, in the late ovaries. These cysts can become large and extreme- 20th century, scientists in Japan discovered that ly painful. They may require surgery. However, the stomach produces a hormone called ghrelin, some women have cysts that cause no pain or any which is intimately associated with both appetite other symptoms for years or even ever. These ovar- and satiety. Because obesity is a major problem in ian cysts are detected only during a routine ultra- North America, Europe, and other parts of the sound or other imaging test that is performed for globe, researchers are attempting to determine if another purpose. obesity can possibly be resolved by manipulating the appetite, perhaps by creating an antighrelin The Testes kind of medication. In fact, researchers are cur- Just as the ovaries are responsible for female sexu- rently seeking to develop such a medication. ality and fertility, the testes are vitally important to male sexuality. The testes control both the male sex drive and the ability to reproduce. Testosterone, a Major Breakthroughs in hormone released by the testes, creates and drives Treatments of Endocrine male sexual characteristics, such as muscle mass, body hair, and sexuality. If a male loses his testes Diseases and Disorders before puberty, he will not develop a deepened Probably the greatest recent breakthroughs in voice or body hair. If one or even both testes are lost treating endocrine diseases have come with star- after puberty, however (for example, because of tes- tling advances in treating diabetes mellitus. For ticular cancer), the man’s deep male voice will not example, physicians have successfully implanted change nor will his basic adult male characteristics. insulin-producing cells from the pancreases of The most common malfunction of the testes is deceased individuals into patients with Type 1 dia- an underproduction of testosterone (hypogo- betes, and these individuals no longer need to take nadism), which is a problem that men of all ages any insulin. may experience, although it is far more commonly In another recent success, in 2003, scientists at seen among older men. Testicular cancer is anoth- Massachusetts General Hospital found that inject- er medical problem of the testes that may also ing spleen cells into the pancreas of diabetic rats Introduction xxiii somehow caused the pancreatic cells of the rats to Conclusion regenerate. This treatment actually cured the labo- Most people never realize the importance of their ratory animals of their diabetes. Researchers were endocrine glands to their continued survival or not expecting this result at all. As of this writing, even that they have such glands working actively they are not clear on how or why it happened; for to keep them alive and healthy. Yet these under- years, the spleen has been regarded by experts as appreciated glands and the entire endocrine system an expendable organ. itself can greatly enhance life as well as cause This research finding is potentially a huge break- extremely serious and even life-threatening med- through for people with diabetes mellitus. Human ical problems. clinical trials will be performed to test whether the This encyclopedia provides basic information same results can be found in people. If so, this may about how the glands and hormones within the lead to what so many patients and doctors have endocrine system function when the system works dreamed of for so long: a cure for diabetes. normally. It also helps explain what happens when Breakthroughs have also been made with the serious medical problems occur and offers informa- testing equipment used by patients with diabetes to tion on how physicians work to help their patients determine their own blood sugar levels. Because resolve these problems. many patients with diabetes are resistant to testing their blood because of the pain and the inconven- ience, researchers have developed devices that can Fisher, D. A. “A Short History of Pediatric Endocrinology nearly painlessly extract a tiny amount of subcuta- in North America.” Pediatric Research 55 (2004): neous fluid from the forearm, and a display read- 716–726. out will show the patient the results of the test Gardner, Lytt I., M.D., ed. Endocrine and Genetic Diseases of within minutes. Childhood and Adolescence, 2d ed. Philadelphia, Pa.: W. Some patients have enormous difficulty main- B. Saunders Company, 1975. taining normal insulin levels. Researchers have Gordon, Richard. The Alarming History of Medicine. New recently developed implantable insulin pumps that York: St Martin’s Griffin, 1993. dole out regular amounts of insulin and can be Kodama, Shohta, et al. “Islet Regeneration During the ordered to provide extra doses on an as-needed Reversal of Autoimmune Diabetes in NOD Mice,” basis. These are only two examples of devices that Science 302 (November 14, 2003): 1,223–1,227. have been created to encourage patients with dia- McDermott, Michael T., M.D. Endocrine Secrets. betes to test their blood and to act upon the findings. Philadelphia, Pa.: Hanley & Belfus, Inc., 2002. Neal, J. Matthew, M.D. How the Endocrine System Works. Williston, Vt.: Blackwell Publishing, 2002. Future Advances Niewoehner, Catherine B., M.D. Endocrine Pathophysiology. Many medical advances in the diagnosis and treat- Madison, Conn.: Fence Creek Publishing, 1998. ment of endocrine diseases are anticipated over the Petit, William, Jr., M.D., and Christine Adamec. The next decade and even earlier. Scientists hope to dis- Encyclopedia of Diabetes. New York: Facts On File, Inc., cover how to use hormones in newer and more 2002. innovative ways. For example, peptide hormones Porter, Roy, ed. The Cambridge Illustrated History of will likely be created as a therapy for many Medicine. Cambridge, England: Cambridge University patients. In addition, experts anticipate that hor- Press, 1996. monal therapies will be used not only to kill abnor- Porterfield, Susan P. Endocrine Physiology, 2d ed. St. Louis, mal cells but also to grow beneficial and healthy Mo.: Mosby, Inc., 2001. cells. Monoclonal antibodies will be developed for Stanbury, John B., M.D. A Constant Ferment: A History of early detection of cancers and detection of cancer the Thyroid Clinic and Laboratory at the Massachusetts spread, as well as to create better therapies for General Hospital: 1913–1990. Ipswich, Mass.: The treating cancer. Ipswich Press, 1991. xxiv The Encyclopedia of Endocrine Diseases and Disorders

Tanner, J. M., M.D. Growth at Adolescence with a General Birth to Maturity, 2d ed. Springfield, Ill.: Charles C. Consideration of the Effects of Hereditary and Thomas, 1962. Environmental Factors Upon Growth and Maturation from ENTRIES A–Z

A acanthosis nigricans A hereditary skin condition the elbows, knees, groin, underarms, knuckles, and that is commonly found among patients with severe even around the thighs and the anus. The patient INSULIN RESISTANCE (a condition in which the body is may also have many papillomas (benign skin not able to use the insulin produced efficiently and, tumors or skin tags) as well as a generalized thick- thus, attempts to overcome this problem by synthe- ening of the skin (hyperkeratosis). The skin areas sizing more insulin). In rare cases, acanthosis nigri- affected by acanthosis nigricans are often hairless. cans is a marker for an aggressive form of internal cancer (malignant acanthosis nigricans). In particu- Diagnosis and Associated Medical Conditions lar, it indicates cancers of the liver or gastrointesti- Acanthosis nigricans may be diagnosed in infancy nal tract (hepatocellular cancer and gastric cancer). or early childhood but generally does not appear With the exception of malignant acanthosis until adolescence or adulthood. Unless it is related nigricans, the condition is more common among to a malignancy, acanthosis nigricans is typically people of African descent, followed by those of associated with insulin resistance syndrome. Hispanic descent, although individuals of any race The presence of acanthosis nigricans may be a may develop acanthosis nigricans. Some medica- risk factor for the development of TYPE 2 DIABETES. tions, such as corticosteroids, ORAL CONTRACEPTIVES, In one study of 89 African Americans with acan- niacin, or GROWTH HORMONES, may sometimes thosis nigricans, 21 percent of the patients were induce the development of acanthosis nigricans. found to have Type 2 diabetes. Acanthosis nigricans Physicians have been aware of acanthosis nigricans is also found in some patients who have been diag- since the 19th century. nosed with ACROMEGALY and CUSHING’S SYNDROME. The incidence of acanthosis nigricans in the pop- In addition, it may also be associated with OBESITY ulation is unknown. Both men and women may and/or POLYCYSTIC OVARY SYNDROME (PCOS) as well develop this condition. It is also found among chil- as with HYPOTHYROIDISM. dren and adolescents. As of this writing, there is no cure for acanthosis nigricans: however, identifying the underlying Signs and Symptoms cause of this condition is important so that it can be Acanthosis nigricans is characterized both by its treated. appearance on the skin and its texture. The skin is The agents used to lighten skin coloration have often described as having a soft and velvety tex- limited success in the treatment of acanthosis nigri- ture. The skin has gray or black patches that give it cans. an overall burned appearance and that cause it to See also DWARFISM; SKIN. appear dirty in these areas. The dark areas are caused by an excessive amount of melanin, a hor- Levine, Norman, M.D. “Acanthosis Nigricans,” Available mone that increases natural skin color. If the skin online. URL: http://www.emedicine.com/DERM/ becomes thick enough, it may become malodorous topic1.htm Downloaded on June 14, 2002. and macerated. Stuart, C. A., et al. “Hyperinsulinemia and Acanthosis Nigricans in African Americans.” Journal of the When present, acanthosis nigricans is usually National Medical Association 89, no. 8 (August 1997): found on the neck. However, it may also appear on 523–527.

1 2 achondroplasia

Wynbrandt, James, and Mark D. Ludman. The excessive amounts of growth hormone. These Encyclopedia of Genetic Disorders and Birth Defects, 2d ed. growth hormone-secreting pituitary tumors or New York: Facts On File, Inc., 2000. adenomas account for about one-third of all pituitary tumors. Rarely, the tumor leading to acromegaly may be cancerous. achondroplasia See DWARFISM; GROWTH HOR- Acromegaly is also called GIGANTISM if it presents MONE. before puberty because the excessive levels of growth hormone cause individuals to attain unusual heights. If the disorder presents after puberty, the ACTH (adrenocorticotropic hormone) A protein individual does not grow taller but will likely pres- hormone that is synthesized and secreted from the ent with characteristic abnormalities that may sig- anterior pituitary gland in a pulsatile manner fol- nificantly alter his or her appearance. It will flatten lowing a specific circadian rhythm (biological both the nose and face and will cause the enlarge- cycle). In most people, their ACTH production is at ment of any bones that have not yet completed its highest level in the morning when they wake up their growth, such as the jaw, hands, and feet. and at its lowest level in the late afternoon. ACTH An overgrowth of tissue in the nasopharyngeal stimulates the adrenal glands to cause growth and area (nose/tongue/throat) may cause hoarseness and the production of steroid hormones, especially may even cause sleep apnea, a potentially dangerous CORTISOL. ACTH is initially secreted as a prohor- condition in which the person stops breathing for fre- mone called PMOC (pro-opiomelanocortin), which quent, short periods during sleep. Snoring is also contains lipotropins, endorphin, and melanocyte- quite common among patients with acromegaly. stimulating hormone (MSH) that can lead to hyperpigmentation. Causes of Acromegaly This excessive skin pigmentation can be seen in Acromegaly occurs in only about three to four peo- diseases such as ADDISON’S DISEASE or primary ple per million. About 20–30 percent of patients adrenal insufficiency. In these cases, inadequate with acromegaly also have DIABETES MELLITUS.In cortisol is produced, thus decreasing the inhibition other rare cases, tumors of the pancreas, lungs, or of the hypothalamus on cortisol release (CR) and adrenal glands (commonly carcinoid tumors) may the anterior pituitary for ACTH. In Cushing’s dis- cause acromegaly by secreting growth hormone. ease, in which ACTH is overproduced, hyperpig- Acromegaly may also be caused by the secretion of mentation can also be seen. With some cancers, another hormone: growth hormone-releasing hor- such as small cell carcinoma of the lung, ectopic mone (GHRH). This hormone stimulates the secre- ACTH may be produced in very large amounts, tion of growth hormone from the pituitary. The leading to hyperpigmentation and a Cushing’s-like hypothalamus, an area of the brain just above the syndrome. pituitary that secretes many hormones that help Stress, such as that from a trauma, serious infec- regulate the pituitary’s function, may also secrete tion, or surgery, can cause higher than normal lev- excessive GHRH, and this secretion may cause els of ACTH to be secreted. HYPOGLYCEMIA (low acromegaly. blood sugar) leads to appropriate physiological increase in ACTH levels. Some emotional states, Signs and Symptoms of Acromegaly such as anxiety or depression, can raise the levels There are many different indicators of the presence of ACTH. In contrast, cortisol is a hormone that of acromegaly. Some signs and symptoms of this inhibits the release of ACTH. disorder are as follows: See also ADRENAL GLANDS;CUSHING’S SYNDROME/ CUSHING’S DISEASE; HORMONES; PITUITARY GLAND. • Oily skin • Headaches (in 60 percent of patients) acromegaly A rare endocrine disorder generally • Achy joints (arthralgias) caused by a benign pituitary tumor that secretes • Back pain (which may be secondary due to acromegaly 3

fractures from OSTEOPOROSIS stemming from photographs from 10–20 years before in order to decreased estrogen or testosterone levels) check these photographs for the typical facial • Extreme sweating (hyperhydrosis) changes of the disease. The physician who suspects acromegaly/gigantism may also order a fasting • Generalized weakness/malaise blood test (impaired glucose fasting level) of • Skin tags (achrochordons) growth hormone and/or insulin-like growth factor • Hypertension (high blood pressure) 1 (IGF-1). These levels are both increased in people • Thickened skin with acromegaly/gigantism. Patients suspected of having acromegaly may • Excess enlargement of the mouth, nose, and also be tested simultaneously for diabetes with an tongue (acral growth, leading to deformities of ORAL GLUCOSE TOLERANCE TEST. This test can serve a the face and teeth) dual purpose. For patients with normal GROWTH • Deepening voice HORMONE secretion, the ingestion of glucose will • Irregular menstrual cycles with lowered estrogen lead to decreased levels of growth hormone. In levels leading to vaginal dryness and hot flashes contrast, the abnormal secretion of growth hor- •ERECTILE DYSFUNCTION/lowered libido/decreased mone found in acromegaly is not suppressible and beard growth/testicular atrophy (due to will not decrease after giving glucose. As a result, if decreased levels of testosterone) the growth hormone levels have not dropped, then acromegaly is likely. In addition, the patient’s blood • Increased prolactin levels, causing galactorrhea glucose levels can be measured to determine if the (breast milk production in non-nursing females) patient has normal glucose tolerance, impaired glu- and hirsutism (excessive hair growth in women) cose tolerance, or overt diabetes mellitus. • Carpal tunnel syndrome (compressed median Imaging tests such as COMPUTERIZED TOMOGRA- nerve, accompanied by numbness, tingling, and PHY (CT) scans or MAGNETIC RESONANCE IMAGING weakness in the wrist, thumb, index, or middle (MRI) scans of the pituitary gland are also ordered. finger) These help to identify tumors that may be causing the acromegaly.

Diagnosis of Acromegaly Medical Problems Caused By or The diagnosis of acromegaly is usually delayed a Associated With Acromegaly long time in adults—by as long as 15 to 20 years. Patients with acromegaly have an increased risk of This occurs because the onset of this medical prob- developing thyroid disorders, such as GOITERS and lem is slow and insidious. Additionally, the signs HASHIMOTO’S THYROIDITIS. In one study that was and symptoms of acromegaly are not immediately reported in a 2002 issue of the Journal of obvious. Endocrinology Investigation, 78 percent of the patients In fact, the changes in the person’s facial fea- with acromegaly also had thyroid abnormalities. tures usually occur so slowly that many patients In addition to causing thyroid disease in the and their own family members do not notice them. majority of patients and causing diabetes in about a Awareness of these changes often occurs only due third of them, acromegaly may be the cause of to the observation from someone who is outside other medical problems. These include hyperten- the family or who has not seen the person for sion (about 25 percent of acromegaly patients are years. As a result, a person may not be diagnosed hypertensive), cardiomyopathy (abnormal heart with acromegaly until 35–50 years old, even pumping action), arthritis, HYPOTHYROIDISM, HYPO- though the problem may have begun many years GONADISM (the decreased ability to make sex steroid before then. In contrast, however, gigantism is very hormones due to damage to the pituitary cells that noticeable and it is diagnosed in the individual dur- control TESTOSTERONE and ESTRADIOL synthesis), and ing or prior to adolescence. kidney stones. Physicians who suspect a patient may have Patients with acromegaly may also experience acromegaly will often ask the patient to bring in visual problems, especially visual field abnormali- 4 acromegaly ties. These occur because the tumor can grow into erally occur within days after surgery. Some the optic chiasm (the major cranial nerve to the patients are treated with radiation therapy, either eyes that lies just above the pituitary gland). as the primary treatment or as a supplemental In addition, individuals with acromegaly are at a treatment after having surgery. greater risk for developing polyps in the colon as Medications are also a common form of treat- well as for developing colorectal cancer. As a result, ment for patients with acromegaly. BROMOCRIPTINE experts recommend that for patients with (Parlodel), pergolide (Permax), and CABERGOLINE acromegaly, a colonoscopy should be performed (Dostinex) are medications that have been success- every two to four years, depending on the recom- ful in improving the quality of life of many patients mendation of the treating physician. with acromegaly. These drugs have some side Individuals with acromegaly also face an effects, such as gastrointestinal upset, nausea and increased risk for developing other forms of cancer. vomiting, and nasal congestion. These side effects Dr. D. Baris and colleagues studied the outcomes can be reduced in patients by starting with a very for patients with acromegaly in Sweden (1965–93) low dose and increasing the dose very slowly. The and Denmark (1977–93) and reported their find- physician may also advise lowering the dose and ings in a 2002 issue of Cancer Causes and Control. having the patient take the medication with a They found that patients with acromegaly had a meal. These drugs are less effective than octreotide significantly increased risk of developing various (Sandostatin), and they will normalize growth hor- forms of cancer, particularly cancer of the small mone levels in only about 15 percent of patients. intestine, colon, and rectum. The patients also Sandostatin or lanreotide (a synthetic form of the faced increased risks for developing cancers of the pancreatic hormone SOMATOSTATIN, which decreases brain, thyroid, kidney, and bone. the production of growth hormone) are both The death rate for patients with acromegaly is injectable drugs and are effective in many cases of two to four times the normal rate. Death typically acromegaly. This medication is usually given after results from cancer or heart disease unless the surgery and before dopamine agonists are used. growth hormone and IGF-1 levels can be brought Injections must be performed frequently, up to every back into the normal range. eight hours. However, there is a depot (long-lasting) form of the drug (Sandostatin Lar) that can be given Treatment of Acromegaly as infrequently as one to four times per month. All patients with acromegaly should be treated due These drugs may cause nausea, discomfort at the to the multiple complications and high mortality injection site, and gas and loose stools in some caused by this medical problem. Acromegaly is patients. About 25 percent of the patients who often treated with pituitary surgery (usually receive Sandostatin or lanreotide will also develop through the sphenoid sinuses, with a technique asymptomatic gallstones. More significantly, called transsphenoidal surgery). This procedure is patients with diabetes mellitus may be able to successful in about 80–90 percent of the cases. reduce their insulin dosage because the acromegaly Neurosurgery is performed if the physician iden- drug can improve glucose control. (Conversely, tifies a microadenoma (a pituitary tumor less than Sandostatin or lanreotide can also worsen diabetes 10 millimeters in size) or a macroadenoma (a symptoms in some patients.) tumor greater than 10 millimeters in size) that is Other drugs that block the action of growth hor- pushing into the optic nerve or into the cavernous mone may also be given to patients with sinuses (the very large veins found on both sides of acromegaly. One such drug is pegvisomant, an oral the pituitary that contain several cranial nerves, growth hormone antagonist medication that blocks the carotid artery, and the jugular vein). The neu- the binding of growth hormone to its receptor. This rosurgeon will perform surgery only if he or she drug has been effective in reducing soft tissue thinks the patient can be cured or significantly swelling and other symptoms in some patients, helped. Remission of many of the patient’s symp- although its long-term safety is not known as of toms, particularly the facial abnormalities, will gen- this writing. Addison’s disease 5

In one study of 112 patients with acromegaly, See also AMENORRHEA; BLOOD PRESSURE/HYPER- reported in a 2000 issue of the New England Journal TENSION; BONE DISEASES, CARNEY COMPLEX; of Medicine, the patients were treated with differing DWARFISM; HYPERPHOSPHATEMIA/HYPOPHOSPHATEMIA; daily doses of pegvisomant (Somavert) over 12 PITUITARY ADENOMAS; PITUITARY GLAND; PREDIABETES. weeks. (A placebo group received a pill with no For further information about acromegaly, con- medication.) A majority of the patients, 93, had tact the following organization: previously received pituitary surgery. Of these, 57 Pituitary Network Association had also been treated with radiation therapy. 223 East Thousand Oaks Boulevard (Four patients withdrew from the study for vary- Number 320 ing reasons.) Thousand Oaks, CA 91360 The researchers found that pegvisomant worked (805) 496-4932 well in most patients, successfully reducing IGF-1 concentrations within about two weeks of starting Baris, D., et al. “Acromegaly and Cancer Risk: A Cohort taking the drug. However, because the study was Study in Sweden and Denmark.” Cancer Causes and conducted for only 12 weeks, the researchers stat- Control 13, no. 5 (2002): 395–400. ed that further study and longer periods of treat- Gasperi, M., et al. “Nodular Goiter Is Common in Patients ment would be needed to determine the continued with Acromegaly.” Journal of Endocrinological safety and effectiveness of the drug. Investigation 25, no. 3 (2002): 240–245. Because pegvisomant blocks the binding of Larsen, P. Reed, et al. Williams Textbook of Endocrinology. growth hormone to the receptor, some patients New York: W. B. Saunders Company, 2001. begin to synthesize more growth hormone. Some LeRoux, Carel, Abeda Mulla, and Karim Meeran. reports have discussed the growth of the tumor and “Pituitary Carcinoma as a Cause of Acromegaly.” New of visual field changes that necessitated a change in England Journal of Medicine 345, no. 22 (November 29, the patient’s medication therapy. 2001): 1,645–1,646. Radiation therapy is often used to treat Trainer, Peter J., M.D., et al. “Treatment of Acromegaly acromegaly. In most cases, 4,000–5,000 rads with the Growth Hormone-Receptor Antagonist (40–50 Gy) are given over five weeks. The growth Pegvisomant.” New England Journal of Medicine 342, of the tumors is often slowed or stopped by radia- no. 16 (April 20, 2000): 1,171–1,177. tion therapy. However, the effects on the secretion of growth hormone are very slow and will decrease only about 10–20 percent per year, thus making Addison’s disease A rare endocrine disease in the patient’s symptomatic response very slow. which the adrenal glands do not produce enough A variety of helpful imaging techniques (CT and CORTISOL (hypocortisolism or primary adrenal MRI) have been used to try to focus the radiation insufficiency). Cortisol is a key hormone that helps directly on the tumor and thus to limit the damage the body respond to stress in many different ways. to the surrounding normal brain tissue. Proton It regulates blood pressure, maintains adequate bean therapy has also been helpful for some blood glucose levels for energy, regulates elec- patients; however, it is not widely available as of trolytes, such as potassium and sodium, and per- this writing. Stereotactic gammaknife therapy is forms many other key functions within the body. now also being used on some tumors. Addison’s disease is also known as chronic primary All forms of radiation therapy can lead to the adrenal insufficiency. Sometimes patients with loss of other pituitary functions over the course of Addison’s disease are also deficient in the hormone many years and can also increase the patient’s risk ALDOSTERONE, which is also produced by the adre- of developing an intracranial malignancy. In addi- nal glands. tion, radiation may cause changes in both visual The disease may be first diagnosed when it is life and cognitive functions, depending on the type and threatening because most patients have few or no amount of radiation used as well as the size of the symptoms in the early stages. Addison’s disease radiated field. occurs in about one in 100,000 people, and it 6 Addison’s disease affects both males and females equally. President Patients with anorexia nervosa may be hyper- John F. Kennedy suffered from Addison’s disease. glycemic. In contrast, patients with Addison’s dis- The average patient with Addison’s disease is ease are more likely to be hypoglycemic. Last, diagnosed at about 40 years of age. Periods of patients with anorexia nervosa are often low in stress, caused by illness, work, or family problems, potassium blood levels, while patients with worsen the already-existing condition. Addison’s disease are hyperkalemic (with excessively high levels of potassium in the blood). Causes of Addison’s Disease Other signs and symptoms of Addison’s disease may include the following: The cause of Addison’s disease is the destruction of the adrenal cortex. In most cases (about 80 percent), • Chronic fatigue the disease appears to stem from an autoimmune reaction of the body to an unknown stimulus. In • Dizziness/light-headedness some cases, the condition may be a hereditary one, • Cold intolerance particularly when diagnosed in males. • Nausea and vomiting In rare cases, patients with acquired immune • Malaise deficiency syndrome (AIDS) develop Addison’s disease as a result of the destruction of their adrenal • Depression glands caused by infections that the patient’s body • Hypotension (low blood pressure) could not fight off. Tuberculosis can also lead to the • Loss of underarm (axillary) and pubic hair in development of Addison’s disease, although this adult women problem is not usually seen in patients in devel- • Elevated levels of blood urea nitrogen (BUN) oped countries such as the United States, Canada, and western Europe. Rarely, Addison’s disease can • Anemia be caused by a systemic fungal infection. Adrenal • Poor concentration hemorrhage and destruction by tumors are addi- • Mood swings tional causes of Addison’s disease. • Hypoglycemia (low blood sugar) • Thyroid disease Signs and Symptoms • Craving for salt In addition to hypocortisolism, Addison’s disease is also characterized by an extreme weight loss and a coppery skin tone. All patients with Addison’s disease experience a significant weight loss before If a Medical Crisis Occurs diagnosis, and about 90 percent evince a darker Individuals diagnosed with Addison’s disease skin coloration than is normal for the patient. The should always wear a medical identification skin color change is a key diagnostic indicator if the bracelet. In the event of an emergency, they will disease is advanced. urgently need to receive glucocorticoid injections, Sometimes the symptoms of Addison’s disease typically given as hydrocortisone, CORTISONE, pred- are confused with those of ANOREXIA NERVOSA,a nisone, dexamethasone, or methylprednisone. severe eating disorder in which the patient engages They also require fluid resuscitation, usually in voluntary self-starvation. Some patients with administered as normal saline (salt water) and dex- Addison’s disease have actually been misdiagnosed trose if needed. In a crisis situation, a patient’s with anorexia nervosa. However, patients with blood pressure may fall to extremely low levels anorexia nervosa typically have yellowish skin, (hypotension). He or she may also experience rather than copper-colored skin. In addition, problems with severe hypoglycemia (low blood patients with anorexia nervosa are more likely to sugar) and excessively high levels of potassium. have high levels of cortisol rather than low levels When experienced in combination, these three (hypocortisolism). symptoms may be life threatening. In fact, if the Addison’s disease 7 condition is left untreated, it is fatal. When patients remainder in the afternoon, thus attempting to with Addison’s disease plan to travel, they should mimic the body’s own circadian pattern. be sure to bring with them needles, syringes, and No one specific test allows the endocrinologist to an injectable form of cortisol for emergency use. monitor a patient’s response to therapy. Most important are the patient’s sense of well-being, blood pressure, appetite, and energy. Serum electrolytes in the Diagnosis and Treatment form of potassium and sodium, as well as the renal If physicians suspect that a patient has Addison’s function tests (blood urea nitrogen and creatinine), disease, they will perform a variety of laboratory are monitored. Renin and ACTH levels are some- tests, including the adrenocorticotropic hormone times helpful in guiding dose changes. (ACTH) or Cortrosyn stimulation test. In this test, Monitoring of patients with Addison’s disease is synthetic ACTH in the form of Cortrosyn is inject- crucial. If too much glucocorticoid replacement is ed intravenously after a baseline cortisol level is used, the excessive medication will cause such measured in the blood. Cortisol levels are then symptoms as weight gain, HYPERGLYCEMIA, hyper- measured in the blood after 30 minutes from the tension, and other problems in a medically induced time of the injection and, on occasion, after 60 form of Cushing’s syndrome. minutes. Patients found to be deficient in aldosterone The insulin tolerance test is considered the gold may need mineralocorticoid replacement in the standard test for the diagnosis of Addison’s disease, form of fludrocortisone (Florinef). but it is used less frequently due to the risk of If patients with Addison’s disease become ill or severe hypoglycemia. In this test, a graded amount feverish, they may need to double or even triple of rapid-acting insulin is administered intravenous- their glucocorticoid dosage. Doctors should discuss ly to the patient in order to induce hypoglycemia this issue ahead of time with all patients who have purposely, and cortisol levels are measured at spe- Addison’s disease. If these patients become acutely cific times. Cortisol is a counterregulatory hor- ill, they will need an emergency intravenous dosage mone. Thus, cortisol levels should increase of glucocorticoids and may also require hospitaliza- appropriately when the body develops hypo- tion. Most patients will recover in a day or two. glycemia. If they do not increase, the test indicates See also ACTH; ADRENAL CRISIS/ADDISONIAN CRISIS; a problem and the presence of Addison’s disease. ADRENAL FATIGUE; ADRENAL GLANDS; CACHEXIA; SKIN. After the biochemical diagnosis is made, an For further information, contact the following imaging test can be used to help determine the organization: cause of the adrenal insufficiency. In most cases, a National Adrenal Disease Foundation COMPUTERIZED TOMOGRAPHY (CT) scan of the adren- 505 Northern Boulevard als is the first test used. With autoimmune Suite 200 Addison’s disease, the adrenal glands may appear Great Neck, NY 11021 normal sized, but they are often atrophic. If there (516) 487-4992 has been a destructive lesion such as hemorrhage or tumor, the glands will appear enlarged. If the Adams, Robert, M.D., et al. “Prompt Differentiation of possibility exists of secondary or tertiary adrenal Addison’s Disease From Anorexia Nervosa During insufficiency, CT or MAGNETIC RESONANCE IMAGING Weight Loss and Vomiting.” Southern Medical Journal (MRI) of the pituitary is often valuable. 91, no. 2 (February 1998): 208–211. Patients diagnosed with Addison’s disease are Oelkers, Wolfgang, M.D. “Adrenal Insufficiency.” New treated with replacement glucocorticoids and, on England Journal of Medicine 335, no. 16 (October 17, occasion, mineralocorticoids. Prednisone, cortisone 1996): 1,208–1,212. acetate, methylprednisone, dexamethasone, or Ten, Svetlana, Maria New, and Noel MacLaren. hydrocortisone can be used. The dose may be given “Addison’s Disease 2001.” Journal of Clinical once daily. However, it is typically split with 50–65 Endocrinology & Metabolism 86, no. 7 (2001): percent being given in the morning and the 2,909–2,922. 8 adolescents adolescents Individuals who are either undergo- first menstruation was 12.1 for black girls, 12.2 for ing or who have recently undergone puberty, usu- Mexican-American girls and 12.7 for white girls. It ally in the age range of about 12–17 years. is unclear why black and Mexican-American girls Adolescents are prone to many of the same experience earlier signs of puberty than white girls. endocrine diseases as children or adults. However, When physicians are considering diagnosing a girl they are at risk for some diseases more specific to with an early puberty, they may wish to take into their age group (although the risk is still low). account racial factors that may indicate that she is Examples of such diseases are MATURITY ONSET DIA- on track compared to other girls of the same race. BETES OF YOUTH (MODY) and DELAYED PUBERTY. EARLY PUBERTY (precocious puberty) is a less fre- Males and Adolescents quently occurring problem. Adolescents are more Males may find adolescence difficult, particularly if prone to developing ANOREXIA NERVOSA than adults, they have a delayed puberty, causing them to be although the illness may persist into adulthood. smaller and less mature than other males of the TYPE 1 DIABETES, formerly called juvenile diabetes, same age. Some parents ask their doctors for may present in early adolescence and will persist GROWTH HORMONE to speed the development of throughout life. However, some patients with Type 1 puberty and growth. This use is controversial. In diabetes are not diagnosed until early adulthood or general, parents are more likely to ask for growth even later. hormone for boys than girls. See also TANNER STAGES. Menstruation and Adolescents The onset of menstruation can be difficult for some Wu, Tiejian, M.D., Pauline Mendola, and Germaien M. adolescent girls, who may find it painful and/or Buck. “Ethnic Differences in the Presence of embarrassing. Secondary Sex Characteristics and Menarche Among Interestingly, the presence of secondary sexual US Girls: The Third National Health and Nutrition characteristics and the onset of menstruation Examination Survey: 1988–1994.” Pediatrics 110, no. among girls in the United States have apparent 4 (October 2002): 752–757. racial and ethnic differences. This is based on information from the Third National Health and Nutrition Examination Study of 1988–94, reported adrenal cortical cancer A malignant tumor of by Dr. Wu and her colleagues in a 2002 issue of the cortex of the adrenal gland, also known as an Pediatrics. adrenocortical carcinoma or adrenal cancer. Only According to this report, the study of 1,168 girls about one or two people in a million develop this ages 10–16 revealed that Mexican-American and very rare form of cancer. When it occurs, it is usu- African-American girls developed pubic hair and ally found among adults who are in their 40s or experienced their first menstrual cycle earlier than 50s, although adrenal cortical cancer also can be the Caucasian girls in the study. Nearly half (49.4 seen in children under the age of five years. It more percent) of the African-American girls had breast commonly occurs in females. Sometimes adrenal development at the age of nine years, compared cortical cancer is found among patients diagnosed with 24.5 percent of the Mexican-American girls with MULTIPLE ENDOCRINE NEOPLASIA, type 1 (MEN 1). and 15.8 percent of the Caucasian girls of the same A tumor found in the adrenal medulla or in an area age. In addition, the average (mean) age of the other than the adrenal cortex is known as a appearance of pubic hair was 9.5 years for African- PHEOCHROMOCYTOMA. American girls, 9.8 years for Mexican-American Some tumors actively secrete hormones, while girls, and 10.3 years for Caucasian girls. others do not. Different studies have shown vari- The onset of menstruation was closer for all able percentages of patients with actively secreting three groups. However, it still occurred earlier for tumors. Patients with actively secreting hormones African Americans and Mexican Americans than are discovered upon a physical evaluation of the for Caucasians. The mean age for the onset of the patient, who typically presents with signs and adrenal crisis/addisonian crisis 9 symptoms of CUSHING’S SYNDROME or virilization for other reasons, endocrinologists suspect the (male symptoms in females). This includes hair presence of a malignant tumor, especially if the where it is not typically seen in females, such as on tumor is greater than five centimeters at its great- the chest, face, and so forth. est dimension. In the case of patients who have a nonsecreting Treatment for adrenal cortical cancer is usually tumor, the tumor is usually identified because of surgery. If the cancer is advanced, the patient may symptoms caused by its large size. In other cases, be treated instead with chemotherapy. Mitotane, a the tumor is found serendipitously when the chemical related to DDT, has been the mainstay of patient has had an imaging study for an unrelated chemotherapy for years. It is used initially in treat- issue. An inactive tumor is more commonly seen in ment, as well as later in treatment, in an attempt older patients. This type often progresses at a faster to prolong the patient’s survival. When the tumor rate than those that are hormonally active. is responding poorly, other agents, such as An adrenocortical tumor is usually curable only cisplatin, etoposide, doxorubicin, cyclophos- when it is identified in an early stage, when the phamide, 5-fluorouracil (5-FU), and vincristine are tumor is still confined to the adrenal gland. At this added to the mitotane. point, that particular adrenal gland can be surgical- Because mitotane damages and destroys both ly removed. Patients can then live a normal life, malignant and healthy adrenal cortical cells, with the other adrenal gland taking over full duty patients treated with mitotane must also be treated to make the appropriate levels of hormones need- with glucocorticoid and mineralocorticoid medica- ed by the body. However, discovering this tumor at tions in order to replace their endogenous cortisol an early stage is not common. In fact, an early and aldosterone. tumor, if discovered, is usually found accidentally. Radiation therapy is rarely used to treat adreno- By the time adrenal cortical cancer is usually iden- cortical cancer. Percutaneous radio frequency tified, it has often metastasized (spread to other tumor ablation has been used for patients with organs), typically to the lung, liver, lymph nodes, small tumors and early disease, with mixed results. and bones. See also ADRENAL GLANDS; AMENNORHEA; CANCER; EARLY PUBERTY; HIRSUTISM IN WOMEN. Diagnosis and Treatment Physicians consider the diagnosis of adrenal cancer Abraham, Jame, and Tito Fojo. “Endocrine Tumors,” in when the patient presents with rapidly progressive Bethesda Handbook of Clinical Oncology. Philadelphia, symptoms of Cushing’s disease or with virilization. Pa.: Lippincott Williams & Wilkins, 2001, 419–440. In contrast, cancers that secrete feminizing hor- Hsing, Ann W., et al. “Risk Factors for Adrenal Cancer: mones or aldosterone are very rare. An Exploratory Study.” International Journal of Cancer A basic tenet of endocrinology is that a medical 65, no. 4 (1996): 432–436. syndrome should be clearly characterized biochem- Ng, L., and J. M. Libertino. “Adrenocortical Carcinoma: ically through laboratory studies prior to obtaining Diagnosis, Evaluation, and Treatment.” Journal of imaging studies. Doing so avoids unnecessary test- Urology 169, no. 1 (2003): 5–11. ing and also helps the physician pinpoint the prob- Vassilopoulou-Sellin, R., and P. M. Schwartz. “Adreno- lem. As a result, laboratory tests may be ordered to cortical Carcinoma: Clinical Outcome at the End of help make a diagnosis. the 20th Century.” Cancer 92, no. 5 (2001): When imaging tests are ordered, a COMPUTERIZED 1,113–1,121. TOMOGRAPHY (CT) scan and MAGNETIC RESONANCE IMAGING (MRI) can identify the presence of a tumor. These tests are also used to define the size of adrenal crisis/addisonian crisis A term usually the tumor as well as to determine whether there is used to describe a life-threatening problem due to any local spread or more distant spread to the liver a lack of adequate cortisol. Individuals in an adre- or the lymph nodes. When an enlargement of an nal crisis present with severe hypotension (low adrenal gland is found on a CT that was performed blood pressure), malaise, fatigue, and dehydration 10 adrenalectomy and may actually fall into a coma. They often have adrenalectomy Removal of an adrenal gland. severe electrolyte abnormalities with profound This procedure is usually necessary because of a hyperkalemia (high potassium levels) that can cancerous tumor, trauma with hemorrhage (severe cause a lethal heart arrhythmia and severe HYPONA- bleeding), or a benign tumor (such as a PHEOCHRO- TREMIA (low sodium levels). MOCYTOMA or aldosteronoma) that has caused the Often the clinical picture is clouded by the acute patient to experience serious physiological conse- illness that induced the crisis, such as urosepsis, quences, such as hypertension. pneumonia, or heart attack. Adrenal crisis can Some physicians have developed a means to often occur in postoperative patients who develop remove the adrenal glands laparoscopically, through a bilateral adrenal hemorrhage that destroys both a small incision in the abdomen. This technique is adrenal glands. safer than an open adrenalectomy, and it also costs Individuals in an adrenal crisis need immediate less money, although it can be a longer procedure emergency care with fluid and electrolyte resusci- for the surgeon to perform. In addition, there is less tation in addition to intravenous stress doses of blood loss with a laparoscopic adrenalectomy. In one steroids. Typically, 100 mg of hydrocortisone are published study, the length of the patient stay given and then repeated every six hours for the decreased from 7.4 days to 2.7 days with a laparo- first 24–48 hours. In addition, the underlying ill- scopic adrenalectomy. However, the tumors must be ness must be diagnosed and treated. small (less than six to seven centimeters in size) in When a patient has a known case of ADDISON’S order to perform this procedure. Laparoscopic sur- DISEASE or another cause of adrenal insufficiency, gery is more technically difficult than using a large the treatment is clearer. However, when a patient incision to remove the adrenal gland and should be presents for the first time with these symptoms, the performed only by experienced surgeons. doctor must be astute enough to consider the diag- If patients have both of their adrenal glands nosis of adrenal crisis and to begin therapy as soon removed, they will develop adrenal insufficiency as possible. and require lifelong treatment with steroids in Individuals with Addison’S disease (hypocorti- order to avoid an ADRENAL CRISIS. If only one adre- solism) are the patients most likely to experience nal gland is removed, patients may require only an adrenal crisis. People with Addison’s disease temporary treatment until the other adrenal gland must be educated about the appropriate stress begins functioning properly and handling the task doses of glucocorticoids they need when ill. In of the body’s entire adrenal needs. addition, they may need a prescription for intra- See also ADRENAL CORTICAL CANCER; ADRENAL muscular steroids, to be given at home, if they are GLANDS; ALDOSTERONISM; CANCER. unable to keep down their oral steroids due to nausea and/or vomiting. Keeping intramuscular Hansen, P., T. Bax, and L. Swanstrom. “Laparoscopic steroids at home is also a good idea if patients live Adrenalectomy: History, Indications, and Current a long distance from medical care. In addition, Techniques for a Minimally Invasive Approach to patients need to know that they must make sure Adrenal Pathology.” Endoscopy 29, no. 4 (1997): they drink fluids and consume extra salt when they 309–314. begin to get ill to prevent the syndrome from pro- Soulie, Michel, et al. “Retroperitoneal Laparoscopic gressing further. They also need to have a medical Adrenalectomy: Clinical Experience in 52 identification bracelet or necklace that identifies Procedures.” Urology 56, no. 6 (2000): 921–925. them as a steroid-using or Addisonian patient. Emergency doses of cortisone or hydrocortisone are required to counteract an adrenal crisis and to adrenal fatigue A condition of impaired adrenal meet the individual’s urgent need for cortisol. If function that is not severe enough to reach the level the patient remains untreated, an adrenal crisis of ADDISON’S DISEASE or ADRENAL INSUFFICIENCY. may be fatal. Adrenal fatigue is rare. However, some natur- See also ADRENAL GLANDS; CORTISOL. opaths and other unscrupulous or uneducated adrenal hormones 11 individuals have actively promoted the condition a further evaluation, such as a biopsy, should be as an extremely common one that will resolve only done, as the risk of malignancy increases as the size with massive doses of vitamins (which they often of a tumor increases. Large adrenal masses are sell), sometimes after administering unscientific often surgically approached via a very large poste- tests that purportedly “prove” that the condition is rior to anterior flank incision. However, the ability present. In addition, some unscrupulous practition- to do many surgeries using much smaller laparo- ers place patients on dangerously high dosages of scopic techniques are readily becoming the norm. prednisone. If an adrenal hemorrhage (heavy bleeding) Any person who is told that he or she has adre- occurs, the patient may develop ecchymoses (evi- nal fatigue should be sure to consult with an dence of bruises) in the flank area of the body. ENDOCRINOLOGIST before pursuing any course of pre- See also ADRENAL CRISIS/ADDISONIAN CRISIS; scribed or over-the-counter medications or before ADRENALECTOMY; ADRENAL FATIGUE; ADRENAL HOR- taking massive dosages of vitamins or minerals. MONES; ADRENAL INSUFFICIENCY; ADRENAL LEUKODYS- See also ADRENAL CRISIS/ADDISONIAN CRISIS; TROPHY; SKIN. ADRENAL GLANDS.

adrenal hormones The adrenal glands produce adrenal glands Endocrine glands located in a several hormones, including ADRENALINE, ALDO- very posterior position in the abdomen. Unless STERONE, and CORTISOL. they are extremely enlarged, as with an adrenal Cortisol is the primary hormone secreted by the adenoma, they cannot be felt by hand. Adrenal cortex of the adrenal glands. Cortisol is necessary hormones must be synthesized and secreted in for life. In many systems of the body, it functions as very specific concentrations to ensure normal a permissive hormone, allowing that organ or sys- health. tem to function at an optimal level. Cortisol is The adrenal glands produce three key hormones: needed to balance basic functions, such as blood ADRENALINE (a catecholamine hormone), ALDOS- pressure, alertness, blood glucose levels, and the TERONE, (a mineralocorticoid), and CORTISOL (a glu- salt and water balance of the body. Excessive levels cocorticoid hormone). The adrenal glands also of cortisol result in CUSHING’S SYNDROME or disease, produce some TESTOSTERONE and other ANDROGENS while insufficient levels lead to ADDISON’S DISEASE. (male hormones). Malfunctions of the adrenal Aldosterone is a hormone that helps to maintain glands can lead to such serious endocrine disorders a good electrolyte (primarily sodium and potassi- as ADDISON’S DISEASE,CUSHING’S SYNDROME, and um) balance in the body. It also maintains normal adrenal hyperplasia. The adrenal glands directly blood pressure. People with Addison’s disease may affect the METABOLISM of every person. also be deficient in aldosterone and require supple- The adrenal glands are best imaged using a COM- mentation. Hyperaldosteronism is a disease that PUTERIZED TOMOGRAPHY (CT) scan, and often the usually involves small, benign tumors of the adre- initial scan is performed without intravenous con- nal glands, which may require an ADRENALECTOMY. trast. The CT scan is particularly helpful in patients Adrenaline (also known as epinephrine) is the with adrenal adenomas or adrenal incidentalomas fight-or-flight hormone that enables people to (nodules found with a CT scan, ultrasound, MAG- become hypervigilant and alert in the event of NETIC RESONANCE IMAGING (MRI) scan or other tech- either real or perceived danger or times of high niques that were performed for another purpose). stress. Both adrenaline and cortisol are counterreg- The Hounsfield units (essentially, a measure of ulatory hormones. In other words, they counter- water content) that can be measured from CT scans balance the effects of insulin and tend to increase of the adrenal glands can help determine if further the level of blood glucose. Thus, tumors that evaluation is indicated. secrete excessive amounts of adrenaline, such as If a mass is present, a cutoff size of five to six PHEOCHROMOCYTOMAS, may lead to increases in the centimeters is typically used to determine whether blood glucose level and overt DIABETES MELLITUS. 12 adrenaline adrenaline A hormone produced in the adrenal adrenal glands, tuberculosis, and hemorrhage. cortex of the adrenal gland. Adrenaline is also Adrenal insufficiency may also be caused by acquired known as epinephrine. Adrenaline, which is also immunodeficiency syndrome (AIDS), fungal infec- referred to as the fight-or-flight hormone, is very tions, or the destruction of the adrenal cortex by can- important. It enables individuals to become highly cers that have spread (metastasized) to that area. alert on an as-needed basis. This ability allows indi- In addition, adrenal insufficiency may be sec- viduals to cope more effectively in the event of real ondary to HYPOPITUITARISM. This problem with the or perceived danger or during periods of high pituitary gland produces inadequate adrenocorti- stress. Adrenaline may also be administered on an cotropic (ACTH) hormone. Adrenal insufficiency emergency basis for individuals experiencing a life- may also be tertiary due to a hypothalamic disorder threatening allergic reaction. in which inadequate levels of corticotropin releas- Adrenaline, which is synthesized in small ing hormone (CRH) are generated, and conse- amounts on a regular basis, also helps individuals quently, inadequate levels of ACTH are also to maintain stable blood pressure. It increases produced. blood pressure when people arise from a sitting The most common form of secondary adrenal position by causing the smooth muscles in blood insufficiency is caused by the use of exogenous vessels to tighten (vasoconstriction). steroids in the treatment of another ailments. Adrenaline is also produced by the autonomic Exogenous steroids are frequently used to treat nervous system in both the peripheral nerves and conditions such as asthma, rheumatoid arthritis, or ganglia as well as in the brain. It is one of the coun- organ transplantations and are often lifelong treat- terregulatory hormones that rise rapidly when ments. blood glucose levels fall. Adrenaline travels to the This use of exogenous steroids leads to the sup- liver to counteract the effects of any insulin in the pression of the pituitary gland and the hypothala- system. By increasing the pulse and causing sweat- mus. The adrenal glands become atrophic or ing, jitteriness, and other symptoms, it alerts indi- dormant as they are not needed to make adequate viduals that there is a problem that requires cortisol since the patient now has an external attention. Adrenaline also helps to break down steroid supply. If these steroids are stopped sud- preformed glucose that is stored in the liver in the denly or tapered off too quickly, the patient will form of glycogen. develop acute adrenal insufficiency or an acute Although measuring adrenaline can be difficult, adrenal crisis. Patients may develop signs and it is possible. A laboratory test can measure the symptoms of steroid withdrawal syndrome. adrenaline level in the blood. Additionally, its Patients with adrenal insufficiency, whether they metabolites can be measured in the urine. These have the primary, secondary, or tertiary forms of the lab tests are helpful in diagnosing PHEOCHROMOCY- condition, will feel extremely weak and tired. They TOMA, a benign tumor of the adrenal gland that can may also have the following signs and symptoms: cause fatal paroxysms of blood pressure. See also ADDISON’S DISEASE; ADRENAL GLANDS; • Loss of appetite and unintended weight loss ADRENAL HORMONES. • Nausea and vomiting • Diarrhea adrenal insufficiency The condition that occurs • Dizziness when the adrenal glands make inadequate cortisol for proper health. Complete adrenal insufficiency is HYPONATREMIA (low sodium in the blood) and typically synonymous with ADDISON’S DISEASE. hyperkalemia (high potassium in the blood) are However, there may be degrees of adrenal insuffi- both signs of adrenal insufficiency that are found ciency, ranging from minimal or partial to complete. only with the primary form of the condition. The most common causes of primary adrenal Patients with primary adrenal insufficiency also insufficiency are autoimmune destruction of the often present with hyperpigmentation of the skin adrenal leukodystrophy 13 and thus their skin appears darker. In the most Patients need to have an emergency dose of extreme case, and if patients are left untreated, intramuscular medication available to them if they they will die. In addition, the hyponatremia may travel. This medication can also be used if patients become life threatening. Individuals should be have an illness accompanied by nausea and vomit- treated with intravenous normal saline (a sodium ing and, consequently, they are unable to keep chloride solution) and glucocorticoid steroid infu- their usual doses of medication down. If patients sions (hydrocortisone). are unable to keep up with their body’s fluid needs and are also unable to keep their steroids down, Diagnosis and Treatment they will need emergency treatment with intra- Adrenal insufficiency is often difficult to diagnose. venous steroids and normal saline. Doctors take a careful medical history and perform See also ADRENAL GLANDS; ADRENAL HORMONES. a physical examination. If adrenal insufficiency is Oelkers, Wolfgang, M.D. “Adrenal Insufficiency.” New suspected, the Cortrosyn (cosyntropin) stimulation England Journal of Medicine 335, no. 16 (October 17, test should be performed. The patient’s blood CORTI- 1996): 1,206–1,212. SOL level is measured and then Cortrosyn (synthetic ACTH) is given intramuscularly or intravenously. The patient’s cortisol blood levels are again measured in 30 minutes and, on occasion, in 60 minutes. adrenal leukodystrophy (ALD) A very rare There is some debate about what constitutes a X-linked genetic disease that primarily affects males normal response. However, most experts think that between the ages of six and 10 years old. Also the 30-minute level should be greater than 20 known as adrenoleukodystrophy, ALD affects one mcg/dl or the difference between the baseline test in 20,000 males. Some female carriers of the disease and the 30-minute levels should be greater than 12 may have a milder adult-onset form of ALD, which mcg/dl. This level of response indicates that the usually presents after age 35. There is also an adult- onset form of ALD among males. This type is not as HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (HPA axis) is intact. In some cases, the test must be repeated, severe as the childhood form and usually presents such as when the results are equivocal. Other tests between the ages of 21 and 35, according to the must then be ordered to determine exactly what National Institute of Neurological Disorders and the adrenal function is like. Stroke. There is also a neonatal form of ALD. Most Patients with adrenal insufficiency are treated patients with ALD die within one to 10 years after with glucocorticoid steroids and, on occasion, min- first exhibiting the symptoms of the disease. ALD is eralocorticoid replacement with medications such also a rare cause of ADRENAL INSUFFICIENCY. as hydrocortisone or cortisone. Patients should also wear a medical identification bracelet identifying Genetic Issues them as individuals with adrenal insufficiency in The ALD gene was first discovered in 1993. It is the event of a medical emergency. located on the ABDC1 gene. Genetic counseling is They will also need to take maintenance doses available if it is suspected that the female may be a of medication and be followed by physicians for the carrier of the disease. (If the male has ALD, he will rest of their lives, with at least twice-yearly follow- exhibit obvious symptoms of illness.) If the family up visits with their endocrinologist. Should these has a son who inherits the genetic defect, he will patients become very ill and/or feverish, they will have the disease. A daughter, however, may inher- usually need to increase the dosage of their hydro- it the defect but will usually be a carrier only. cortisone. Typically, a doubling of the dose is done However, about 20 percent of female carriers will for a minor illness and a tripling of the dose is rec- also develop a mild form of ALD. ommended for a major illness. However, patients with adrenal insufficiency should consult with Effects of ALD their own physicians about dosage needs should an Adrenal leukodystrophy affects the nervous system illness occur. and the adrenal cortex. It causes a progressive and 14 adrenal leukodystrophy severe deterioration to the myelin sheath that insu- form of the disease. However, this form of ALD can lates the nerve cells in the brain and also causes the also cause worsening brain deterioration. adrenal glands to deteriorate. Patients with ALD With neonatal ALD, the signs and symptoms are amass large amounts of unbranched, very long mental development delays, seizures, adrenal dys- chain fatty acids (VLCFA), particularly hexa- function, and an enlarged liver. cosanoate (C26:0), in their brains and adrenal cor- Women who are carriers of ALD and who have tex. Because patients with ALD lack an enzyme to mild symptoms of ALD may experience urinary break down these fatty chains, the chains accumu- problems, worsening stiffness, and weakness in late even further and cause severe damage. ALD is their lower legs. also classified as a peroxisomal disorder, with per- oxisomes being the intracellular organelles located where this enzyme is deficient. Diagnosis and Treatment The diagnosis of ALD is initially made based on the Background on Lorenzo’s Oil presenting symptoms and signs. A laboratory test is ALD became more prominently known to the gen- available for VLCFA. It is a highly accurate test for eral public with the success of the movie Lorenzo’s males who have ALD. The laboratory test is not Oil. It was based on a true story of parents who widely available, however, and it can be performed sought and found a treatment (not a cure) for only at a few specialized laboratories. their son who was diagnosed with adrenal ALD can cause adrenal insufficiency in male leukodystrophy when he was a small boy in the patients, which is a possible indicator of the dis- early 1980s. In 2003, Lorenzo was 25 years old, ease. Blood tests will also show abnormalities of according to information posted on The Myelin the HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (HPA Project (http://www.myelin.org). At that time, he axis), such as high levels of the adrenocorticotrop- could communicate only by eye blinks and by ic hormone (ACTH). Female carriers typically do not wiggling his fingers. develop adrenal insufficiency, although they may Lorenzo’s oil, which combines oleic acid and on rare occasion develop mineralocorticoid insuffi- euric acid, is not approved by the Food and Drug ciency (hypoaldosteronism). Administration (FDA) as a treatment for ALD. A MAGNETIC RESONANCE IMAGING (MRI) test may However, at the time of this writing, it reportedly reveal classic patterns of the presence of ALD. can be obtained by patients with ALD who partici- However, correctly diagnosing ALD in females is pate in a clinical trial at the Kennedy Krieger much more difficult. The VLCFA test is accurate in Institute in Baltimore, Maryland. Experts report the majority (85 percent) of cases. In most cases of that Lorenzo’s oil is usually not effective if the neu- women with ALD, though, results of adrenal tests rological impairment has already begun. Some and brain MRIs are usually normal. insurance companies will reimburse patients for the Patients with ALD may be treated with adrenal medication, but many will not. As of 2003, a two- hormones, which may be necessary to sustain the month supply of Lorenzo’s oil costs about $440. patient’s life. As mentioned, some patients with ALD are treated with Lorenzo’s oil. A bone marrow Signs and Symptoms of ALD transplant is another treatment option, though it is Boys with ALD exhibit poor memory, are with- experimental and very dangerous. A bone marrow drawn, and perform poorly in school. They may transplant will decrease the amount of VLCFA in also have learning disabilities, seizures, poor mus- the tissue. Unfortunately, it does not seem to cle coordination, vision problems, deafness, diffi- reverse any of the neurological deficits that the culty walking (gait disorders), increased skin patient experiences, and thus, it is not usually pigmentation, and progressively worsening recommended for patients with either adult-onset dementia. ALD or neonatal ALD. The symptoms and signs of adult-onset ALD For further information on ALD, contact the fol- progress much more slowly than the childhood lowing organizations: AIDS 15

The Myelin Project within two years of their initial infection with HIV. 1747 Pennsylvania Avenue Northwest People with AIDS also have an increased risk for Suite 950 developing a wide variety of endocrine diseases and Washington, DC 20006 disorders, such as ADDISON’S DISEASE, thyroid dis- (202) 452-8994 ease, HYPOGLYCEMIA, lymphomas, and PANCREATITIS. http://www.myelin.org Thyroid Disease National Institute of Neurological Disorders The thyroid diseases that patients with AIDS may Building 31, Room 8A-96 develop range from infections of the thyroid gland 31 Center Drive to HYPOTHYROIDISM or HYPERTHYROIDISM. They may MSC 2540 also develop EUTHYROID SICK SYNDROME, in which Bethesda, MD 20892 their THYROID-STIMULATING HORMONE (TSH) level, http://www.ninds.nih.gov the key test for diagnosing thyroid disease, may be National Organization for Rare Disorders (NORD) only minimally abnormal. P.O. Box 1968 Often patients with AIDS have abnormal levels 55 Kenosia Avenue of thyroid hormones, such as total T4 or free T4. Danbury, CT 06813 Patients with AIDS also have abnormally high lev- (203) 744-0100 els of thyroid-binding globulin (TBG), which http://www.rarediseases.org increase as they become sicker. Because T4 is 99.7 percent bound (thus only a tiny amount is avail- United Leukodystrophy Foundation able to the cells for use), the increased TBG levels 2304 Highland Drive will lead to increased total T4 levels. This finding Sycamore, IL 60178 could lead the physician to believe that the patient (815) 895-3211 or (800) 728-5483 (toll-free) has developed hyperthyroidism. However, in this http://www.ulf.org case, this is a laboratory abnormality and is not indicative of true thyroid disease. The clinical sig- Laureti, S., et al. “Etiological Diagnosis of Primary nificance of a rising TBG in AIDS patients is Adrenal Insufficiency Using an Original Flowchart of unknown, causes no symptoms, and is not treated. Immune and Biochemical Markers.” Journal of Clinical Some medications used to treat patients with Endocrinology & Metabolism 83, no. 9 (1998): AIDS, such as rifampin (Rifampicin, Rifadin, 3,163–3,168. Rimactane), can affect the thyroid laboratory results Moser, Hugo W., M.D., Ann B. Moser, and Steven J. in patients with normal thyroid function. Some Steinberg. “X-Linked Adrenoleukodystrophy.” Available patients who are already taking levothyroxine as a online. URL: http://www.geneclinics.org/ profiles/ thyroid supplement may need to take a higher dose x-ald/details.html. Downloaded on February 15, 2004. of their thyroid medication when they are taking Moser, H. W., et al. “Adrenoleukodystropy: Survey of 303 rifampin, as it will accelerate T4 metabolism. Cases: Biochemistry, Diagnosis, and Therapy.” Annals of Neurology 16, no. 6 (1984): 628–641. Effects on the Adrenal Glands Many AIDS patients have slightly increased adrenocorticotropic hormone (ACTH) and cortisol AIDS (acquired immune deficiency syndrome) A levels. As in many serious illnesses, the serum cor- severe and, as of this writing, incurable but highly tisol levels can increase, which is the body’s reac- treatable illness of the immune system. AIDS is tion to stress. At autopsy, many AIDS patients have caused by the human immunodeficiency virus evidence of a cytomegalovirus (CMV) infiltration (HIV). The time period from when the HIV virus is of the adrenal glands. Overall, about one in 20 actually contracted to when a person is diagnosed patients with AIDS have ADRENAL INSUFFICIENCY. with AIDS may be as long as 10 years or more, Most of this is secondary to CMV, tuberculosis, HIV although some people are diagnosed with AIDS itself, hemorrhage, and tumors. 16 AIDS

Patients with AIDS also often have lower than prior to death. Studies have shown that infections normal levels of adrenal androgens, such as dehy- and malignancies of the pancreas were much more droepiandrosterone (DHEA). Androgen replacement common among deceased AIDS patients than has not proven to be beneficial for these patients. among individuals who died of other causes. Some drugs that are given to patients with Patients with AIDS may also have an increased AIDS, such as ketoconazole (Nizoral) or meges- risk for developing INSULIN RESISTANCE and HYPER- terol acetate (Megace), can also affect the adrenal GLYCEMIA. Some patients initially experience hypo- glands. For example, ketoconazole may cause glycemia (low blood sugar) and later develop adrenal insufficiency by decreasing the patient’s hyperglycemia. synthesis of cortisol. Megestrol acetate is used to Treatment with pentamidine (Nebupent or increase a patient’s appetite, but it may on occa- Pentaur) apparently increases the risk of the sion also lead to the development of a secondary patient developing both hypoglycemia and dia- adrenal insufficiency. betes. Treatment with megestrol acetate, a drug The hormone itself has some glucocorticoid used to counteract anorexia (the loss of appetite, activity and thus can induce a Cushing’s syndrome- not to be confused with anorexia nervosa) and type picture. If the drug is stopped suddenly, it can cachexia (a wasting away), both common charac- lead to a condition of a secondary adrenal insuffi- teristics among patients with AIDS, can sometimes ciency because the production of ACTH from the cause diabetes mellitus. pituitary and corticotropin releasing factor (CRF) from the hypothalamus have been suppressed. On Other Endocrine Effects rare occasions, primary adrenal insufficiency has Other drugs that are given to many patients with been diagnosed in patients on megestrol; the etiol- AIDS may cause endocrine disorders that will need ogy is unknown. to be treated. For example, foscarnet (Foscavir) that is given to improve OSTEOPOROSIS may cause Effects on the Pituitary Gland HYPOCALCEMIA and nephrogenic DIABETES INSIPIDUS. Some studies have shown that the posterior pitu- Megestrol acetate may cause lowered testosterone itary function, where desmopressin acetate levels. Amphotericin B (Fungizone) that is given to (DDAVP) is secreted after traveling from the hypo- patients to treat life-threatening fungal infections thalamus, is impaired in many hospitalized patients may result in renal (kidney) magnesium and potas- with HIV. Additionally, as many as half of these sium wasting. AIDS patients on antiretroviral ther- hospitalized patients had HYPONATREMIA (below- apy may develop lipodystrophy. normal levels of sodium in the blood due to the presence of excessive water). In some cases, hospi- Growth Hormone as a Treatment talized patients were treated with trimethoprim, an Some physicians have used growth hormone to antibiotic that can cause or contribute to the devel- treat their patients with AIDS. Growth hormone opment of hyponatremia. may help patients who suffer from cachexia. It has Gonadal Function also been shown to be partially effective in treating As AIDS progresses, the testosterone levels of HIV-induced lipodystrophy syndrome, perhaps by helping reduce fat content and by increasing lean patients decrease, but FOLLICLE-STIMULATING HOR- (muscle) body mass. MONE (FSH) and LUTEINIZING HORMONE (LH) do not decrease appropriately. As a result, patients can See also CACHEXIA; GROWTH HORMONE; THYROID develop hypogonadotropic hypogonadism. In BLOOD TESTS. women with AIDS, the serum testosterone levels Grinspoon, Steven, and Marie Gelato. “Editorial: The are usually slightly below those of their age- Rational Use of Growth Hormone in HIV-Infected matched controls. Patients.” Journal of Clinical Endocrinology & Metabolism 86, no. 8 (2001): 3,478–3,479. Effect on the Pancreas Sellmeyer, Deborah E., and Carl Grunfeld. “Endocrine and Autopsies of patients with AIDS have revealed many Metabolic Disturbances in Human Immunodeficiency pancreatic abnormalities that were not diagnosed Virus Infection and the Acquired Immune Deficiency aldosteronism 17

Syndrome.” Endocrine Reviews 17, no. 5 (1996): ly caused and characterized by small benign adre- 518–532. nal tumors called aldosteronomas. Patients with primary aldosteronism have hypertension, aldosterone A hormone synthesized by the adre- hypokalemia (low potassium levels), and on occa- nal glands (in the zona glomerulosa), that works to sion, muscle weakness and/or nonspecific malaise. maintain normal electrolyte (mostly sodium and Primary aldosteronism is also one of the few caus- potassium) levels in the body as well as normal es of hypertension that can be cured and is seen blood pressure. Aldosterone prevents the loss of among only about 1–2 percent of all patients. salt and water when the patient is deficient in sodi- Women are more likely to experience this condi- um or has low blood pressure. Aldosterone levels tion than men. are regulated by the patient’s potassium and sodi- Secondary hyperaldosteronism is a more com- um levels, blood pressure, angiotensin II, and renin mon condition than primary hyperaldosteronism. as well as by the activity of the person’s sympa- Possible causes, in addition to hypertension, include thetic nervous system. heart failure, cirrhosis of the liver, or nephrotic syn- A severe illness may cause the aldosterone lev- drome. This ailment is caused by increased levels of els to fall to very low levels. Either excessive levels aldosterone that have been induced by low blood of aldosterone (hyperaldosteronism) or insufficient pressure or other factors that may impair blood flow levels of this hormone (hypoaldosteronism) will and/or the delivery of salt to the kidney. When this cause medical problems for the patient. occurs, the kidney increases the production of Aldosterone levels may be measured in both the aldosterone in an attempt to save salt and water and blood and the urine. Patients who will be undergo- thus restore normal blood pressure and blood flow ing a test for their aldosterone levels may be asked to the kidneys. Doctors can distinguish primary to refrain from taking any diuretic medications, aldosteronism from secondary aldosteronism by antihypertensive drugs, oral contraceptives, estro- measuring the patient’s plasma renin levels. gens, and real licorice candy for about four hours to Idiopathic aldosteronism is another form of the as long as one month before having the test to medical problem. It is found primarily among avoid invalid or confusing test results. men. Patients with this condition are usually Patients with abnormally high aldosterone levels hypertensive. may have benign adrenal tumors, adrenal cancer, or liver disease, such as cirrhosis, or may have heart Signs and Symptoms failure. Women in their third trimester of pregnancy Many patients with either primary or secondary may also have abnormally high levels of aldosterone. aldosteronism have no signs or symptoms. If symp- Very low levels of aldosterone (hypoaldostero- toms are present, they may include: nism) may occur due to the surgical removal of the adrenal glands, ADDISON’S DISEASE, TYPE 2 DIABETES, • Headaches renal tubular acidosis type 4 (TRA IV, also known • Frequent urination as hyporeninemic hypoaldosteronism), or the tox- • Muscle cramps emia that can occur in pregnancy. See also ALDOSTERONISM; BLOOD PRESSURE; CON- • Muscle weakness and paresthesias (pins and nee- GENITAL ADRENAL HYPERPLASIA; HORMONES. dles); these symptoms are less frequently seen aldosteronism Refers to excessive levels of Diagnosis and Treatment ALDOSTERONE within the bloodstream, a condition Doctors who suspect aldosteronism will perform a classified as primary aldosteronism, secondary aldos- physical examination and take a complete medical teronism, or idiopathic aldosteronism. Most cases of history. The patient’s blood pressure is usually at aldosteronism are associated with hypertension. least somewhat high. Routine laboratory tests for Primary aldosteronism, also known as primary conditions such as hypokalemia or hypomagne- hyperaldosteronism or Conn’s syndrome, is usual- semia (low magnesium levels) may indicate the 18 alternative medicine presence of aldosteronism. In fact, as many as 80 Sawka, Anna M., M.D., et al. “Primary Aldosteronism: percent of patients with aldosteronism have Factors Associated with Normalization of Blood hypokalemia. Pressure After Surgery.” Annals of Internal Medicine Because low body potassium can impair the 135, no. 4 (August 21, 2001): 258–261. ability of the pancreas to produce insulin, patients with aldosteronism may also have abnormal glu- alternative medicine Refers to nontraditional or cose tolerance blood test results. Plasma renin lev- complementary medicine that relies on herbs, sup- els are suppressed in patients with primary plements, and other treatments such as acupunc- aldosteronism and are high in patients with sec- ture or massage therapy, rather than on traditional ondary aldosteronism. The cortisol blood levels are prescribed medications and over-the-counter treat- usually normal. ments. After a biochemical diagnosis of primary hyperal- Dietary supplements, also known as nutraceuti- dosteronism is made, and only then, imaging studies cals, are also popular with proponents of alterna- are obtained. COMPUTERIZED TOMOGRAPHY (CT) scans tive medicine. In fact, alternative remedies are can reveal most aldosteronomas present in the adre- popular among many consumers. Some are seek- nal glands. On some occasions, MAGNETIC RESONANCE ing a quick fix for their often chronic medical prob- IMAGING (MRI) and nuclear scans may be necessary lems. Others hope for improved general health or to diagnose these lesions, which can be quite small. longevity by taking vitamins, minerals, and other If aldosteronomas are found, the preferred treat- substances. As a result, alternative medicine has ment is usually to remove the adrenal gland that become a multibillion dollar business in the United contains them surgically (adrenalectomy). Existing States. hypertension improves shortly after the surgery is Some individuals encourage people with performed in about a third of patients. Some endocrine diseases to use vitamins, herbal reme- patients may also need spironolactone (Aldactone), dies, and supplements. For example, as of this writ- an aldosterone agonist, for about three to four ing, some purveyors of medications over the weeks before having the surgery. This therapy min- Internet encourage the use of coconut oil or sea imizes the risk of postoperative hypoaldosteronism kelp as a substitute for thyroid hormone or to as well as helps the body achieve normal potassium increase the overall METABOLISM. This is dangerous levels before surgery. Some patients have laparo- advice. Individuals with HYPOTHYROIDISM need to scopic adrenalectomies. Although technically diffi- take prescribed LEVOTHYROXINE to treat their cult for the surgeon, these procedures often give hypothyroidism or they risk a serious worsening of patients faster and easier recoveries. their condition. In addition, people who have not When patients have idiopathic aldosteronism, been diagnosed with any thyroid disease should they are usually not treated with surgery. Instead, not seek to increase their metabolism with herbal they are treated with spironolactone therapy, with remedies or other drugs. dosages ranging from 25–400 mg per day. Diseases such as DIABETES MELLITUS, hyperten- Unfortunately, spirolactone is associated with many sion, and many other serious chronic diseases can- side effects, especially when patients take more not be cured with herbal remedies and may, in fact, than 100 mg per day. Side effects may include be worsened by them. In addition, some patients fatigue, ERECTILE DYSFUNCTION, GYNECOMASTIA may take an herbal remedy or supplement instead (breast enlargement in males), hyperkalemia, irreg- of a proven medication for their illnesses, which ular menstruation, and gastrointestinal problems. can lead to a worsening of their illness. To minimize these side effects, men are usually prescribed 50 mg or less per day of spironolactone. Vitamins, Herbs, and Supplements See also BLOOD PRESSURE/HYPERTENSION. According to an article published in a 2002 issue of Ganguly, Arunabha, M.D. “Primary Aldosteronism.” New the Journal of the American Medical Association, a sur- England Journal of Medicine 339, no. 25 (December 17, vey of about 2,600 individuals ages 18 and older in 1998): 1,828–1,834. the United States revealed that 40 percent of this alternative medicine 19 population took vitamins and minerals and 14 per- Ban of Ephedra cent took at least one herbal or other supplemental In late 2003, the FDA issued an announcement drug. Among prescription drug users, an average of that the organization planned to ban all sales of any 16 percent took an herbal remedy or supplement. dietary supplements containing ephedra and ma The greatest users of herbal remedies or supple- huang. Because of the vagaries of the law sur- ments were patients taking fluoxetine (Prozac) or rounding dietary supplements, the ban did not 22 percent of this group. Clearly, a large number of become effective for 60 days from the date it was people in the United States use herbal remedies. issued. However, the FDA actively and immediate- Multivitamins were the most popular vitamin ly solicited consumers to cease their use of any used by the survey subjects, followed, in order of drugs such as ephedra and ma huang that contained popularity, by vitamin E, vitamin C, calcium, mag- ephedrine alkaloids. nesium, zinc, folic acid, vitamin B12, vitamin D, According to the FDA press release, “Ephedra is and vitamin A. The most popular herbal remedies an adrenaline-like stimulant that can have poten- and supplements were, in order, starting with the tially dangerous effects on the heart. FDA’s evalua- bestselling: ginseng, ginkgo biloba, Allium sativum, tion also reflects the available studies of the health glucosamine, Saint-John’s-wort, Echinacea angusti- effects of ephedra. This includes many studies folia, lecithin, chondroitin, creatine, and Serenoa reviewed by the RAND Corporation, which found repens. Because of changes in advertising as well as little evidence for effectiveness other than short- trends among consumers, the most popular herbs term weight loss, as well as evidence suggesting and supplements among consumers will likely safety risk. Other recent studies have also con- change from year to year. However, it is also like- firmed that ephedra use raises blood pressure and ly that vitamins, herbs, and supplements as a otherwise stresses the circulatory system, effects group will continue to be popular among many that have been conclusively linked to significant consumers. and substantial adverse health effects like heart In 2003, the American Academy of Clinical problems and strokes.” Endocrinologists (AACE) published a comprehensive monograph providing information on dietary Supplements Promoted for supplements and nutraceuticals. According to this Endocrine Health, Questionably report, nutraceuticals are “dietary supplements that contain a concentrated form of a presumed Many manufacturers promote supplements and bioactive substance originally derived from a food, nutraceuticals for improving endocrine health but now present in a nonfood matrix, and used to although neither the AACE nor the FDA have eval- enhance health in dosages exceeding those obtain- uated the majority of these claims. For example, able from normal foods.” coenzyme Q10 is promoted to improve hypercho- The report further explains that there are some lesterolemia, coronary artery disease, and conges- disease-related claims, made by purveyors of tive heart failure, while chromium, magnesium, nutraceuticals, that are actually approved by the vitamin E, zinc, and other supplements are claimed Food and Drug Administration (FDA) and support- to be effective in improving glucose control. There ed by strong evidence. Examples of such claims is no evidence to date that such claims are valid. include calcium decreasing the risk of OSTEOPORO- SIS, fiber decreasing the risk of CANCER and coro- Medication Interactions nary artery disease, and soy protein decreasing the May Occur with Alternative Remedies risk of coronary artery disease. In contrast, the FDA Some dietary supplements and nutraceuticals has particularly warned consumers against some interact with medications that patients may already specific nutraceuticals, such as hydroxybutyric be taking and thus may consequently boost, weak- acid, which can lead to seizure, coma, and death, en, or somehow change the effect of the prescribed and plantain, which may cause myocardial infarc- drug. Saint-John’s-wort has a potential interaction tion (heart attack). with many drugs, including amitriptyline (Elavil), 20 alternative medicine simvastatin (Zocor), warfarin (Coumadin), and a relief from following conventional medical treatment variety of oral contraceptives. Ginkgo leaf is known and therapies. For example, massage therapy or to have potential drug interactions with aspirin, acupuncture may provide temporary relief for warfarin (Coumadin), and trazodone (Desyrel). patients with aching muscles and stress-induced ten- Patients taking thyroid medication may experience sion that have not responded to medications. a drug interaction when also taking bugleweed, red Occasionally, clinical studies back up the claims yeast, kelp, calcium, iron, or bonemeal. of alternative medicine proponents. For example, Women who are taking estrogens may have a studies have indicated that patients with some drug interaction if they also take androstenedione, chronic diseases, such as osteoarthritis, may bene- chasteberry, grapefruit juice, fenugreek, licorice fit from taking regular dosages of supplements such root, saw palmetto, or Siberian ginseng. Patients as glucosamine. The problem is that many patients taking oral hypoglycemic medications may experi- may generalize from these specific benefits, assum- ence a drug interaction with many different sup- ing that if glucosamine improves their arthritis, plements or nutraceuticals, such as devil’s claw, then another herb may improve their diabetes, fenugreek, feverfew, garlic, ginger, guar gum, psyl- thyroid disease, heart disease, or other serious lium, stinging nettle, and others. In one last exam- chronic ailment. This is not a valid assumption. ple, patients taking insulin may experience a medication interaction if they also take chromium Potential Problems with Alternative Remedies or ginseng. Many people mistakenly believe that alternative remedies are inherently safe because they are nat- Reasons for the Popularity ural. (Most prescribed medications are or were also of Alternative Remedies plant based.) At the same time, some people Alternative medicine has a particular appeal for believe that herbal remedies and supplements are patients with chronic diseases that cannot be cured somehow more powerful than medications pre- but can only be managed, especially illnesses or scribed to them by their physicians. conditions that are very difficult for patients to deal Despite this common belief in the inherent safe- with. Patients may become frustrated with their ty and efficacy of supplemental remedies, the physicians and seek something more than what reverse has been shown to be true. For example, their doctors can provide. Unfortunately, patients when considering the safety issue, researchers have also often fail to report the use of alternative med- found that some drugs sold over the counter as icines to their physicians and, consequently, risk herbal remedies actually contained prescribed dangerous medication interactions. drugs not listed on the container, such as testos- Sometimes doctors recommend alternative terone. Other herbal remedies have been found to medicine to their patients. According to the contain dangerously high levels of lead, mercury, National Center for Health Statistics in the and even arsenic. “National Ambulatory Medical Care Survey: 2000 Some forms of alternative medicine have caused Summary,” physicians ordered alternative thera- disease or even death. A study in Japan reported pies at 31 million visits in the United States in that some Chinese dietary supplements were asso- 2000. There were a total of 823.5 million visits to ciated with causing HYPERTHYROIDISM and liver fail- physicians in 2000, bringing the number of times ure. In the United States in 2003, a baseball player that alternative remedies were recommended to died, reportedly from using a drug that contained about 4 percent of the total visits. ephedra. His was not the first death from using this supplement. Some herbal remedies are known to Benefits of Alternative Medicine have toxicities. For example, licorice root and ma Supporters of alternative medicine and treatments huang are cardiotoxic (dangerous to the heart), say that herbal supplements, acupuncture, and other chapparal leaf, ma huang and pennyroyal oil are alternative options may provide relief to patients hepatotoxic (dangerous to the liver), and nux vom- with chronic problems who have gained little or no ica and starfruit may cause convulsions. amenorrhea 21

This does not mean that all or even most herbal ue to battle over whether the Dietary Supplement remedies are dangerous or toxic; however, it is very and Health Education Act should be made stricter. important for consumers to discuss their plan to take De Smet, Peter A. G. M. “Herbal Remedies.” New England any such drug with their physicians beforehand. Journal of Medicine 347, no. 25 (December 19, 2002): Additionally, there is very little standardization 2,046–2,056. from one manufacturer’s herbal remedy or supple- Food and Drug Administration. “FDA Announces Plans ment to that produced by another manufacturer. to Prohibit Sales of Dietary Supplements Containing Registered pharmacist Peter De Smet stated in his Ephedra.” Available online. URL: http://www.fda.gov 2002 article in the New England Journal of Medicine, /oc/initiatives/ephedra.december2003/advisory.html. “Standardization of herbal remedies can be diffi- Posted December 30, 2003; downloaded January 16, cult, because herbs contain complex mixtures and 2004. because the constituents responsible for the Kaufman, David W., et al. “Recent Patterns of Medication claimed effects are often unknown. Since herbal Use in the Ambulatory Adult Population of the United remedies are exempt from rigorous regulation in States: The Slone Study.” Journal of the American the United States, there may be considerable varia- Medical Association 287 (2002): 337–344. tion in the composition of an herbal remedy among Marcus, Donald M., M.D., and Arthur P. Grollman, M.D. manufacturers and lots, as well as discrepancies “Botanical Medicines—The Need for New Regulations.” between label information and actual content.” New England Journal of Medicine 347, no. 25 (December 19, 2002): 2,073–2,075. The Dietary Supplement and Mechanick, Jeffrey I., M.D., et al. “American Association Health Education Act of Clinical Endocrinologists Medical Guidelines for the The Dietary Supplement and Health Education Act Clinical Use of Dietary Supplements and Nutraceuti- in the United States has been a key force behind cals.” Endocrine Practice 9, no. 5 (September/October the explosive sales growth of herbs and supple- 2003): 417–470. ments. Many people in the United States are unaware that herbs and supplements fall under the amenorrhea Absence of the menstrual period in Dietary Supplement and Health Education Act, a woman or girl who would normally menstruate. enacted by Congress in 1994. Pregnancy is a normal cause of amenorrhea. In the This law upholds different standards and absence of a pregnancy, most women of childbear- requirements for herbs and supplements compared ing age should menstruate unless the uterus has with those held for both prescribed drugs and over- been surgically removed, as with a hysterectomy. the-counter drugs in the United States. This law is Amenorrhea may also be an indicator of an under- also the reason why the FDA had such difficulty lying illness or of INFERTILITY. banning ephedra. Many physicians believe this is a bad law. They Primary Amenorrhea feel it is far too lenient and believe that producers Primary amenorrhea is a condition diagnosed in a of herbs and other supplements should be subject woman who has failed to menstruate by the age of to the same regulations that govern over-the- 18 years. Most females menstruate well before that counter medications and prescribed drugs. age. However, if other pubertal changes have Those who produce herbal remedies and supple- occurred, such as pubic and underarm hair and ments have a broad freedom to sell their wares and breast development, most doctors do not worry do not have to perform extensive clinical testing about the failure to menstruate until a female is 18 beforehand, as must be done with prescribed and years old or older. They may, however, order clini- over-the-counter drugs. In addition, the FDA must cal tests to reassure the patient about her health, prove that an herb or supplement is dangerous including tests for estrogen levels and thyroid levels. before removing it from the consumer market. As of Doctors diagnose primary amenorrhea by taking this writing, politicians and drug companies contin- a careful medical history, finding out the age of the 22 American Association of Clinical Endocrinologists patient’s mother when she began to menstruate (in (ASHERMAN’S SYNDROME). Some drugs, such as bar- the event that late-age menstruation is common biturates, corticosteroids, ORAL CONTRACEPTIVES, for the family), and asking about a present possible and some tranquilizers, may also cause amenor- pregnancy as well as any recent weight changes rhea. In addition, arduous physical exercise, such and any gynecological surgery the woman has had. as is seen with ballet dancers or professional ath- All of these factors can affect menstruation. letes, may cause amenorrhea. Rarely, secondary Some diseases that may cause primary amenor- amenorrhea is caused by ANDROGEN EXCESS or rhea are ACROMEGALY, ANOREXIA NERVOSA, Stein- hyperandrogenism, which is an excessively high Leventhal syndrome, TURNER SYNDROME, HERMA- level of male hormones. PHRODITISM, DIABETES, Crohn’s disease, tuberculosis, If the cause of the amenorrhea is resolved, then thyroid disease, and heart disease. A tumor such as menstruation may either resume again or start for a prolactinoma may also cause amenorrhea. the first time in a female who has not menstruated If a patient is diagnosed with primary amenor- before. rhea, doctors should check for cryptomenorrhea, a See also ANDROGEN RESISTANCE; ANDROGENS; EAT- condition in which menstruation occurs but an ING DISORDERS; MENSTRUATION, PAINFUL; POLYCYSTIC imperforate hymen or other obstruction prevents OVARY SYNDROME; THYROTOXICOSIS. the blood from leaving the body. The doctor may Ammer, Christine. The New A to Z of Women’s Health, 4th order X-rays of the patient’s hands to determine ed. New York: Facts On File, Inc., 2000, pp. 23–25. the patient’s bone age. If bones have fused, adult Lupo, Virginia R., M.D., and Catherine B. Niewoehner, growth has been achieved, and menstruation M.D. “Endocrinology of Female Reproduction,” in should have commenced. If the bones have not yet Endocrine Pathophysiology. Madison, Conn.: Fence fused, the first menstruation (menarche) may be Creek Publishing, 1998. anticipated to occur within a short period. Of course, a pelvic examination should also be performed by a gynecologist to check for the presence of any abnormalities. American Association of Clinical Endocrinologists When no medical problems are identified, doc- (AACE) The leading professional organization of tors usually advise the female to come back in six physicians who specialize in the clinical evalua- months for a follow-up examination. tion and care of patients with a variety of endocrine disorders, such as DIABETES MELLITUS, Secondary Amenorrhea thyroid disease, OSTEOPOROSIS, and other illnesses. When a nonpregnant woman who has menstruat- The AACE was founded in 1991 and has over ed in the past has not menstruated for three or 4,000 members from the United States and 63 more consecutive months, she may be diagnosed other countries. with secondary amenorrhea. Doctors need to dis- The AACE publishes a monthly peer-reviewed tinguish between amenorrhea and oligomenorrhea clinical journal, Endocrine Practice. It has also pub- (which are scanty menstrual periods with fewer lished numerous clinical guidelines on such topics as than 90 days between them). HYPERTHYROIDISM, HYPOTHYROIDISM, HYPOGONADISM, As with primary amenorrhea, patients with sec- the Women’s Health Initiative, and many other ondary amenorrhea need a thorough physical important topics. examination and the taking of a complete medical The organization sponsors a yearly scientific history. They will also need a pelvic examination clinical session where the latest advances in the and appropriate laboratory tests. diagnosis and treatment of endocrine disorders are Causes of secondary amenorrhea may include reviewed and discussed. the following: ovarian cysts or tumors, POLYCYSTIC The AACE offers annually updated, patient-ori- OVARY SYNDROME, pituitary damage caused by post- ented press releases to the public, including such partum hemorrhage, and an endometrium that releases as “Thyroid Awareness,” “Stand Strong was destroyed in an overzealous curettage Against Osteoporosis,” and “A Campaign for anabolic steroids 23

Intensive Diabetes Self-Management.” This infor- For further information, contact the ADA: mation can be reviewed at the AACE Web site: American Diabetes Association (ADA) www.aace.com. Patients can also go to this Web 1701 North Beauregard Street site to locate an endocrinologist near them who has Alexandria, VA 22311 an interest in their particular endocrine-related (703) 549-1500 or (800) 342-2383 (toll-free) problem. http://www.diabetes.org For further information, contact the AACE: AACE 1000 Riverside Avenue, Suite 205 American Thyroid Association (ATA) An organiza- Jacksonville, FL 32304 tion of physicians and scientists interested in scientif- (904) 353-7878 ic research on the thyroid gland. The primary mission http://www.aace.com of the American Thyroid Association is to foster and support thyroid research, both on normal thyroid physiology and disease states. The organization also aims to disseminate new information on the thyroid American Diabetes Association (ADA) A non- gland to clinicians, researchers, and the general pub- profit organization formed in 1940 by physicians lic. The Web site of the American Thyroid Association concerned about diabetes treatment and research. has a section, set aside for patients, that offers infor- Their mission is to prevent and cure diabetes as mation on specific thyroid issues. well as to improve the lives of everyone affected by The American Thyroid Association publishes the the disease. journal Thyroid, which has clinical and basic science Along with major federal agencies, the ADA has articles on the problems and physiology of the thy- cosponsored very large and significant clinical trials roid gland. It also publishes Clinical Thyroidology, a of patients with diabetes, such as the Diabetes synopsis of research studies accompanied by expert Control and Complications Trial (DCCT), as well as commentary. The ATA advocates for the public in many other important studies. areas such as patient testing, public health issues, The American Diabetes Association provides and insurance coverage. In addition, the ATA pub- information to both diabetes medical professionals lishes updated laboratory guidelines for physicians, and to consumers with diabetes. The organization laboratories, hospitals, and teaching purposes. produces the four most widely read, professional For further information, contact: peer-reviewed journals published on diabetes, including Diabetes, Clinical Diabetes, Diabetes Care, American Thyroid Association and Diabetes Spectrum. In addition, the ADA pub- 6066 Leesburg Pike, Suite 550 lishes a weekly online newsletter, DIABETES E- Falls Church, VA 22041 News Now! available with other newsletters that (703) 998-8890 individuals can sign up to receive at http:// http://www.thyroid.org diabetes.org/site/PageServer?pagename=EM_signup. The ADA also sponsors an online community forum, where patients and other interested indi- anabolic steroids Refers to a group of syntheti- viduals may discuss issues about diabetes of any cally created steroids that typically have glucocorti- type. The ADA Web site posts a tip of the day as coid and androgen-like effects. These drugs are well as information on opportunities to volunteer sometimes used illegally by body builders seeking and donate to the ADA. In addition, the Web site to increase their muscle mass more quickly than also offers access to a vast array of diabetes-related weight lifting efforts can achieve. The term anabolic resources. The ADA also has an advocacy center refers to the ability of these compounds to help build that allows people to advocate for their own dia- up the body, typically by increasing the incorpora- betes-related causes in their local and state govern- tion of amino acids into proteins. The naturally ments as well as the federal government. occurring steroids, such as the male hormones 24 androgen excess

(androgens such as TESTOSTERONE) produced by the women; also known as hyperandrogenism. testes, also have anabolic effects. Androgens are produced in the testes, ovaries, and Anabolic steroids have systemic effects. Their the adrenal glands. Thus, an evaluation of this use will also lead to oily skin, acne, increased hair problem must sort out the degree of the excess and growth in places other than the scalp, decreased where the excess androgens are produced. hair growth on the scalp, and often cause users to Androgen excess may result in HIRSUTISM in have a more aggressive temperament. women (excessive body hairiness), acne, and As of this writing, grand jury hearings have been AMENORRHEA (failure to menstruate) or oligomen- held about the use of illegal anabolic steroids by both orrhea (infrequent menstruation). Women with amateur and professional athletes. In addition, a new androgen excess may also have problems with hair anabolic steroid known as tetrahydrogestrinone loss (alopecia) rather than with hirsutism. Some (THG) was uncovered by authorities in 2003 and was women with severe androgen excess may also subsequently banned by the Food and Drug experience a deepening of their voice, clitoral Administration (FDA). This drug was formerly unde- enlargement, and increased muscle mass, symp- tectable by even very sophisticated testing methods; toms known as virilization. When virilization is however, the detection of this steroid is now possible. present, the physician must consider the possible Synthetic androgens are also available for med- diagnosis of an androgen-producing tumor, either ically indicated reasons, such as hypogonadism, or benign or malignant. serious chronic conditions, such as the human Excessive levels of androgen may be a genetic immunodeficiency virus (HIV), severe burns, liver problem. Androgen excess may also be caused by failure, pulmonary (lung) disease, kidney failure, illnesses, such as ADRENAL CORTICAL CANCER, CON- wound healing, and postoperative recovery. GENITAL ADRENAL HYPERPLASIA, or POLYCYSTIC OVARY Androgens are also given to men with some SYNDROME. forms of advanced CANCER, particularly prostate cancer. For men with prostate cancer, testosterone makes cancer grow. By suppressing testosterone, androgen resistance Inability of the body to use men’s lives can be extended, sometimes for years. some or all of the male hormones that are natural- (Androgen therapy is not, however, a cure for ly produced. This problem is typically caused by a prostate cancer or for any other form of cancer.) genetic defect. It may be due to a problem with the For further information on the abuse of anabol- receptor for testosterone or due to an enzyme defi- ic steroids, contact: ciency (as in a deficiency of the 5-alpha reductase enzyme that changes testosterone to dihydrotestos- National Institute on Drug Abuse (NIDA) terone, the biologically active form of testosterone 6001 Executive Boulevard within the cells). Room 5213 As a steroid hormone, testosterone must bind to Bethesda, MD 20892 the surface of the cell it is going to affect via a spe- (301) 443-1124 cific receptor. The receptor may be regarded as a http://www.nida.nih.gov loading dock, albeit a loading dock that is very spe- See also ANDROGENS. cific to testosterone. Thus, most other steroid hormones are unable to bind (or dock) there as they Basaria, Shehzad, Justin T. Wahlstrom, and Adrian S. have the wrong three-dimensional shape for bind- Dobs. “Anabolic-Androgenic Steroid Therapy in the ing. Once the testosterone is docked, it must then be Treatment of Chronic Diseases.” Journal of Clinical internalized. Thus, the testosterone must be brought Endocrinology & Metabolism 86, no. 11 (2001): into the cell and moved to the nucleus of the cell. 5,108–5,117. Once there, the testosterone will interact with the DNA within that particular cell to cause its effects. androgen excess The overproduction of male When binding to the DNA, testosterone can hormones; usually a problem experienced in stimulate the synthesis of new proteins or it may androgen resistance 25 inhibit other processes. Thus, at any stage of the With incomplete androgen insensitivity, the patient process, a defective protein or bonding can lead to appears as a normal female with normal breasts and androgen resistance because the androgen cannot external genitalia, with the exception of an bind and cause the appropriate effects. enlarged clitoris and/or fusion of the posterior labia. Androgen resistance may range from severe to In contrast, the patients who have Reifenstein’s very mild forms. Three forms are described below. syndrome appear to be males, but they present with GYNECOMASTIA (breast enlargement) and perineo- Complete Androgen Resistance scrotal hypospadias (an opening in the area behind At its most extreme, complete androgen resistance the scrotum or directly in the scrotum). (previously called testicular feminization) prevents In both of these syndromes, infants present with the development of normal male sexual character- what is known as ambiguous genitalia. When eval- istics. Consequently, the individual looks like a uating these infants, the endocrinologist must also female but has no true uterus, ovaries, or vagina. consider the diagnoses of 5-alpha reductase defi- During puberty, the individual develops secondary ciency syndrome, mixed gonadal dysgenesis, and sexual characteristics, such as breasts; however, other defects in the synthesis of testosterone. since there is no uterus, the individual cannot Among males, the size of the penis is usually the menstruate and is also infertile. These patients typ- deciding factor for making the gender choice. ically present during puberty, concerned because Having a very tiny penis (MICROPENIS) may lead to they have never menstruated. (Genetically, they the parents’ decision to raise the child as a female; are typically 46-X, Y and also have normal (for a however, this is a controversial issue. (According to male) or elevated testosterone levels and elevated authors Erica A. Engster, M.D. and Antoinette M. luteinizing hormone (LH) levels.) Moran, M.D., in their chapter in Endocrine In some cases, the condition is actually Physiology, a micropenis in an infant is a penis that unknown to the individual and the family, who is less than or equal to two centimeters in size.) In have always assumed the person to be a female. other cases of partial androgen resistance, the child The androgen resistance is not discovered until the is given large doses of testosterone to stimulate the time of expected puberty or even later, when the growth of the penis. If a course of testosterone fails individual attempts to get pregnant. At that time, it to induce growth, the parents may then be advised is discovered that “she” is genetically a male, an to raise the baby as a girl. obviously shocking revelation. The testicular remnants of the person are often found in the Mild Androgen Resistance abdomen or inguinal area. Thus, in women with In its mildest form, androgen resistance may lead to both primary amenorrhea and inguinal or labial symptoms such as infertility caused by insufficient masses, this diagnosis must be suspected. sperm (oligospermia) or to minimal breast enlarge- Note that complete androgen resistance is not at ment. However, despite these signs, the individual all the same as transsexualism or gender dysphoria, is clearly male in his physical appearance, orienta- which refers to a person who is born genetically and tion, and behavior. physically a male (or female) but who, at a very young age (as young as three or four years old), feels Diagnosis and Treatment trapped in the wrong body. For example, a male The diagnosis of androgen resistance may be missed feels he is truly female. These patients have normal altogether in some cases of complete androgen hormone levels for their genetic makeup, and they resistance. This occurs when the family and doctors do not have abnormalities of hormone resistance. assume that the individual is actually a female rather than a male. However, if the child has both female Incomplete/Partial Androgen Resistance and male characteristics (incomplete testicular femi- The two primary forms of incomplete or partial nization), the condition is usually diagnosed earlier. androgen resistance are categorized as incomplete Blood tests will reveal that for patients with androgen insensitivity and Reifenstein’s syndrome. androgen resistance, testosterone levels are in the 26 androgen resistance range for males rather than females. In addition, See also AMENORRHEA; HERMAPHRODITISM; HYPOG- levels of LUTEINIZING HORMONE (LH) will usually be ONADISM;KLINEFELTER SYNDROME; OVARY; TESTES/TES- high. FOLLICLE-STIMULATING HORMONE (FSH) levels TICLES;TURNER SYNDROME. will be in the normal range. An ultrasound test will For further information on androgen resistance, reveal that no uterus is present, and it may also contact the following organization: reveal the presence of intra-abdominal testes. To differentiate androgen resistance from either Androgen Insensitivity Syndrome an androgen deficiency or a deficiency of 5-alpha Support Group (AISSG) reductase enzyme, physicians may measure the P.O. Box 2148 concentrations of both testosterone and dihy- Duncan, OK 73534-2148 drotestosterone (DHT). Individuals who have http://www.medhelp.org/ais androgen resistance will have normal ratios of testosterone to dihydrotestosterone. However, with Engster, Erica A., M.D. and Antoinette M. Moran, M.D. 5-alpha reductase deficiency syndrome, the DHT “Sexual Determination, Sexual Differentiation, and levels are decreased, and thus the testosterone to Puberty,” in Endocrine Physiology. Madison, Conn.: DHR ratio is then increased. Fence Creek Publishing, 1998, 1,237–1,255. If doctors find the presence of intra-abdominal Grino, P. B., et al. “Androgen Resistance Associated with testes, these testes are usually removed after the a Qualitative Abnormality of the Androgen Receptor individual is fully grown as they serve no purpose and Responsive to High Dose Androgen Therapy.” in an individual with a female gender identity and Journal of Clinical Endocrinology & Metabolism 68, no. 3 could later become malignant. After puberty, the (1989): 578–584. individual with complete androgen resistance is given estrogen replacement therapy in order to androgens Male hormones that play a key role in maintain the female identity. sexual development, sexual interest and ability, In rare cases, large doses of male hormone have muscle mass, weight, body hair, energy levels, been given to induce a normal development of the bone density, and other functions. The most promi- penis. For example, in an article in a 1989 issue of the nent male hormone is TESTOSTERONE, a hormone Journal of Clinical Endocrinology & Metabolism, a baby that affects sexual desire and potency, muscle mass, had a very small penis and small testes that could be and the presence of body hair. Women also have felt in the labialscrotal folds and had no vagina. some testosterone, although the testosterone levels Laboratory tests revealed that the infant had in females are normally lower than those found in normal 5-alpha reductase activity and androgen most men. Most androgens in men are produced in 1 1 resistance. At the ages of 2 /2 and 3 /2 years, this the TESTES. Some androgens are also produced by child was given large doses of testosterone, which the ADRENAL GLANDS. resulted in the further growth of the penis and When men become androgen deficient for any also enabled the doctors to correct the child’s reason, they will have less muscle mass, decreased hypospadias surgically. The doctors in this case bone density (which may lead to OSTEOPOROSIS), hypothesized that the androgen receptor function sparser body hair, and significantly decreased causing the androgen resistance was successfully libido. They may develop ERECTILE DYSFUNCTION, treated by the high doses of androgen. It is although most men with very low androgen lev- unknown if the boy later required any future els may retain a normal ability to have erections doses of androgen. but find they have very little sex drive (as well as When the androgen resistance is mild and the other medical problems). The voice will remain primary sign is infertility, treatment can be aimed deep in the adult male because he has already at increasing testicular function with medications, undergone puberty. However, hypogonadal men such as human chorionic gonadotropin (HCG) may develop GYNECOMASTIA, or enlargements of and gonadotropin-releasing hormone (GnRH.) the breast tissue. anorexia nervosa 27

Androgen Therapies (DEA) in the United States classifies these anabolic Low androgen levels seen with hypogonadism are steroids as controlled or scheduled drugs, just as treated with supplemental androgens, typically in drugs such as narcotics are scheduled drugs. the form of testosterone. Rarely, very small Apparently, anabolic steroids can improve ath- amounts are used in boys who have delayed puber- letic performance for some individuals. However, ty and then for only a short time. Androgen their use may also cause severe side effects such as replacement is available as an intramuscular injec- liver damage, tumor growth in the liver and brain, tion or a topical gel or skin patch. It is also available and wild personality swings, with fits of rage and in pill form. However, pills are not used for long- uncontrolled behavior. Other side effects include term replacement therapy as such use can lead to acne, oily skin, increased blood pressure, infertility, serious problems, including tumors. sleep apnea, and gynecomastia. The topical approach is best, as it allows for Women who abuse androgens may experience physiological concentrations of androgens in the acne, hirsutism, amenorrhea, and virilization. bloodstream. In contrast, when injections are used, Although men and women may both develop initially the testosterone level normalizes, but then psychological and physical dependencies on ana- it goes too high for several days, after which it bolic steroids, most abusers are males. In some returns to normal. In addition, prior to the next cases, users become not only more aggressive but injection, the testosterone level may fall below nor- may also exhibit symptoms of mental illness. mal. As a result, injections are best given every See also ANABOLIC STEROIDS; DELAYED PUBERTY; 10–14 days, although many men prefer to receive HYPOGONADISM; HYPOGONADOTROPISM. them only every three to four weeks. Bagatell, Carrie J., M.D., and William J. Bremner, M.D. Some patients receive androgens to help control “Androgens in Men—Uses and Abuses.” New England Fanconi’s anemia or aplastic anemia. Androgens Journal of Medicine 334, no. 11 (March 14, 1996): are also used to treat sickle cell anemia or other 707–714. forms of blood diseases, such as the anemia caused by kidney failure. anorexia nervosa A severe eating disorder and Women and Androgen Therapy psychiatric problem that is primarily characterized The main use of androgens in women is in the by purposeful self-starvation. About 5 million treatment of decreased libido. In this situation, the Americans suffer from anorexia nervosa. Some androgen is often combined with an estrogen, as in experts define anorexia nervosa quantitatively as a the combination trade medications Estratest and BODY MASS INDEX (BMI) of equal to or less than 17.5 Estratest HS. On other occasions, an androgen is kg/m2. (The average healthy person has a BMI used in the treatment of endometriosis, a condition within the range of about 19–24.) in which the cells from the endometrial lining The term anorexia nervosa should not be con- implant in a variety of places around the pelvis and fused with the single word anorexia, which indi- abdomen, causing the woman to develop pain, cates a usually temporary lack of appetite in people menstrual derangements, and infertility. Women who are ill. Individuals with anorexia nervosa are taking such drugs may experience temporary mas- usually hungry but purposely avoid food, often culinizing side effects, such as HIRSUTISM, smaller because of a delusional belief that they are fat, breast size, and INFERTILITY. despite the fact that they are significantly below normal in body weight. The condition can be life Abuse of Androgen Drugs threatening and may require the treatment of a Some individuals, especially some athletes and body variety of specialists, including an ENDOCRINOLO- builders, take artificially synthesized androgens, not GIST, a psychiatrist, and other physicians. for a medical purpose but to increase their muscle Occasionally, experts misdiagnose patients as mass. The Drug and Enforcement Administration having anorexia nervosa because of a significant 28 anorexia nervosa weight loss due to a different condition. This can Sometimes adolescent girls with Type 1 diabetes occur when the patient has ADDISON’S DISEASE, TYPE 1 develop eating disorders such as anorexia nervosa. DIABETES,GRAVES’ DISEASE, and other illnesses that Generally, the scenario is that a girl, once very slen- cause extreme weight loss. As a result, any individ- der due to undiagnosed diabetes, is diagnosed with ual suspected of having anorexia nervosa should the illness and properly placed on insulin therapy. receive a thorough medical screening before a She gains weight with better blood glucose levels. definitive diagnosis is given. In addition, her appetite usually improves when Patients with anorexia nervosa also have a sig- she is less ill, leading to a larger caloric intake. nificantly greater risk of abusing substances such as The increased weight may greatly distress the alcohol, cocaine, and other drugs. According to female adolescent. In an attempt to revert to her Food for Thought: Substance Abuse and Eating former lower weight, an adolescent may radically Disorders, a 2003 report by the National Center on reduce the amount of food that she eats or may Addiction and Substance Abuse at Columbia manipulate her insulin dosages to induce a weight University, researchers have found that teenage loss. Some adolescents with diabetes will binge on girls with eating disorders have a five times greater food and then purge (bulimia nervosa), although risk of abusing alcohol or illegal drugs than girls of such behavior does not appear to be characteristic the same age who do not have an eating disorder; for the adolescent with diabetes. a 50 percent risk versus a 9 percent risk. Signs and Symptoms of Anorexia Nervosa Risk Factors In addition to a significant weight loss, other indi- Anorexia nervosa occurs in about 1–2 percent of cators of anorexia nervosa include: the population. It is much more prominent among females, who have a 20 times greater risk of devel- • Menstrual problems or the lack of menstruation oping the condition than males. Caucasian females (AMENORRHEA) for three or more months are more likely to develop anorexia nervosa than • Very fine hair on the side of the faces and arms women of other races, although females of other • Thinning hair races also exhibit this behavior. Women who are • Brittle nails active in modeling, ballet dancing, or athletic pur- suits are more likely to develop anorexia nervosa • Unexplained fatigue than others, as are females who are perfectionists. • Sensitivity to cold Some studies indicate that overprotective parent- • Light-headedness ing may be a factor leading to the development of anorexia nervosa. When males exhibit anorexia nervosa, they are Diagnosis and Treatment of Anorexia Nervosa more likely to be athletes or dancers, for whom Doctors primarily diagnose anorexia nervosa based attaining and maintaining a specific weight is con- on the signs and symptoms exhibited by a patient sidered important by their peers. as well as the presence of a significant weight loss and a below-normal body weight. Laboratory tests A Genetic Problem for patients with anorexia nervosa are often in the Some studies have indicated a genetic influence on normal range, although some patients are anemic anorexia nervosa, with a seven to 12 times greater or hypoglycemic. Some tests of thyroid function risk among the relatives of individuals with may be abnormal, such as abnormal levels of anorexia nervosa. A study of 672 female twins, ages reverse triiodothyronine (rT3). In most cases, if the 16–18 years, performed by K. L. Klump and col- anorexia nervosa is resolved, any negative labora- leagues and reported in a 2001 issue of Psychological tory results will normalize as well. Medicine, identified 26 individuals with anorexia Electrolytes will often be out of balance if the nervosa who had a strong genetic component. patient has abused diuretic drugs or laxatives. anovulation 29

Cortisol blood levels may be elevated. Scans of Klump, K. L., et al. “Genetic and Environmental bone loss indicate bone density abnormalities in as Influences on Anorexia Nervosa in a Population- many as 50 percent of patients with anorexia ner- Based Twin Sample,” Psychological Medicine 31, (2001): vosa. Experts report that bone loss can occur in 737–740. young anorexic women as early as six months from Mehler, Philip S., M.D. “Diagnosis and Care of Patients the onset of the anorexic behavior. with Anorexia Nervosa in Primary Care Settings.” Treatment for anorexia nervosa may include Annals of Internal Medicine 134, no. 11 (2001): taking antidepressants or other psychiatric medica- 1,048–1,059. tions as well as receiving psychological counseling. National Center on Addiction and Substance Abuse at Individuals who are severely ill will need hospital Columbia University. Food for Thought: Substance Abuse care or long-term residential treatment. Generally, and Eating Disorders. New York: National Center on hospitalized patients are those who are 25–30 per- Addiction and Substance Abuse at Columbia cent below the ideal body weight for their height. University, 2003. In contrast, patients who are 85–90 percent of their normal weight may often be treated successfully on an outpatient basis. Physicians treating patients with anorexia ner- anovulation The failure to release an egg in the vosa need to be careful with what is known as ovulation process, which then leads to INFERTILITY. refeeding syndrome, a problem that may occur Women with regular menstrual cycles typically when a severely anorexic patient is given meals have predictable times of ovulation. Those women that are high in calories. This problem is most like- with AMENORRHEA (failure to menstruate) usually ly to occur in the first two to three weeks of refeed- have complete anovulation and, thus, do not ovu- ing. It may cause cardiovascular collapse and even late at all. Women with irregular cycles (oligomen- heart failure because the severely malnourished orrhea) have an erratic pattern of ovulation. person cannot cope with higher-than-normal (for Anovulation has many different etiologies (caus- her) calories. To avoid this problem, the hospital- es). POLYCYSTIC OVARY SYNDROME (PCOS) is often a ized patient should have the electrolyte levels, cause of anovulation. Patients with PCOS often have especially of phosphorus, monitored at least every insulin resistance syndrome (IRS). In addition to IRS, other day. After several weeks of gaining weight, LUTEINIZING HORMONE secretions are often abnormal. such monitoring is usually no longer needed. The combination leads to hyperandrogenism, the See also AIDS; DIABETES MELLITUS; EATING DISOR- likely underlying cause of the anovulation. Other HYPOTHYROIDISM DERS; GHRELIN;PRADER-WILLI SYNDROME. causes of anovulation are and For further information on anorexia nervosa, MENOPAUSE. The physician should screen the patient contact the following organizations: for thyroid dysfunction before attempting any direct treatment for anovulation. National Association of Anorexia Nervosa and Said Brinda N. Kalro, M.D., in a 2003 article in Associated Disorders Endocrinology and Metabolism Clinics, “With the avail- P.O. Box 7 ability of ovulation-inducing agents, there is a pos- Highland Park, IL 60035 sibility that thyroid disorders may be overlooked in (847) 831-3438 women presenting with menstrual irregularities http://www.anad.org and anovulation. Pregnancy in women with overt Becker, Anne E., M.D., et al. “Eating Disorders.” New thyroid disease is uncommon, but when it does England Journal of Medicine 340, no. 14 (April 8, 1999): occur, it can be fraught with complications and 1,092–1,098. have grave consequences. Therefore, evaluation of Colton, Patricia A., et al. “Eating Disturbances in Young the thyroid axis in women presenting with thyroid Women with Type 1 Diabetes Mellitus: Mechanisms problems is imperative.” and Consequences.” Psychiatric Annals 29, no. 4 (April Successful diagnosis and treatment of the under- 1, 1999): 213–218. lying disease may resolve a woman’s anovulation. If 30 anovulation the cause cannot be determined, sometimes ovula- that metformin is not approved by the Food and tion can be stimulated with fertility drugs. These Drug Administration (FDA) for treating PCOS as of drugs should be administered and monitored by a this writing. Many times the changes that occur physician who is experienced in treating women with insulin resistance after taking this drug will with infertility. cause ovulation to occur in the first month of treatment. As added benefits, metformin can also lead Diagnosis of Anovulation to weight loss, decrease the risk of diabetes, Before diagnosing a patient with anovulation, the decrease the woman’s triglyceride levels, and also physician takes a thorough medical history and diminish the androgen levels and help ameliorate gives the patient a physical examination, including any hirsutism that is present. a pelvic examination. In addition, the physician If metformin fails to resolve infertility, an estrogen orders tests of the woman’s hormone levels, such therapy, such as clomiphene citrate, can be utilized. as luteinizing hormone (LH), FOLLICLE-STIMULATING This medication stimulates FSH secretion and leads to HORMONE (FSH), ESTRADIOL, progesterone, PRO- ovulation in about 75 percent of patients, according LACTIN, and thyroid hormones. to Stephen Franks in his 2003 article for Endocrinology The woman’s basal body temperature (her tem- and Metabolism Clinics of North America. If this treat- perature immediately upon arising in the morning) ment does not work, ovulation may be successfully may also be measured to determine if ovulation is induced with gonadatropin medications. occurring, as there is an increase of 0.5–1.0 degree Patients may also be given injections of human Fahrenheit in body temperature during ovulation. menopausal gonadotropin (HMG). Ultrasound However, most physicians consider it more accu- scans and measurements of estradiol will then rate and simpler to measure hormonal changes in reveal if a follicle is produced. If not, the dosage of the woman’s blood and/or urine than to rely upon the HMG is often increased and the doctor will the woman’s basal temperature. An ultrasound continue to monitor the patient. scan may also show the presence or lack of a devel- When a dominant follicle is identified, the HMG oping follicle that precedes ovulation. is stopped and the patient is given one intramuscular injection of human chorionic gonadatropin PCOS and Anovulation (HCG) in order to trigger her ovulation. If this treat- According to experts, although PCOS is the most ment is not effective at causing ovulation to occur, common cause of anovulation, why anovulation HMG is given again in order to create follicles. occurs with this endocrine disorder is unknown. Sometimes surgery is used to treat infertile What is known is that women with PCOS and women with PCOS, particularly women who are anovulation present with normal serum FSH levels resistant to clomiphene. Such women receive a and elevated LH levels. Usually there is also evi- laparoscopic ovarian diathermy. Patients may find this procedure preferable to multiple injections. dence of hyperandrogenism leading to HIRSUTISM See also FEMALE REPRODUCTION; THYROID BLOOD (excess body hair within areas where women typi- TESTS. cally do not have hair but men do, such as on the face and chest). In addition, the patient usually Barbieri, R. L. “Metformin for the Treatment of Polycystic does not menstruate (amenorrhea) or has infre- Ovary Syndrome.” Obstetrics & Gynecology 101, no. 4 quent menstrual periods (oligomenorrhea). The (2003): 785–793. woman’s ovaries may be found to be polycystic Franks, Stephen, M.D. “Assessment and Management of (with multiple cysts) on an ultrasound. Anovulatory Infertility in Polycystic Ovary Syndrome.” In vitro fertilization, a procedure to create an Endocrinology and Metabolism Clinics of North America 32, embryo outside the womb, is generally not the first no. 3 (2003): 639–651. line of treatment for women with PCOS who wish Kalro, Brinda N., M.D. “Impaired Fertility Caused by to become pregnant. Instead, the antidiabetes drug Endocrine Dysfunction in Women.” Endocrinology and metformin is generally the first therapy used for Metabolism Clinics of North America 32, no. 3 (2003): infertility/anovulation if PCOS is suspected. Note 573–592. atherosclerosis/arteriosclerosis 31 antibodies Proteins that are synthesized mainly Individuals with high levels of apolipoprotein B by B lymphocytes. Antibodies are also known as may face a greater risk of suffering from coronary immunoglobulins. There are five different classes heart disease since apo B is the primary protein of antibodies, including IgG, IgA, IgD, IgE, and IgM. within LDL cholesterol. In contrast, apolipoprotein The immune system creates immunoglobulins to E is associated with LDL cholesterol. fight off foreign invaders, such as bacteria and See also CHOLESTEROL; HYPERLIPIDEMIA. viruses. Many of the known autoimmune conditions seen in endocrinology are caused by an immunoglobulin-mediated attack, which then Asherman’s syndrome Secondary amenorrhea leads to the damage and destruction of an organ. (cessation of menstruation) caused by damage to HASHIMOTO’S THYROIDITIS is an example of an and scarring of the endometrium. It is not a autoimmune disease. With Hashimoto’s thyroiditis, reversible condition. Typically, Asherman’s syn- antibodies to thyroid protein, which are known as drome is caused by a postpartum hemorrhage peroxidase, are created. They gradually destroy the (heavy bleeding) and an overzealous dilation and thyroid gland, leading to HYPOTHYROIDISM. Often T curettage (D and C) procedure. Asherman’s syn- lymphocytes also participate in the destructive drome can also occur after an instrumentation of autoimmune process, exacerbating it even further. the uterus that leads to infection or inflammation. The diagnosis of Asherman’s syndrome is confirmed by an ULTRASOUND that fails to reveal any uterine lining stripe as well as by a failure of the Particles that circulate through- apolipoproteins patient to have a withdrawal bleed after the admin- out the body carrying blood, fats, or lipids. istration of progesterone hormone. The lack of lining Cholesterol and triglycerides are insoluble in plas- and the scarring of the uterus can also be visualized ma and thus must be transported. They circulate as and the diagnosis confirmed by a hysteroscopy, lipoproteins, which are combinations of phospho- which is an instrument scan into the uterus. lipids and apoproteins. The aproteins support the structure of these particles, making them soluble in Klein, S. M., and C. R. Carcia. “Asherman Syndrome: A the blood. They also activate enzymes critical for Critique and Current Review.” Fertility and Sterility 24, normal lipid metabolism and act as targets for no. 9 (1973): 722–735. receptors. They are recognized by the receptors on cells and thus can dock and be taken up into those cells for specific purposes. atherosclerosis/arteriosclerosis A complex There are five classes of lipoproteins. These pathological condition in which the body reshapes include chylomicra, high-density lipoproteins and also damages the surface of the blood vessels as (HDL), intermediate-density lipoproteins (IDL), a direct consequence of various interactive meta- low-density lipoproteins (LDL), and very low- bolic processes that involve lipids (fats), white density lipoproteins (VLDL). blood cells, antibodies, platelets, and other hor- As of this writing, researchers have identified at mones and proteins. The current theory about least nine types of apolipoproteins. These what causes atherosclerosis is that most atheroscle- apolipoproteins can be measured and may repre- rosis is a product of an inflammation of the sent surrogate measurements for lipid levels. If endothelium (the lining of blood vessels that comes apolipoprotein (apo) B levels are elevated, typical- into direct contact with circulating blood). This ly LDL levels are elevated. If apo A-I levels are inflammatory process is ongoing and may progress high, usually the HDL is high. At this time, they are and regress, depending upon the local conditions to mainly used as research tools to study how the which the endothelium is exposed. body metabolizes these lipids and to help in design- If the damaging process to the vessel continues, ing medical therapies to improve lipid levels and the blood vessel may become occluded (blocked). decrease the risk of ATHEROSCLEROSIS. However, more frequently, plaque accumulates 32 atherosclerosis/arteriosclerosis from within the endothelium and finally ruptures • Hypertension into the lumen of the blood vessel, exposing lipids • An age of 65 and older (the risk for atheroscle- and other proteins directly into the bloodstream. rosis increases with age) This sets off a massive cascade of events that per- • Lack of exercise petuates the problem locally. The body harnesses the white blood cells, proteins, hormones, inter- • Insulin resistance syndrome leukins (hormones made by the white blood cells), • A family history of atherosclerosis and the platelets, ultimately creating an occlusive blood clot (thrombus). Diagnosis and Treatment This clot results in even more blocking of blood Atherosclerosis is diagnosed by a physician taking a flow and also prevents sufficient oxygen from complete medical history and doing a physical reaching the affected organ. Depending on the exam. The physician will note any history of prior severity of the blood flow blockage, atherosclerosis heart attack, stroke, positive family history of ath- may lead to a heart attack, stroke, or other serious erosclerosis, symptoms suggesting angina, transient medical problems. ischemic attack (TIA) (a ministroke), or claudifica- Experts now know that most myocardial infarction. During the physical examination, the doctor tions (heart attacks) occur in blood vessels that are will check for the absence of pulses, presence of only initially less than 50 percent blocked but, bruises, and tobacco-stained fingers and teeth. because of less stable caps on the vessel’s lining, are These may suggest the presence of atherosclerosis. much more likely to rupture. In contrast, vessels The doctor will also order laboratory tests to that have not yet ruptured but have progressed to measure factors that contribute to the development 80–99 percent occlusion have thick, fibrous cover- of atherosclerosis, such as lipids, glucose, kidney ings which, although they limit blood flow, are function, C-reactive protein (CRP), homocysteine, much less likely to rupture and lead to a complete and lipoprotein a (Lp a). Individuals who already occlusion. In addition, as the condition has typical- have atherosclerosis need treatment, usually in the ly progressed slowly, the tissue that is endangered form of medications that improve their lipid pro- has often had sufficient time to develop collateral files, lower their blood pressure, normalize their blood vessels upon which to rely. These are vessels glucose, and make their platelets less sticky. Some that have bypassed the diseased area and, thus, individuals may respond well to taking very low help the organ—and the patient—to survive. doses (81 mg) of aspirin, such as a baby aspirin, each day. Risk Factors Most physicians treating patients with athero- Risk factors for atherosclerosis, include the following: sclerosis also recommend lifestyle changes. These include stopping smoking, increasing the daily • High levels of “bad” cholesterol (low-density intake of fiber, obtaining at least minimal exercise lipoproteins) every day, such as walking (30 minutes, five times • Low levels of “good” cholesterol (high-density per week), and following a heart-healthy nutri- lipoproteins) tional plan. • Obesity See also CHOLESTEROL. •DIABETES MELLITUS B

basal-bolus therapy The concept of treating DIA- Many patients are now able to receive their bis- BETES MELLITUS with INSULIN by using a combination phosphonate doses weekly due to the long half- of a long-acting (NPH/Lente/Ultra Lente) or very lives of the newer medications. (The medications long-acting (glargine) insulin with rapid-acting remain in the bone for a long time.) Typically, bis- (aspart, lyspo) insulin in order to mimic the normal phosphonates are all poorly absorbed and must be mode of insulin secretion in the pancreas. The basal taken on an empty stomach with water only (not insulin is given once or twice a day to shut off pro- coffee, tea, juice, or any fluids other than water). duction of excess glucose from the liver, while the Patients must then remain upright for at least one bolus insulin is given to help metabolize the calo- hour, because these compounds can irritate the ries (mainly carbohydrates) that are consumed esophagus and cause inflammation (esophagitis) or with each meal or snack. This technique allows for ulceration if they reflux from the stomach into the very tight control of blood glucose levels and esophagus. enables patients to vary the times and types of their Newer bisphosphonates can also be given intra- meals. venously. The only indication for this treatment This therapy is also done with insulin pump currently approved by the Food and Drug therapy, where one or more basal rates are prepro- Administration is for humoral hypercalcemia of grammed, to allow the pump to deliver small malignancy and bone pain due to metastases. amounts of insulin continuously for 24 hours. The As of this writing, researchers are trying to patient “plugs in” boluses for each meal or snack, develop bisphosphonates that can be given only depending upon the glucose level, anticipated car- once per year for the treatment of osteoporosis. bohydrate intake and activity levels. For pump See also HYPERCALCEMIA; OSTEOBLASTS. patients, only short-acting insulin is used. Fleisch, Herbert. “Bisphosphonates: Mechanisms of Action.” Endocrine Reviews 19, no. 1 (1998): 80–100. bisphosphonates Drugs used to treat patients with OSTEOPOROSIS,PAGET’S DISEASE, humoral blood pressure/hypertension Blood pressure is a hypercalcemia of malignancy, and disorders of dys- measure of diastolic and systolic pressure as exert- trophic bone deposition. Bisphosphonates are pared upon the walls of the blood vessels and arteries. ticularly effective at inhibiting the action of OSTEO- Blood pressure may be temporarily elevated during CLASTS, the cells that break down bone. They have sickness or times of stress, or it may be temporarily also been used to treat patients with cancer that lowered. Hypertension refers to chronically high has metastasized (spread) to the bones leading to levels of blood pressure. It is defined as a systolic bone pain and/or hypercalcemia. Some examples pressure (the upper number in the measurement of of bisphosphonate medications are etidronate blood pressure) of 140 mm Hg or higher and a dias- (Didronel), alendronate (Fosamax), risedronate tolic pressure (the lower number) of 90 mm Hg or (Actonel), zoledronate (Zometa), tiludronate greater. About 50 million people in the United (Skelid), and pamidronate (Aredia). States are hypertensive. Hypertension is most com-

33 34 blood pressure/hypertension mon among African Americans and individuals age CLASSIFICATION AND MANAGEMENT OF 65 years and older. The Pima Indians of Arizona BLOOD PRESSURE FOR ADULTS have the highest rates of hypertension in the world. Category Systolic (mm Hg) Diastolic (mm Hg)

New Category of Prehypertension Normal Less than 120 and Less than 80 Prehypertension 120–139 or 80–89 In 2003, the National Heart, Lung, and Blood Stage 1 hypertension 140–159 or 90–99 Institute released new hypertension guidelines that Stage 2 hypertension More than 160 or More than 100 included a new prehypertension category of Source: National Heart, Lung, and Blood Institute. “JNC 7 Express: The patients. It includes individuals with systolic blood Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.” pressures between 120 and 139 and diastolic blood National Institutes of Health, National Heart, Lung, and Blood pressures between 80 and 89. Although prehyper- Institute, National High Blood Pressure Education Program, NIH Publication No. 03-5233, May 2003. tension is not a disease state, patients whose blood pressure falls within this range should be carefully watched by their physicians. In addition, if they Diagnosis of Hypertension have specific additional medical problems, such as Blood pressure is measured with a cuff device after DIABETES MELLITUS, chronic kidney disease, or a pre- the patient has been sitting quietly for at least five vious history of heart attack, or if they are at high minutes in a chair. Hypertension is best diagnosed risk for coronary heart disease or recurrent stroke, by medical staff, such as the nurse or the doctor, these particular prehypertensive patients should rather than by patients themselves using home also be given antihypertensive medications. devices. At least two measurements of a patient’s blood pressure should be taken to ensure accuracy. Causes of Hypertension Individuals who are smaller or larger than most Hypertension is a medical problem accompanying adults should be tested with a pressure device that many endocrine diseases, such as HYPERPARATHY- is suitable to their size and that can cover at least ROIDISM, ACROMEGALY,CUSHING’S SYNDROME, diabetes 80 percent of the patient’s arm. Once hypertension mellitus, HYPERTHYROIDISM, PHEOCHROMOCYTOMA, has been established, home monitoring of blood DIABETIC NEPHROPATHY, and ALDOSTERONISM. Other pressure may help patients to track their own blood causes of high blood pressure include obstructive pressure levels and enable them to report any dra- sleep apnea, kidney disease, and heart disease. In matic increases to their physicians. most cases, hypertension is treated with recom- Laboratory tests can provide further information mendations for therapeutic lifestyle changes, such about hypertension. Doctors generally order a uri- as appropriate nutrition, weight loss, exercise, and nalysis as well as blood tests that measure complete stress management as well as medications. Rarely, blood count, serum electrolytes (especially sodium hypertension can be cured, such as when the cause and potassium), blood urea nitrogen (BUN) levels, is aldosteronism or pheochromocytoma, conditions calcium blood levels, creatinine, glucose levels, and that can be resolved with surgery known as an plasma lipid levels. The patient’s urine may also be ADRENALECTOMY. checked for albumin excretion, and an electrocar- Sometimes medication causes hypertension. For diogram may be ordered as well. example, ORAL CONTRACEPTIVES may raise an individual’s blood pressure to hypertensive levels. They Treatment of Hypertension often do so by increasing the synthesis of angio- Most physicians treat hypertension by helping tensinogen in the liver, which is converted to bring down the patient’s systolic pressure. For most angiotensin, a potent vasoconstrictor on its own, patients, once their systolic pressure has dropped, and which will also stimulate the adrenal glands to their diastolic pressure will fall as well. If hyperten- synthesize excess aldosterone, leading to further sion is caused by or related to a medical problem, vasoconstriction and salt and water retention. successful treatment of that medical problem Smoking also exacerbates the risk for hypertension. should improve the patient’s hypertension. blood sugar 35

Weight loss among obese individuals should has been, as well as other factors, such as whether improve or even normalize high blood pressure. the patient has another serious coexisting illness Hypertension can also be treated with improvements such as diabetes. The patient’s serum creatinine in diet; increasing the intake of fruits and vegetables and potassium levels should be checked at least can lower blood pressure in many individuals. Highly once or twice each year. salted foods should be avoided. Foods rich in potassi- In general, if blood pressure goals have been um, such as bananas, should generally be consumed. reached, patients may be followed up at three- to Some medications reduce potassium levels, making it six-month intervals. However, patients with dia- even more important that patients eat a diet that is betes or heart disease may need more frequent vis- rich in potassium. Some patients will also need to its with their physicians. take supplemental potassium. See also ATHEROSCLEROSIS/ARTERIOSCLEROSIS; Patients who smoke should be advised to stop CHOLESTEROL; HYPOTENSION; ORTHOSTATIC HYPOTEN- smoking immediately to improve their blood pres- SION; TYPE 1 DIABETES; TYPE 2 DIABETES. sure levels. Patients who drink alcohol should August, Phyllis, M.D. “Initial Treatment of sharply curtail drinking or avoid alcohol altogether. Hypertension.” New England Journal of Medicine 348, Male hypertensive patients should consume no no. 7 (2003): 610–617. more than two drinks per day and females and other individuals of lighter weight should limit their consumption to a maximum of one drink per day. blood sugar Refers to glucose, although other Regular exercise is another important lifestyle forms of sugar can be found in the bloodstream. component of keeping hypertension within con- Blood sugar can be measured by drawing a sample trol. Even taking a brisk walk for 30 minutes on of blood from a patient’s vein. It is now often most days of the week can be sufficient to improve measured immediately in the doctor’s office, using health for many hypertensive patients. Some exer- a glucose monitor and a small sample (one to 10 cises, however, should be avoided, such as heavy microliters) that is taken from a fingertip or the weight lifting or exercises that would tend to raise forearm. The presence of unusually high levels of the patient’s blood pressure. blood sugar is referred to as HYPERGLYCEMIA, while Many people with high blood pressure need two unusually low levels indicate HYPOGLYCEMIA. or more medications to keep their blood pressure at People with sustained levels of hyperglycemia (a an acceptable level. Many studies have shown that fasting glucose that is greater than 126 mg/dl on the average patient with hypertension requires 3.5 two occasions, or a random glucose level that is drugs per day to normalize blood pressure. Many greater than 200 mg/d, or an abnormal glucose tol- different types of medications may be prescribed to erance test) are diagnosed with DIABETES MELLITUS, patients with hypertension, including thiazide-based typically either TYPE 1 DIABETES or TYPE 2 DIABETES.If diuretics, beta-blockers, angiotensin-converting the patient’s levels of blood sugar are above normal enzyme (ACE) inhibitors, calcium channel antago- but not high enough for a diagnosis of diabetes, he nists, alpha-blockers, and angiotensin-receptor or she may be diagnosed with PREDIABETES. antagonists. Each type of drug has its own indica- Individuals both with and without diabetes can tions, contraindications, and side effects. have hypoglycemia. This condition is typically defined as a glucose level less than 55 mg/dl along Follow-ups on Patients with Hypertension with the appropriate signs and symptoms of hypo- Once hypertension has been diagnosed, regular glycemia. follow-ups with a physician are essential. The tim- Patients with prediabetes must work to get this ing of the medical follow-ups (weekly, biweekly, high blood sugar problem under control with a monthly, or on some other schedule) is up to the proper nutrition plan and exercise. They are at risk individual doctor. It usually depends on how for developing diabetes. This is especially true if severe the hypertension is, how effective treatment there is a family history of diabetes. 36 body mass index

People with diabetes must maintain a glucose betes and/or hypertension, may also be candidates level that is as close to normal as possible. for weight loss surgery. Numerous major studies have proven that keeping See also ANOREXIA NERVOSA;CUSHING’S SYN- blood sugar close to normal will greatly reduce the DROME/CUSHING’S DISEASE; EATING DISORDERS; GASTRIC risk for many complications of diabetes, such as SURGERY FOR WEIGHT LOSS; OBESITY;PRADER-WILLI SYN- DIABETIC NEPHROPATHY, DIABETIC NEUROPATHY, and DROME. DIABETIC RETINOPATHY. National Institutes of Health. “The Practical Guide: See also IMPAIRED GLUCOSE TOLERANCE. Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.” National Heart, Lung and Blood Institute, NIH Publication No. body mass index (BMI) A specific formula based 00–4084, October 2000. on an individual’s height and weight that helps to determine whether a person is underweight, of optimal weight, overweight, obese, or severely bone age The age of a person based on the indi- obese. BMI is derived from a person’s weight in vidual’s skeletal maturity. Bone age is also known kilograms divided by the height in meters squared. as skeletal age. It is determined by taking X-rays of For patients with very small frames or with signifi- the hand and the wrist (usually the left hand/wrist cant muscle mass, the calculation does not give a of a child) and considering the size of the growth very accurate assessment. plates at the ends of the bones (the epiphyses). Since the mathematical formula is difficult for These bone shapes are then compared with stan- most people to calculate easily, tables have been cre- dards to determine bone age. Usually the Greulich ated that enable patients to use their height in inch- and Pyle atlas of radiographic standards are used es and their weight in pounds to determine whether for a comparison basis. X-rays taken to determine they fit into the below-normal normal weight, over- an individual’s bone age can be easily misinterpret- weight, obese, or severely obese category. ed, however, and an experienced radiologist is cru- According to the National Heart, Lung, and cial to provide the correct interpretation. Blood Institute (NHLBI) of the National Institutes The bone age represents a percentage of the of Health, weight categories of BMI are as follows: adult age, and it can also be used to calculate a child’s growth potential. Delayed bone age can be Optimal weight: 21–24.9 caused by HYPOTHYROIDISM, a growth hormone defi- Overweight: 25.0–29.9 ciency, chronic illnesses, as well as other causes. Obese: 30–39.9 Sometimes physicians check the bone age in chil- Severely obese: 40.0 and greater dren whose actual age and birth date are known, such as in the case of adolescents who have a According to the Centers for Disease Control DELAYED PUBERTY or an EARLY PUBERTY or who have and Prevention (CDC), individuals with a BMI of experienced growth failure or delay. Sometimes the less than 18.5 are underweight. child’s age is not known, such as with some children Individuals with a BMI of 40 or greater are con- adopted from foreign orphanages. The bone age sidered to be potential candidates for surgical inter- information will help the physician determine vention with a gastric bypass procedure. Other whether further growth can be anticipated in a child. considerations for this procedure include the If the child’s long bones (at the epiphyses) have regional distribution of the fat. For example, people not yet fused, this is an indication that some poten- whose fat lies primarily around the waist area are tial for growth remains. Thus, if a child is age 12 or at greater risk for serious health problems than are older, is significantly shorter than normal for the people whose fat is primarily located in their hip child’s age, and has a bone age of 9.5 years, the area. Patients with a BMI of 35.0 who also have child still has significant growth potential. other serious illnesses (comorbidities), such as dia- Conversely, if a child is age 17 and has a bone age breast-feeding 37 of 18 years, the epiphyses are closed and the child differences in bone mineral density if even slightly has no further potential for growth in height. different areas of a bone are being measured. If a child has short stature and has growth hor- Bone mass density can also be tested using what mone deficiency, physicians may decide that is called quantitative computerized tomography growth hormone can be prescribed as long as the (QCT) scanning and can be estimated with forms of epiphyses are not yet fused. ultrasound. However, this technique is primarily See also GROWTH HORMONE. used for screening as opposed to making serial measurements. Low bone mass density is computed at 2.5 standard deviations versus the peak bone mass seen in bone diseases Illnesses that cause an underpro- a person of the same sex between the ages of 20–30 duction of bone mass, such as osteoporosis, an years old. This is known as the T-score. Another overproduction of bone, such as PAGET’S DISEASE measure, the Z-score, compares a patient’s bone and ACROMEGALY, or abnormal bone, seen to vary- density with an age-matched control. ing extents in OSTEOPOROSIS, fibrous dysplasia, and Low bone density is known as OSTEOPOROSIS. Paget’s disease. Disorders of bone may be induced Individuals with osteoporosis are at risk for devel- by nonendocrine causes, such as cancer, infection, oping serious fractures, particularly fractures of the vitamin deficiency, disorders of cartilage produc- hip. Sometimes patients have a bone mass density tion, and genetic defects. that is not sufficiently low to merit a diagnosis of Bone density can be measured using a variety of osteoporosis but that may be low enough to fit the techniques, most commonly with the dual-energy criteria for OSTEOPENIA. Patients with osteopenia X-ray absorptiometry scan (DEXA SCAN). Bone biop- also need to work to improve their bone density so sies are helpful in some cases. Blood and urine tests that their condition does not further deteriorate to can help to determine the activities of the major the level of osteoporosis. cells within the bone, namely, the osteoclasts, See also BONE AGE; CALCIUM BALANCE. which help to break down the bone, and the osteoblasts, which help to create the new bone. See also CALCIUM BALANCE; OSTEOBLASTS; OSTEO- breast-feeding Providing nutrition to newborns, CLASTS; OSTEOMALACIA; OSTEOPENIA; OSTEOPOROSIS; older infants, and sometimes toddlers through milk RICKETS. produced by a woman’s breasts. Breast-feeding is also known as lactation. Breast-feeding is strongly encouraged in the United States and other coun- bone mass measurement A test to determine the tries as a positive and nutritious way to feed a baby. density of bone mass. In most cases, bone mass is Some studies have indicated that women with measured with a dual-energy X-ray absorptiometry HYPOCALCEMIA (below-normal levels of calcium in (DEXA) scan. Typically, bone measurements are their blood) may actually show improvement in made in the spine and the hip, but they can also be this condition during pregnancy and lactation, taken in other areas of the body. With primary largely because of the production of PROLACTIN,a hyperparathyroidism, cortical bone is lost prior to hormone linked to pregnancy, childbirth, and trabecular bone. Thus bone density is also meas- breast-feeding. Some women who were hypocal- ured at the wrist, where there is a greater prepon- cemic may even become temporarily hypercal- derance of cortical bone. cemic while breast-feeding, as may some women An experienced clinician is needed to interpret with previously normal calcium blood levels. these X-rays, because osteoarthritis can falsely ele- A very small number of women, however, such vate readings, especially in the spine. Positioning as women with DIABETES MELLITUS who have prolif- the patient for the scan is critical, especially if serial erative retinopathy (an eye disease that may cause data are being compared, as there can be significant blindness), should consider refraining from breast- 38 bromocriptine feeding their babies. The act of breast-feeding can bromocriptine (Parlodel) A medication that worsen their retinopathy. Physicians have also dis- increases dopamine secretion in the brain and can couraged breast-feeding among women being treat- be used to treat patients with hyperprolactinemia ed for hyperthyroidism, although this view is (whether it is associated with a pituitary tumor or moderating. A recent report in the Journal of Clinical not) and ACROMEGALY. Bromocriptine is a Endocrinology & Metabolism, which studied 51 infants dopamine agonist. This means that it is a medica- who were nursed by mothers taking methimazole tion that increases the amount of dopamine in the (Tapazole), an antithyroid drug, revealed that the brain and thus inhibits prolactin secretion from the babies had normal THYROID-STIMULATING HORMONE pituitary gland. It can cause some patients to expe- (TSH) levels as well as other normal thyroid levels. rience significant nausea. Therefore the medication The children’s intellectual development, at 48 and must be started at very low doses and slowly 74 months, was normal as well. increased in order to obtain the appropriate clinical See also HYPERCALCEMIA; INFANTS; POSTPARTUM and biochemical response in the patient. THYROID DISEASE; PREGNANCY. Bromocriptine is usually given once per day. For further information on breast-feeding, con- CABERGOLINE (Dostinex) is usually used as the tact: second-line drug in the treatment of hyperprolactinemia. It causes less nausea than bromocrip- La Leche League International tine, and it can often be dosed only one or two 1400 North Meacham Road times per week. Pergolide (Permax) is another Schaumburg, IL 60173–4840 medication used to treat patients with hyperpro- (847) 519-7730 lactinemia. http://www.lalecheleague.org

Azizi, F., et al. “Thyroid Function and Intellectual Development of Infants Nursed by Mothers Taking Methimazole.” Journal of Clinical Endocrinology & Metabolism 85 (2000) no. 9: 3,233–3,238. C cabergoline (Dostinex) A medication used to treat severity of cachexia in these illnesses is often the patients with hyperprolactinema and, on occasion, primary determining factor in both quality of life those with ACROMEGALY. In the treatment of hyper- and eventual mortality.” prolactinemia, which is mainly caused by microadenomas of the pituitary gland, cabergoline causes less Signs and Symptoms nausea than BROMOCRIPTINE (Parlodel) and needs to The primary indicators of cachexia include: be dosed only one or two times per week. Cabergoline works by increasing the amount of • Severe fatigue dopamine in the brain and thus decreasing the • Lack of appetite (anorexia, not to be confused secretion of PROLACTIN. Similar drugs, such as per- with anorexia nervosa) golide (Permax) and bromocriptine have been suc- • A weight loss of as much as 10 percent of body cessful in improving the quality of life of many weight or more patients with hyperprolactinemia and acromegaly. • Severe weakness cachexia A state of abnormal metabolism causing a wasting away of the body’s muscle mass as Diagnosis and Treatment well as body weight. It generally occurs due to an The diagnosis is made based on the patient’s cur- inadequate intake of nutrition to meet the body’s rent weight compared with the recent past weight. metabolic needs. It may also be caused by the Patients in a state of cachexia are often treated with increased stress on the body from an illness, which small, frequent, high-fat meals; nutritional supple- then results in increased metabolic needs that the ments; and drugs, such as megestrol acetate or body is unable to meet. Some elderly patients fail cyproheptadine, to stimulate the appetite. In a to eat enough food to meet their nutritional needs. study reported in a 2003 issue of Gut, the Cachexia is found in severely ill patients with researchers studied 200 patients with pancreatic such diseases as cancer, acquired immune deficien- cancer who had cachexia. They found that omega- cy syndrome (AIDS), rheumatoid arthritis, and 3 fatty acid supplements increased lean body mass other very serious illnesses and medical conditions. and appetite in these patients. The researchers also Some untreated endocrine disorders can lead to noted that the subjects’ weight gain also improved cachexia. These include HYPERTHYROIDISM (of any their quality of life. cause), ADDISON’S DISEASE, and CUSHING’S SYN- Elderly patients are often afflicted with cachex- DROME caused by the ectopic secretion of excess ia. According to an article in a 1999 issue of The adrenocorticotropic hormone (ACTH), typically American Journal of Clinical Nutrition, cachexia is caused by a malignant tumor. associated with above-normal levels of proinflam- It is important for physicians to treat cachexia matory cytokines, such as tumor necrosis factor- because for some patients, treatment may mean alpha, interleukin, serotonin, and interferon. Said the difference between life and death. Said authors the authors, “Reduction in the concentrations of Daniel L. Marks and Roger D. Cone, in their 2001 these cytokines is associated with weight gain.” article in Recent Progress in Hormone Research, “The They stated that drugs that stimulate appetite and 39 40 calcitonin weight gain in geriatric patients, such as progesta- other forms. However, it is absorbed more slowly tional agents, pentoxifylline, cyproheptadine, and and less efficiently, and thus larger amounts are thalidomide, may decrease cytokine levels and thus required. Some patients are given calcitonin in increase appetite and weight. combination with HORMONE REPLACEMENT THERAPY, which has been found to increase the bone density Fearon, K. C. H., et al. “Effect of a Protein and Energy in some patients significantly. Calcitonin may also Dense N-3 Fatty Acid Enriched Oral Supplement on be injected subcutaneously or intramuscularly. Loss of Weight and Lean Tissue in Cancer Cachexia: A Some patients may be allergic to the salmon- Randomised Double Blind Trial.” Gut 52, no. 10 derived form of calcitonin, although this reaction (2003): 1,479–1,486. can also be seen with recombinant human calci- Marks, Daniel L., and Roger D. Cone. “Central tonin. Calcitonin may also cause such side effects as Melanocortins and the Regulation of Weight During flushing, nausea, and diarrhea, although these Acute and Chronic Disease.” Recent Progress in Hormone effects are not common, and when they appear, are Research 56, (2001): 359–376. often short-lived. In contrast, due to the large Yeh, Shing-Shing, and Michael W. Schuster. “Geriatric amounts of endogenous calcitonin secreted by Cachexia: The Role of Cytokines.” American Journal for patients with medullary carcinoma of the thyroid Clinical Nutrition 70, no. 2 (August 1999): 183–197. (MCT), these symptoms may be severe. Some studies have shown that calcitonin also has an analgesic (pain-killing) effect on patients who calcitonin A hormone produced by the parafol- have acute bone fractures. Most of this data has been licular c cells of the thyroid gland. The exact phys- accumulated by studying the injectable form of calci- iological reasons for the existence of calcitonin are tonin. However, the inhaled nasal spray has also unclear. However, it is known that calcitonin is been utilized. In one study, the nasal spray was found involved with calcium and bone metabolism as to be more effective than the injectable calcitonin. well as in breast milk letdown and lactation. Controversy remains about whether either the Calcitonin may be secreted in large quantities in nasal spray or the injected calcitonin is effective in patients who have a rare form of THYROID CANCER: treating the pain of fractures and, if so, which is medullary carcinoma of the thyroid (MCT). As a superior. Neither preparation is approved by the result, the measurement of calcitonin in the blood- Food and Drug Administration (FDA) for the treat- stream can be used to help diagnose and monitor ment of bone pain caused by FRACTURE, but this form of thyroid cancer. endocrinologists have found it to be useful. Injectable, synthetically derived calcitonin may See also BISPHOSPHONATES; CALCIUM BALANCE. be used to treat already diagnosed OSTEOPOROSIS. It was first approved for this purpose by the Food and Lyritis, G. P., et al. “Analgesic Effects of Salmon Drug Administration (FDA) in 1984. (Calcitonin is Calcitonin in Osteoporotic Vertebral Fractures: A not, however, approved for the prevention of Double-Blind Placebo Controlled Case Study.” osteoporosis.) Both nasal calcitonin (Miacalcin) Calcification Tissue International 49, no. 6 (December and injectable calcitonin (Calcimar) are FDA- 1991): 369–372. approved to treat postmenopausal osteoporosis. Overgaard, K., et. al. “Effect of Salcatonin Given Calcitonin may also be used to treat PAGET’ DIS- Intranasally on Bone Loss and Fracture Rates in EASE and the HYPERCALCEMIA caused by malignant Established Osteoporosis.” British Medical Journal 305, tumors (humoral hypercalcemia of malignancy, or no. 6,853 (September 5, 1992): 556–561. HHM). With Paget’s disease, due to the need for long- Overgaard, K., et. al. “Effect of Salcatonin Given term usage, the calcitonin may lose its efficacy Intranasally on Early Postmenopausal Bone Loss.” because of the formation of antibodies that bind to it. British Medical Journal 299, no. 6,697 (August 19, Most patients use calcitonin in the form of a 1989): 477–479. nasal spray and find using the nasal calcitonin Silverman, Stuart L., M.D. “Calcitonin.” Endocrinology and (Miacalcin) to be more attractive than using the Metabolism Clinics of North America 32 (2003): 273–284. calcium balance 41 calcitriol Synthetic vitamin D that is prescribed as those found in ORAL CONTRACEPTIVES or in ESTRO- for people with a calcium deficiency/HYPOCAL- GEN REPLACEMENT THERAPY. CEMIA. Most commonly, these are patients who If patients who take calcium supplements need have either kidney failure or HYPOPARATHYROIDISM. a short-term increase in their calcium absorption, Calcitriol increases the absorption of calcium from they may wish to spread out their intake of calcium the gut into the blood. It is commercially available supplements throughout the day. They should take as Rocaltrol in 25- and 50-microgram capsules. the calcium supplement with their meals and avoid Generic formulations of calcitriol are also available taking it along with foods that are high in oxalate, to patients. such as spinach or nuts, or that are high in phy- Because it is the most potent and longest-acting tates, such as wheat bran or soybeans. vitamin D metabolite available, calcitriol can also The most commonly used forms of calcium sup- easily lead to HYPERCALCEMIA (excessively high lev- plements are oyster shell calcium or calcium car- els of calcium in the blood) and to hypercalciuria bonate. Other forms of calcium, such as calcium (excessive levels of calcium in the urine) among citrate, maltase, and glaciate, can be used, although patients who take the medication. Thus, calcitriol they are usually more expensive. Calcium lactate is should be used judiciously by physicians, with reg- another form of calcium, but it is often difficult to ular monitoring of a patient’s blood calcium levels. obtain. See also CALCIUM ABSORPTION; CALCIUM BALANCE; See also CALCIUM BALANCE; HYPERCALCEMIA; VITAMIN D; VITAMIN D RESISTANCE. HYPOCALCEMIA; HYPOPARATHYROIDISM; PARATHYROID GLANDS.

Levenson, David I., M.D., and Kevin Al Ohayon. “A calcium absorption The continuing process by Practical Analysis of Calcium Supplements.” which calcium is absorbed, usually in the intes- Alternative Therapies in Women’s Health Archives 2 (April tines. Calcium absorption is monitored by physi- 1, 2000): 28–31. cians by measuring the amount of calcium found in the urine over a period of 24 hours. A normal level that indicates good absorption and generally ade- calcium balance Refers to the processes involving quate vitamin D levels is between 2 and 4 the gut (absorption), kidneys (filtering and reab- mg/kg/day. sorption as well as vitamin D metabolism), Calcium absorption in the intestines is primarily parathyroid glands (the four glands in the neck, driven by VITAMIN D. Thus, deficiencies of vitamin D by the thyroid gland), and bone (where calcium is lead to poor calcium absorption, a decreased serum stored and used for structural integrity). Among calcium (calcium in the blood), and a rise in parathy- other functions, calcium is needed for muscle roid hormone (PTH) levels. This increased PTH helps contractions, to activate nerves, and to cause to decrease the loss of calcium from the kidneys, and blood to clot. Some experts believe that insuffi- it also helps to move some calcium from the bone cient calcium in childhood and adolescence may back into the bloodstream. Typically, 40–50 percent contribute to the development of OSTEOPOROSIS in of ingested calcium is absorbed, but a large portion of later adulthood. absorbed calcium is lost via intestinal secretion. Although many people are mildly or moderate- Medications may also affect calcium absorption. ly deficient in calcium, elderly adults (age 65 and Some antibiotics, such as penicillin and chloram- older) and adolescents are the most likely to have phenicol, may increase calcium absorption. Factors below-normal levels of calcium (hypocalcemia) in that decrease calcium absorption include high fiber their bloodstreams, primarily because of diets that in the diet, foods high in oxalic acid or phytic acid, are low in calcium and/or vitamin D. Others have an existing lactase deficiency, and some medica- excessive levels of calcium in the bloodstream. The tions. These medications include GLUCOCORTICOIDS, most common cause of excess calcium in the blood anticonvulsants, tetracycline, and estrogens, such is primary hyperparathyroidism. 42 Canadian Diabetes Association

Individuals who cannot gain sufficient calcium Provincial Offices: from their diets may take calcium supplements, usually in tablet form. In addition, prescribed vita- British Columbia–Yukon Division min D (CALCITRIOL) is usually given to such indi- 360-1385 West 8th Avenue viduals to boost their blood levels of calcium. Vancouver, BC V6H 3V9 According to a 2000 article in Alternative Therapies (604) 732-1331 or (800) 665-6526 (toll-free) in Women’s Health Archives, calcium carbonate is the most popular calcium supplement, followed by cal- Alberta/Northwest Territories Division cium citrate. Some patients take bonemeal to boost 1010-10117 Jasper Avenue NW their calcium levels, while others take dolomite, Edmonton, AB T5J 1W8 which is a combination of calcium carbonate and (780) 423-1232 or (800) 563-0032 (toll-free) magnesium carbonate. Saskatchewan Division Less popular means of increasing calcium intake 104-2301 Avenue C North include taking supplements of calcium lactate, calci- Saskatoon, SK S7L 5Z5 um gluconate, and calcium citrate malate. If intra- (306) 933-1238 or (800) 996-4446 (toll-free) venous calcium is needed, in the event of a medical emergency, calcium gluconate is usually used. Manitoba Division See also CALCIUM ABSORPTION; HYPERCALCEMIA; 102-310 Broadway Avenue HYPOCALCEMIA; HYPOPARATHYROIDISM. Winnepeg, MB R3C 0S6 Bove, Lisa Anne. “Restoring Electrolyte Balance: Calcium (204) 925-3800 or (800) 226-8464 (toll-free) & Phosphorus” 59, no. 3 RN (March 1996): 47–5l. Ontario Division Levenson, David I., M.D., and Kevin Al Ohayon. “A 15 Toronto Street Practical Analysis of Calcium Supplements.” Suite 800 Alternative Therapies in Women’s Health Archives 2 (April Toronto, ON M5C 2E3 1, 2000): 28–31. (416) 363-3373 or (800) 226-8464 (toll-free) Tordoff, Michael G. “Calcium: Taste, Intake, and Appetite.” Physiological Reviews 81, no. 4 (October 1, New Brunswick Division 2001): 1,567–1,597. 165 Regent Street Suite 3 Canadian Diabetes Association (Association Fredericton, NB E3B 7B4 Canadienne du Diabète) Formed in 1953, the (506) 452-9009 or (800) 884-4232 (toll-free) Canadian Diabetes Association is a nongovernmen- tal advocacy organization for research and educa- Nova Scotia Division tion that helps an estimated 2 million Canadians 6080 Young Street who have diabetes. It has 150 branches throughout #101 the country. The organization also funds research Halifax, NS B3K 5L2 through the Charles H. Best Research Fund. The (902) 453-4232 or (800) 326-7712 (toll-free) Canadian Diabetes Association estimates that by Prince Edward Island Division 2010, the number of Canadians with diabetes will Charlottetown Area Health Centre increase to 3 million. 1 Rochford Street National Office: Charlottetown, PEI C1A 9L2 (902) 894-3005 National Life Building 1400-522 University Avenue Newfoundland and Labrador Division Toronto, Ontario M56 2R5 354 Water Street (416) 363-0177 or (800) BANTING (toll-free in Suite 217 Canada) St. John’s, NF A1C 1C4 www.diabetes.ca (709) 754-0953 Carney complex 43

Affiliate: including reduced sex drive, impotence, hot flashes, mood swings, breast swelling, weight gain, and Association Diabète Québec (Quebec Diabetes loss of muscle mass. Though hormone therapy Association) eventually fails and men become hormone resist- 5635, Rue Sherbrooke Est ant, the therapy may be effective in extending their Montreal, PQ H1N 1A2 lives for years. (514) 259-3422 or (800) 361-3504 (toll-free num- See also OVARIAN CANCER; PANCREATIC CANCER; ber) PARATHYROID CANCER; PHEOCHROMOCYTOMAS; TESTIC- ULAR CANCER; THYROID CANCER. cancer A malignant tumor. Any organ within For further information on cancer, contact: the endocrine system (or within the entire body) American Cancer Society can develop a malignant tumor. Physicians who 1599 Clifton Road NE suspect a cancerous tumor will almost always per- Atlanta, GA 30329 form a biopsy, which is the removal of tissue from (404) 320-2408 or (800) 227-2345 (toll-free) the area that may be cancerous. A pathologist eval- http://www.cancer.org uates whether the tissue is actually cancerous. The cancer is then staged by the physician, National Cancer Institute which means that the severity of the cancer is eval- Division of Cancer Epidemiology and Genetics uated. Whether the cancer has spread to other 6120 Executive Boulevard, MSC-7242 parts of the body or to other organs is also deter- Executive Plaza South mined. Most physicians assess the stage of cancer 7th Floor using the TNM (tumor/node/metastasis) system, Bethesda, MD 20892 which varies somewhat depending on the form of (301) 496-1611 the cancer. Lange, Paul H., M.D., and Christine Adamec. Prostate When possible and if identified early enough, Cancer for Dummies. New York, N.Y.: Wiley Publishing, cancer is often surgically excised. If the tumor is 2003. not operable because it is too difficult to reach, is at an advanced stage of tumor, or for other reasons (such as the ill health of the patient), the patient Carney complex A rare condition, originally may be treated with radiation therapy, chemother- described by J. A. Carney in 1985. Carney complex apy, and other forms of treatment. Patients who is caused by a genetic mutation and is usually con- have advanced cancers may seek to join clinical tri- sidered a form of a multiple endocrine neoplasia als, in which they may be selected to test medica- (MEN) syndrome. Symptoms of Carney complex tions or therapies that are not available to the gen- include skin lesions, such as pigmented lentigines eral public. and blue nevi on the eyes, face, lips, neck, and Hormone therapy (also called endocrine therapy trunk, as well as endocrine tumors (adrenal, pitu- by the physicians who use it) is sometimes used to itary, testicular, and thyroid) and nonendocrine treat advanced cancer. For example, with prostate tumors (atrial, breast, and skin). cancer, oncologists may give men hormone med- Carney complex is considered a developmental ications to block the production of TESTOSTERONE. disorder, although it may not be diagnosed until The reason is that testosterone enhances cancer early adulthood. Men and women are about equal- growth, and thus, lower levels of testosterone will ly affected by this disorder, and half the cases are mean less aggressive tumor growth. diagnosed after the age of 20 years. In many cases, Hormone therapy usually includes luteinizing the characteristic skin changes occur during puber- hormone-releasing hormone (LH-RH) agonists and ty and may fade by the time the patient is in his or sometimes other drugs, such as antiandrogens, to her 40s. All patients are found to have some adre- treat prostate cancer. These drugs frequently cause nal gland abnormalities at the time of surgery and men to experience a wide variety of side effects, biopsy or at autopsy. 44 Centers for Disease Control and Prevention

Carney complex causes a form of Cushing’s syn- Bethesda, MD 20892-2560 drome, due to bilateral adrenal micronodular (800) 860-8747 or (301) 654-3327 hyperplasia, in about one of every four patients. http://www.niddk.nih.gov The pituitary tumors are typically adenomas. For further information on the CDC, contact the About 15 percent of the pituitary tumors cause organization at: gigantism. The atrial tumors are typically myxomas and may cause obstruction of the mitral valve of 1600 Clifton Road NE the heart, embolism, and constitutional symptoms Atlanta, GA 30333 such as weight loss, fever, and fatigue (with anemia (404) 639-3534 or (800) 311-3435 (toll-free) and thrombocytopenia). Some patients have thy- http://www.cdc.gov roid tumors and some may also have acromegaly. The disease decreases the normal expected life span in most patients. cerebral vascular diseases Diseases that cause Patients with Carney complex should receive damage to the blood vessels in the brain and neck regular medical attention, and any tumors should and that can lead to stroke or heart disease. People be treated. Physicians should vigilantly check for with some endocrine diseases, such as DIABETES MEL- the development of further tumors. LITUS or hypertension, have a higher risk of develop- See also ACROMEGALY;CUSHING’S SYNDROME/ ing cerebrovascular diseases than do nondiabetics. CUSHING’S DISEASE; GIGANTISM; MULTIPLE ENDOCRINE Elderly individuals (age 65 and older) are at particu- NEOPLASIA. lar risk for developing cerebral vascular diseases. Carney, J. A., et al. “The Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity.” Medicine 64, no. 4 (July 1985): 270–283. cholesterol One of several fats (lipids) that circulate Stratakis, Constantine A., Lawrence S. Kirschner, and J. in the body as lipoproteins, including low-density Aidan Carney. “Clinical and Molecular Features of the lipoproteins (LDL) and high-density lipoproteins Carney Complex: Diagnostic Criteria and Recom- (HDL). HDL is considered to be good cholesterol mendations for Patient Evaluation.” Journal of Clinical because it works to keep blood vessels healthy via a Endocrinology & Metabolism 87, no. 9 (2001): process known as reverse cholesterol transport. 4,041–4,046. Conversely, LDL is considered to be bad cholesterol because it damages the blood vessels and can lead to ATHEROSCLEROSIS and then heart attack, stroke, Centers for Disease Control and Prevention peripheral vascular disease, and finally, death. (CDC) The primary federal agency in the United Patients with some diseases, such as Type 2 DIA- States that oversees the government agencies that BETES MELLITUS, typically have lower-than-normal provide research and information on diabetes and HDL levels. Even when they have normal or only other major diseases. For example, the National slightly elevated LDL levels, they are at greater risk Center for Health Statistics compiles data and sta- of developing complications. This is because their tistics on incidence of diseases, deaths, hospitaliza- LDL cholesterol tends to be more atherogenic as it tions, and many other topics. has been glycosylated—that is, glucose molecules The National Institute of Diabetes and Digestive have attached atop the proteins in the LDL, ren- and Kidney Diseases (NIDDK) is an important dering the LDL more likely to attach to blood ves- branch of the CDC. Contact the NIDDK at: sel walls and cause problems. In addition, the HDL Building 31 of patients with Type 2 diabetes does not work as Room 9A04 well as it should either. It is less efficient than Center Drive among nondiabetics in transporting cholesterol MSC 2560 from the blood vessel to the liver. cholesterol 45

Thus, the target LDL cholesterol level is lower for levels of 160 and above are considered high, and those with diabetes. Patients with diabetes should 190 and above is very high. A level of HDL choles- contact their physicians for information on the LDL terol below 40 is considered problematic. cholesterol levels that are appropriate in their case. Patients diagnosed with cholesterol disorders are first asked to work on therapeutic lifestyle changes, Risk Factors including changes in nutrition (lower fat and cho- Other individuals in addition to those with diabetes lesterol intake and increased fiber intake) and have a greater-than-normal risk for developing attention to weight and exercise. If these measures health problems associated with their cholesterol lev- fail to bring a patient’s lipid levels to the goal, med- els. These at-risk individuals tend to be those who: ications are frequently needed. Patients with diabetes as well as cholesterol dis- • Have hypertension orders are urged to get their glucose levels as close • Are obese to normal as possible. Patients with hypertension • Have a very inactive lifestyle will be advised to bring their blood pressure levels • Are either African American or Native American down as well. Regular exercise is also usually rec- • Eat a very high-fat diet ommended. It need not be strenuous or difficult; even a daily walk is a good exercise that can help to improve health. Recommended Levels of Cholesterol If a patient has high LDL levels and dietary mod- The National Heart, Lung, and Blood Institute ifications do not bring about sufficient changes, released their new guidelines for cholesterol con- doctors may then decide to prescribe cholesterol- trol in 2002, provided in the chart that follows. lowering drugs in the statin series of medications. (Statins were formerly known as HMG CoA reduc- CLASSIFICATION OF LDL, TOTAL tase inhibitors.) Aspirin therapy may also be con- AND HDL CHOLESTEROL (MG/DL) sidered, especially if the patient is at risk for a heart attack or stroke, has diabetes, or has ever had LDL Cholesterol: Primary Target of Therapy either a heart attack or stroke in the past. Less than 100 Optimal 100–129 Near optimal/above optimal For further information on cholesterol levels, 130–159 Borderline high contact: 160–189 High 190+ Very high The National Heart, Lung, and Blood Institute Total Cholesterol Building 31, Room 5A52 Less than 200 Desirable 31 Center Drive MSC 2486 200–239 Borderline high Bethesda, MD 20892 240+ High (301) 592-8573 HDL Cholesterol http://www.nhlbi.nih.gov Less than 40 Low 60+ High National Cholesterol Education Program. “Third Report Source: National Cholesterol Education Program. “Third Report of the of the National Cholesterol Education Program National Cholesterol Education Program (NCEP) Expert Panel on (NCEP) Expert Panel on Detection, Evaluation, and Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).” NIH Publication No. 02-5215, Treatment of High Blood Cholesterol in Adults (Adult September 2002. Treatment Panel III).” NIH Publication No. 02-5215, September 2002. Diagnosis and Treatment Pearlman, Brian L., M.D. “The New Cholesterol Cholesterol problems are diagnosed based on the Guidelines: Applying Them in Clinical Practice.” patient’s blood levels of HDL and LDL. Thus, LDL Postgraduate Medicine 11, no. 2 (August 2002): 13–26. 46 chromogranin A chromogranin A A peptide hormone cosecreted believe that this sign, which uses a blood pressure with catecholamines. It is elevated in patients who cuff to elicit the characteristic flexing of the wrist have neuroendocrine tumors, such as a PHEOCHRO- and finger joints, is more reliable (sensitive and MOCYTOMA, GASTRINOMA, or carcinoid and specific) than is Chvostek’s sign. medullary carcinoma of the thyroid. However, See also CALCIUM BALANCE; HYPOCALCEMIA; chromogranin A is not specific nor is it sensitive HYPOPARATHYROIDISM; TETANY. enough to be used as a diagnostic test. It is mainly Hofmann, E. “Chvostek Sign.” American Journal of Surgery used as a tumor marker, if no better markers are 96, no. 1 (1958): 33–38. available, to help physicians follow the progress of Urbano, Frank L., M.D. “Signs of Hypocalcemia: a patient’s therapy for a specific tumor. Chvostek’s and Trousseau’s Signs.” Hospital Physician See also THYROID CANCER. 36, no. 3 (March 2000): 43–45.

Chvostek’s sign A simple test used during a physical examination to check for severely low levels clonidine suppression test A diagnostic/confir- of calcium in the blood, originally noted by 19th- matory medical test given when there is a very high century Austrian surgeon Frantisek Chvostek. suspicion of the presence of a PHEOCHROMOCYTOMA, Chvostek’s sign is considered a classic sign of an adrenal gland tumor that causes paroxysmal hypocalcemia. hypertension, flushing, headaches, and orthostatic With this test, the physician taps the midcheek- hypertension. This test is only done for a patient bone near the area where the facial nerve is locat- whom the endocrinologist strongly suspects of hav- ed (where the seventh cranial nerve exits the ing a pheochromocytoma, and whose total blood salivary/parotid gland). If the person is hypocal- plasma levels are borderline, typically between cemic, this action will usually elicit a sneering-like 1,000 and 2,000 pg/ml (or 5.9–11.8 nmol/l). For contraction in the patient’s cheek, nose, and corner patients whose levels are even lower than this of the mouth. range, other stimulatory tests may need to be done Patients who exhibit Chvostek’s sign will need to ascertain a diagnosis. supplemental doses of calcium and will often also The clonidine suppression test should only be need vitamin D supplements to stimulate the fur- conducted in patients who are well hydrated to ther absorption of calcium from their gut. avoid the onset of severe hypotension (low blood Unfortunately, about 20–25 percent of patients pressure). The patients are instructed to avoid eat- who do not have hypocalcemia will also demon- ing for at least four hours before the test. Some strate some facial twitching with this test. In addi- types of medications must be completely avoided tion, some patients who actually do have before the test, such as beta-blockers, diuretics, and hypocalcemia will not produce the Chvostek’s sign. tricyclic antidepressants. Other medications for the Chvostek’s sign is also sometimes positive in the treatment of hypertension should be withheld for absence of hypocalcemia when patients have other about 12 hours prior to this test to minimize any illnesses, such as myxedema, rickets, measles, and effect on the test results. diphtheria. In addition, some healthy patients may Clonidine is a commercially available oral anti- show a positive Chvostek’s sign, while some hypertensive drug that works to lower blood pres- patients who actually have hypocalcemia will show sure by stimulating alpha-2 adrenoreceptors in the a negative Chvostek’s sign. At best, Chvostek’s sign brain, thus leading to a decrease in sympathetic is merely a good basic indicator of possible hypocal- nervous system outflow from the brain. This typi- cemia and should be followed up by a blood test of cally causes there to be lower levels of cate- the patient’s calcium level. cholamine in the system, which, in turn, allows Another diagnostic test for hypocalcemia, blood vessels to relax and thus blood pressure to TROUSSEAU’S SIGN, was noted by 19th-century drop. Patients with a pheochromocytoma have less French physician Armand Trousseau. Most experts of a decrease in their plasma catecholamines. congenital adrenal hyperplasia 47

The drug can cause drowsiness and dry mouth cannot predict if and when the person will regain in 30–40 percent of patients who receive it. It also consciousness. DIABETIC KETOACIDOSIS, a severe has a potent first-dose effect, whereby a patient’s imbalance of glucose and acids in the bloodstream, blood pressure may drop precipitously with the may cause a coma. There are also other endocrine first dose. causes of coma, such as severe HYPOTHYROIDISM, Baseline plasma catecholamine levels are meas- from which the patient may suffer from a myxede- ured from an indwelling intravenous catheter in ma coma. In some cases, a blow to the head may the patient. (The simple act of inserting a needle or cause a coma, as may an overdose of medications intravenous drip will cause the release of some cat- or a severe medication interaction. Sometimes a echolamines and thus “falsely” elevate the cate- patient enters a coma state and the cause cannot be cholamine levels. Physicians realize this.) determined. After baseline catecholamine levels are taken, The comatose individual needs emergency treat- 0.3 mgs of clonidine is orally ingested by the ment and usually also requires hospitalization. patient. Three hours later, the patient’s plasma cat- Rarely, a patient will recover from coma after many echolamine levels are remeasured. years. Some patients have recovered after 20 years If the patient’s total plasma catecholamine levels or more in a comatose state. fall to less than 500 pg/ml (or 2.96 nmol/l) or to See also DIABETES MELLITUS; MYXEDEMA COMA; less than a 50 percent decline from the patient’s TYPE 1 DIABETES; TYPE 2 DIABETES. baseline levels, the diagnosis of a pheochromocytoma is excluded with a 92 percent certainty. Overall, the clonidine suppression test has a 97 computerized tomography (CT) A specific type percent sensitivity, which means that 97 percent of of X-ray imaging study that is frequently used to patients with a pheochromocytoma will have an diagnose and monitor a wide variety of medical abnormal test. It also has a 67 percent specificity, diseases and conditions. The CT scan is also known which means that two-thirds of patients without a as a computerized axial tomography or CAT scan. pheochromocytoma will have a normal response Sometimes physicians will order contrast dye to be and one-third will have a false positive test. injected into the patient’s veins to highlight partic- Abnormal blood levels are as follows: ular organs or areas of the body. For endocrine disorders, the CT scan is particu- Epinephrine: over 90 pg/ml larly helpful in assessing problems with the ADRE- Norepinephrine: over 550 pg/ml NAL GLANDS as well as in evaluating any of the Dopamine: over 150 pg/ml cancers associated with the endocrine system. The CT scan can also be used to image the HYPOTHALA- In looking at the combination of the epineph- MUS and PITUITARY GLAND, but most of this imaging, rine, norephinephrine, and dopamine levels (the as of this writing, is done with MAGNETIC RESO- total plasma catecholamines), abnormal blood lev- NANCE IMAGING (MRI). els are those that are greater than 500 pg/ml. See also ULTRASOUND.

Segen, Joseph C. and Joseph Stauffer. The Patient’s Guide to Medical Tests. New York, N.Y.: Facts On File, Inc., 1998. congenital adrenal hyperplasia (CAH) Refers to Sjoberg, R. J., K. J. Simcic, and G. S. Kidd. “The Clonidine a set of inherited disorders that cause an increased Suppression Test for Pheochromocytoma: A Review of size in the adrenal glands and that are nearly Its Utility and Pitfalls.” Archives of Internal Medicine 152, always (about 95 percent of the time) caused by no. 6 (1992): 1,193–1,197. mutations in genetic coding. These disorders cause an insufficient synthesis of CORTISOL. The most common genetic defect within the cat- coma A state of unconsciousness that may last egory of congenital adrenal hyperplasia is a 21- for days, weeks, or even years. Often physicians hydroxylase 21-OH deficiency, which represents 48 congenital hypothyroidism over 90 percent of all the cases of congenital adre- (Deltasone) or cortisone acetate (Cortef). If this nal hyperplasia. This defect is found in an estimat- therapy fails, the removal of the adrenal glands ed one in 12,000 to one in 15,000 births in the (ADRENALECTOMY) may be needed. If performed, United States. It is transmitted as an autosomal this surgery is usually done on adults. Surgery will recessive condition. induce the symptoms of full-blown ADDISON’S DIS- EASE, but many physicians argue that Addison’s Signs and Symptoms disease is easily more manageable than CAH with Newborns and children with congenital adrenal bilaterally enlarging adrenal glands. hyperplasia present with either the salt-wasting Children with CAH also need annual X-rays to form (with HYPOTENSION, low sodium levels and determine their BONE AGE and their growth. high potassium levels) or the simple virilizing form In the less common cases of congenital adrenal (with ambiguous genitalia). These are the classical hyperplasia that is due to deficiency of 3 beta- forms of 21-hydroxylase 21-OH congenital hyper- hydroxysteroid dehydrogenase, levels of 17 OH plasia. Six to seven out of 10 newborns with con- progesterone and 17-hydroxypregnenolone accu- genital hyperplasia have the salt-wasting form. mulate. In congenital adrenal hyperplasia that is HIRSUTISM is not typically evident until later in life. due to 17 OH deficiency, androgens and cortisol These patients cannot synthesize adequate corti- cannot be produced. With the 11 beta-hydroxylase sol and ALDOSTERONE (and lose excess sodium but deficiency form of CAH, aldosterone and cortisol retain excess potassium). Thus they will also are not produced in adequate amounts. In the 17- secrete greater-than-normal amounts of adreno- ketosteroid reductase deficiency form of congenital corticotropic hormone (ACTH). Because of this adrenal hyperplasia, TESTOSTERONE cannot be syn- increased androgen production, women may also thesized from androstenedione. become virilized. See also ADRENAL GLANDS. Patients with CAH may also suffer from cate- Gmyrek, Glenn A., M.D., et al. “Bilateral Laparoscopic cholamine deficiency, which can worsen shock. Adrenalectomy as a Treatment for Classic Congenital The nonclassical or late form of CAH presents in Adrenal Hyperplasia Attributable to 21-Hydroxylase puberty or after puberty. Females with this form Deficiency.” Pediatrics 109, no. 2 (February 2002). have menstrual irregularities and hirsutism/viriliza- Available online. URL: http://pediatrics.aapublica- tion that is clinically impossible to distinguish from tions.org/cgi/content/full/109/2/e28. Downloaded POLYCYSTIC OVARY SYNDROME (PCOS). Many females January 15, 2004. have adrenal incidentalomas (adenomas). Boys Speiser, Phyllis W., M.D. and Perrin C. White, M.D. may have testicular tumors that are actually com- “Congenital Adrenal Hyperplasia.” New England prised of adrenal tissue that grows in the scrotum. Journal of Medicine 349, no. 8 (August 21, 2003): Diagnosis and Treatment 776–788. The diagnosis of congenital adrenal hyperplasia is based on signs and symptoms as well as medical history. If physicians suspect CAH, the gold stan- congenital hypothyroidism A rare condition in dard test for this disorder is used: the corti- which low levels of thyroid hormone are found in cotrophin (Cortrosyn) stimulation test. With this newborn infants. An estimated one in every 4,000 test, cosyntropin (synthetic ACTH) is injected after infants has congenital hypothyroidism, according to measuring the basal levels of 17-(OH) proges- the American Academy of Clinical Endocrinologists. terone, and the patient’s blood levels of 17-hydroy- Of these cases, 85 percent are sporadic and 15 per- prosterone are measured 60 minutes later. Salt cent are inherited. Most of these cases are caused by wasting is measured through testing the blood for a genesis of thyroid tissues or ectopic tissue. For serum electrolytes, plasma renin, and aldosterone. unknown reasons, congenital hypothyroidism Patients with congenital adrenal hyperplasia are occurs twice as frequently in girls as boys. treated with glucocorticoids such as prednisone Interestingly, the incidence is more common in cortisol 49

Hispanic children (one in 2,000) and much rarer in amiodarone (Cordarone), a heart medication, or by African-American children (one in 32,000). Some iodine-containing contrast agents ingested by the of the cases have a central etiology and are often mother, thus inducing the production of antibodies associated with other midline defects, such as cleft by the mother while pregnant. palate and eye abnormalities. See also HYPOTHYROIDISM. Infants who have Down syndrome have an Leger, J., et al. “Severity of Hypothyroidism and increased risk for the diagnosis of congenital Inadequate Treatment Limit School Achievement in hypothyroidism. In one large population study of Children with Congenital Hypothyroidism.” Acta newborn infants that identified 97 infants with Paediatrics 90 (2001): 1,249–1,256. congenital hypothyroidism, reported in a 1997 Roberts, Helen E., et al. “Population Study of Congenital issue of the American Journal of Medical Genetics, the Hypothyroidism and Associated Birth Defects, researchers found that newborn babies with Down Atlanta, 1979–1992.” American Journal of Medical syndrome had a 35 times greater risk of having Genetics 71, no. 1 (July 11, 1997): 29–32. congenital hypothyroidism compared with babies Vogiatzi, Maria G., M.D. and John L. Kirkland, M.D. without Down syndrome. In addition, babies with “Frequency and Necessity of Thyroid Function Tests in Down syndrome are at a greater risk for developing Neonates and Infants with Congenital Hypothy- hypothyroidism later in infancy. As a result, the roidism.” Pediatrics 100, no. 3 (September 1997). American Academy of Pediatrics recommends that Available online. URL: http://pediatrics.aapublications. babies with Down syndrome be screened for org/cgi/content/full/100/3/e6. Downloaded January 20, acquired hypothyroidism at birth, at the four- to 2004. six-month stage, at the 12-month stage, and once a year afterward. An early diagnosis is important. If infants with Conn’s syndrome See ALDOSTERONISM. hypothyroidism are not diagnosed and treated, they will develop cretinism, which is manifested by mental retardation, slowed growth, intolerance to cold, constipation, dry skin, as well as other symp- cortisol An important hormone synthesized and toms typical of hypothyroidism. Untreated children released by the adrenal glands to help activate will often also be deaf and mute. At birth, these many critical body processes, including alertness, children may have few signs and symptoms vigilance, blood pressure, blood glucose level, and because their bodies still have some thyroid (T4) the ability to respond to physical and social stressors. hormone from their mothers. They may have Cortisol is synthesized in the adrenal cortex in slightly increased birth weight, enlarged fontanels the layer known as the zona fasciculata, under the (soft spots), hoarse cries, poor movement, consti- control of hypothalamic corticotropin releasing fac- pation, enlarged tongue, jaundice, and low body tor (CRF) and pituitary adrenocorticotropic hor- temperature. mone (ACTH). It has a circadian rhythm; cortisol All states in the United States require neonatal levels usually drop when an individual sleeps and screening for congenital hypothyroidism. Infants begin to rise again shortly before awakening afflicted with congenital hypothyroidism are treat- occurs. If very low levels of cortisol are produced, ed with supplemental thyroid hormone (levothy- this is called Addison’s disease or hypocortisolism, roxine), and their pediatricians and pediatric a condition that can become life threatening, requir- endocrinologists also carefully monitor them. Even ing emergency doses of hydrocortisone. Very high with treatment, some infants born with severe con- levels of cortisol cause Cushing’s disease. Cortisol is genital hypothyroidism may experience mild cog- one of the COUNTERREGULATORY HORMONES,a nitive defects later in life according to a study hormone that is released in response to an action reported in a 2001 issue of Acta Paediatrics. elsewhere in the body. Transient congenital hypothyroidism can occur See also ADDISON’S DISEASE;CUSHING’S SYN- due to excess iodine, caused by the mother taking DROME/CUSHING’S DISEASE; HORMONES. 50 cortisone cortisone Synthetically produced cortisol. control plus episodes of hypoglycemia, the brain, Cortisone is used in replacement for the glucocor- which can use only glucose for fuel, adapts by ticoid hormone, meaning it helps to maintain improving its ability to extract glucose from the blood glucose levels among its many actions. Some bloodstream. It does this by increasing the synthe- individuals have below-normal levels of cortisol, sis of glucose transporters (GLUT). such as patients with ADDISON’S DISEASE. These This increase means that although patients patients can be treated with daily doses of cortisone should begin to feel the symptoms of hypoglycemia acetate, allowing them to live long and full lives. at a blood glucose level of about 65 mg/dl (with Without cortisone or other glucocorticoids, howev- symptoms such as an increased pulse, sweating, er, these patients would die. nervousness, tremulousness, nausea, and hunger), In an acute crisis, such as a patient with previ- such symptoms will not occur as the brain has been ously undiagnosed or inadequately treated able to extract enough glucose to keep functioning Addison’s disease or among patients who have in a normal fashion. However, as the blood glucose developed a secondary adrenal insufficiency (typi- continues to fall, the brain then begins to malfunc- cally due to being tapered off their glucocorticoid tion, which is the neuroglycopenic phase of hypo- therapy too quickly), intravenous forms of corti- glycemia. At this time, patients are typically unable sone as well as normal saline are administered. to make the correct decisions to obtain food or These treatments are lifesaving. drink to correct the hypoglycemia, and will need Cortisone is also used to treat patients with a help from someone else or they may develop a variety of medical problems, such as various forms seizure or fall into a coma. of arthritis. Fortunately this process can be ameliorated. It is See also CORTISOL; HORMONES. one of the few times in diabetes management when the endocrinologist will instruct patients to allow their glucose blood levels to run higher than counterregulatory hormones Hormones released normal. Over a three- to six-week period, this will in response to an action elsewhere within the body. help to reset the alarm system in the brain and will For example, if a person develops HYPOGLYCEMIA most likely return the patient to a normal counter- (low blood sugar), glucagon is released to stimulate regulatory response. the breakdown of glycogen from the liver to coun- In patients who develop hypoglycemic teract the hypoglycemia. Counterregulatory unawareness due to the complication of autonom- hormones include CORTISOL (the body’s natural cor- ic neuropathy, this problem is not reversible. These tisone), GLUCAGON, epinephrine (ADRENALINE), and patients must be treated cautiously to avoid hypo- GROWTH HORMONE. Cortisol and epinephrine are glycemia. Interestingly, after five years of Type 1 released by the adrenal glands. Epinephrine and diabetes, most patients will not be able to release norepinephrine are also synthesized by the sympa- glucagons in response to hypoglycemia although it thetic nervous system. The pituitary releases growth is, in fact, present in their pancreases. hormone, and the pancreas releases glucagon. See also HORMONES. Another example of a counterregulatory hormone at work occurs when a person undergoes severe stress. Epinephrine is released to help the Creutzfeldt-Jakob disease (CJD) A brain disorder individual deal with that stress by maintaining blood that affects memory, behavior, coordination, and pressure and pulse as well as by increasing blood vision. Creutzfeld-Jakob disease was named after flow to muscles, part of the fight-or-flight response. two German neurologists, Dr. Hans Gerhard Some people with DIABETES MELLITUS develop Creutzfeld and Dr. Alfons Maria Jakob, who iden- reduced rates of response from their counterregu- tified the disease in the 1920s. CJD is a very rare latory hormones. This may be caused by either disease, occurring in only about one per million tight glycemic control or by autonomic neuropa- patients. In the most severe form of the illness, the thy. When patients have had excellent blood sugar individual becomes blind and mentally unstable, Crow-Fukase syndrome/POEMS syndrome 51 with rapidly progressing dementia, and loses all Prior to the development and availability of voluntary control of movements. The patient may recombinant growth hormone, a synthetic sub- lapse into a COMA. The disease is always fatal: death stance, this hormone was obtained from cadavers. occurs within a year of the onset for most (90 per- There were several cases of CJD that resulted from cent) of patients. transfers of these growth hormone extracts to pedi- When CJD is present, it is usually found among atric patients who were using them to remedy patients ages 60 and older. However, some patients short stature. This horrible complication ended the have developed CJD as young as age 26. Patients cadaver growth hormone program. with an early onset present with emotional symp- For further information, contact the following toms, such as anxiety, insomnia, and social with- organizations: drawal. However, they are not usually diagnosed Creutzfeldt-Jakob Disease Foundation until they present with neurological symptoms, P.O. Box 5312 such as abnormal gait, paresthesias (pins and nee- Akron, OH 44334 dles), and pain. (800) 659-1991 (toll-free) The diagnosis of CJD has been enhanced by the http://www.cjdfoundation.org establishment of the National Prion Disease Pathology Surveillance Center, located at Case National Organization for Rare Disorders (NORD) Western University. The Center performs free tests 55 Kenosia Avenue for patients suspected of having CJD, including P.O. Box 1968 analysis of DNA extracted from the blood or brain Danbury, CT 06812 tissue, analysis of the cerebrospinal fluid, and (203) 744-0100 other tests. http://www.rarediseases.org CJD is categorized as a transmissible spongiform Tyler, Kenneth L., M.D. “Creutzfeldt-Jakob Disease.” New encephalopathy (TSE), a medical condition com- England Journal of Medicine 348, no. 8 (February 20, mon to humans and animals. The most prominent 2003): 681–682. form of animal TSE is bovine spongiform encephalopathy, popularly known as mad cow disease, although it also affects sheep and goats. Crow-Fukase syndrome/POEMS syndrome First Types of CJD described by Dr. R. S. Crow in 1956 and then by Dr. There are three primary forms of CJD. Sporadic M. Fukase in 1968, this condition was once known CJD is the most common form, accounting for as Crow-Fukase syndrome. Most experts now use about 85 percent of all cases. Hereditary CJD occurs the acronym POEMS for this medical condition, in about 5–10 percent of all cases. The third type, which stands for polyneuropathy, organomegaly, acquired CJD, results from damage to the brain or endocrinopathy, monoclonal gammoapathy, and nervous system. skin changes. Patients with POEMS have disorders in at least three of the areas described by the Causes of CJD acronym. Only several hundred cases of this med- What causes CJD is unknown, although theories ical condition have been identified worldwide. do exist. Some researchers believe that a slow- The polyneuropathy involves dysfunction of acting virus can cause CJD, although no one has many sensory and motor nerves and becomes pro- been able to isolate such a virus. gressively worse. The organomegaly refers primari- With hereditary CJD, the disorder results from a ly to the enlarged spleen, lymph nodes, and liver. genetic mutation. However, not everyone with the The endocrine disorders experienced by men with mutated gene actually develops CJD. Therefore this syndrome include GYNECOMASTIA and ERECTILE there may be other yet-undiscovered factors, such DYSFUNCTION, while many women with this syn- as something that triggers the action of the mutat- drome have AMENORRHEA. Patients of both genders ed gene to lead to the disease’s onset. may have glucose intolerance and DIABETES MELLI- 52 Cushing’s syndrome/Cushing’s disease

TUS as well as HYPOTHYROIDISM, HYPOPARATHY- ACTH, as in a small cell tumor of the lung, the ROIDISM, and hyperprolactinemia. patient may present with only weight loss, POEMS is somewhat more commonly seen hypokalemia (low potassium blood levels), and among men than women, and the onset of the syn- hyperglycemia. The patient may show none of the drome usually occurs when patients are in their typical physical features associated with excess glu- 50s or early 60s. Patients present with severe diar- cocorticoid activity. rhea, shortness of breath, peripheral edema, weakness, and paresthesias (numbness and tingling). Symptoms of Cushing’s Syndrome in an Adult Skin changes, such as flushing, may occur as well as alopecia (loss of some or all of the hair). The syn- •HYPERGLYCEMIA drome appears to be caused by a disorder of plasma • Menstrual disturbances such as AMENORRHEA or blood cells, although what drives this change is oligomenorrhea (periods become irregular or unknown. Treatment is usually corticosteroids, stop altogether) such as prednisone, given at high doses. •OSTEOPOROSIS Rehmus, Wingrield, M.D. “POEM Syndrome.” Available • Muscle weakness (more prominent in the online. URL: http://www.emedicine.com/derm/ shoulder and hip girdle muscles, also called topic771.htm. Downloaded on February 1, 2004. proximal muscle weakness or myopathy) • Depression Cushing’s syndrome/Cushing’s disease Rare • Extreme fatigue endocrine disorders that occur in about 10–15 • Thin skin that is easily bruised and heals slowly patients per million people each year. These disor- •HIRSUTISM (excess hair growth and in atypical ders are named after Dr. Harvey Williams Cushing, areas) in women, especially on the face, neck, who first identified the symptoms in 1932. chest, thighs, and abdominal area Both disorders are due to excessive levels of cor- • Decreased fertility among men and/or lack of tisol in the bloodstream. However, Cushing’s dis- interest in sex and diminished libido ease refers specifically to the condition in which the excess secretion of cortisol is due to a problem • Moon-shaped face in the central nervous system. Cushing’s disease • Stretch marks on the skin, especially on the includes either an overproduction of adrenocorti- abdomen, typically greater than one centimeter cotropic hormone (ACTH) by the pituitary or an in diameter and violet colored overproduction of corticotropin releasing factor • Large deposition of fat at the base of the neck, (CRF) by the hypothalamus. In some cases, both sometimes called buffalo hump ACTH and CRF are overproduced. • Sleep disorders Cushing’s syndrome refers to any clinical syndrome where the effects of excessive glucocorticoids are present, as with the administration of Symptoms of Cushing’s Syndrome exogenous steroids (such as the use of prednisone in a Child or Adolescent in the treatment of asthma, lupus, and or rheumatoid arthritis), or in the cases of the ectopic produc- • Delayed growth tion of ACTH and adrenal tumors. • Hyperglycemia (a high glucose/high blood sugar In 90 percent of the cases of Cushing’s syndrome, level) and diabetes the patient is an adult. In 10 percent, the patient is a child or adolescent. Most patients are adult • Excessive weight gain, particularly in the face, females between the ages of 20 and 50 years old. neck, and abdomen (also called central, truncal, In patients with rapidly progressive Cushing’s or centripetal OBESITY) syndrome caused by the ectopic production of • Hypertension Cushing’s syndrome/Cushing’s disease 53

•DELAYED PUBERTY or a very EARLY PUBERTY in a (MRI) scans of the pituitary, depending on the case. child Because Cushing’s disease or syndrome is often dif- • Amenorrhea (missed periods in females) or ficult to diagnose, angiographic studies of the arter- oligomenorrhea (irregular menses) ies, and sometimes the veins, are done to make absolutely certain where the pathology lies. • Extreme fatigue Treatment Diagnosis Once diagnosed, treatment of Cushing’s disease or syndrome depends on the underlying cause. It can Cushing’s syndrome/disease is diagnosed with lab- be treated with medication, chemotherapy, radiation oratory tests, including a 24-hour measurement of treatments, surgery, or a combination of these treat- urinary free cortisol, measurement of cortisol in ments. Surgery can provide a cure if the cause is an the blood at different times throughout the day, adrenal tumor. For ectopic syndromes, treatment is and a dexamethasone suppression test. In addition, aimed at the underlying cancer and medications are CRF testing and direct measurements of ACTH and given to decrease the production of cortisol. dehydroepiandrosterone (DHEAS) in the blood can If the syndrome is secondary to exogenous be used. Sometimes physicians will order a meas- steroid use, the glucocorticoid medication being urement of 17-hydroxycorticosteroids, which are used is tapered to the lowest possible dosage for the the metabolites of cortisol in the urine. Cortisol lev- particular patient. els that are greater than 50–100 mcg per day in the See also CORTISOL. 24-hour urine collection test may indicate that the For further information, contact: patient has Cushing’s disease/syndrome. With the dexamethasone test, the patient is Cushing’s Support and Research Foundation, Inc. given dexamethasone, which is a glucocorticoid 65 East India Row 22B drug. Cortisol levels are then measured at specific Boston, MA 02110 times in both the blood and urine. If a person has a (617) 723-3824 normal hypothalamic-pituitary-adrenal (HPA) axis, Pituitary Network Association the ingestion of excessive dexamethasone should 223 East Thousand Oaks Boulevard suppress the production of CRF and ACTH, thus Suite 320 leading to decreased amounts of cortisol in the Thousand Oaks, CA 91360 blood and the urine. If a patient has Cushing’s dis- (805) 496-4932 ease or syndrome, production of cortisol will not respond normally, and the cortisol levels will Amos, Aaron, and J. William Roberts. “Cushing’s remain inappropriately high in the blood and urine. Syndrome Associated with a Pheochromocytoma.” As with all laboratory tests, some false positives Urology 52, no. 2 (1998): 331–335. and false negatives will occur. For example, the Lindholm, J., et al. “Incidence and Late Prognosis of patient who has used excessive alcohol or taken Cushing’s Syndrome: A Population-Based Study.” estrogen can affect the test results. Drugs such as Journal of Clinical Endocrinology & Metabolism 86, no. 1 phenobarbital and phenytoin (Dilantin) can also (2001): 117–123. affect results. Alcoholic patients may develop a Moro, Mirella, et al. “The Desmopressin Test in the form of pseudo-Cushing’s syndrome. Differential Diagnosis between Cushing’s Disease and As with other endocrine disorders, imaging tests Pseudo-Cushing States.” Journal of Clinical are done only after a biological diagnosis is made. Endocrinology & Metabolism 85, no. 10 (2000): This order of events helps the doctor avoid focusing 3,569–3,574. on any false-positive results, as adrenal inciden- Newell-Price, John, et al. “The Diagnosis and Differential talomas are quite common. Typically, COMPUTER- Diagnosis of Cushing’s Syndrome and Pseudo- IZED TOMOGRAPHY (CT) scans of the adrenal glands Cushing’s States.” Endocrine Reviews 19, no. 5 (1998): are used, as are MAGNETIC RESONANCE IMAGING 647–672.

dehydration Severely low levels of fluid in the Individuals taking certain medications are also body that are insufficient to meet the individual’s at risk, especially patients who are taking diuretic needs. Symptoms of dehydration include thirst, dry drugs. Individuals who are wounded and are skin and mucous membranes, light-headedness, bleeding severely are at risk of dehydration and and nausea. need intravenous fluids as soon as possible. The primary causes of dehydration are as follows: Risk Factors • Inadequate fluid intake Children who are ill and feverish may be at risk for dehydration if they do not receive appropriate • Hyperglycema (high blood sugar levels) medical treatment. Sometimes elderly people (ages • Excessive vomiting 65 and over) become dehydrated because they are • Severe diarrhea not given sufficient fluids by staff members in a • Diuretic medications nursing home or by their own family members. This may constitute poor care, particularly if the • Excessive bleeding patient becomes unconscious. The elderly may also • Diabetes insipidus fail to drink sufficient fluids because of forgetful- ness associated with problems such as Alzheimer’s disease or depression. Diagnosis and Treatment People with some diseases, particularly DIABETES Dehydration is diagnosed by assessing the medical MELLITUS, are at risk for developing dehydration. history, conducting a physical examination, and Dehydration can occur in patients with poorly con- taking laboratory tests of the patient. In a person trolled diabetes mellitus as they have very high lev- with vomiting or diarrhea, a history of poor fluid els of glucose that can lead to osmotic diuresis. In intake may be all that is needed to make the diag- this circumstance, the high levels of sugar that are nosis of dehydration. In the elderly and the young, filtered and lost in the kidney pull along extra however, sometimes the history is not accurate or water and lead to increased urination. This will is not obtained at all. Thus physical signs, such as lead to dehydration if there is inadequate fluid poor skin turgor (when the skin is pulled, it does replacement. This situation is more likely to occur not quickly resume to normal) may indicate dehy- in the very young and the elderly, who may not be dration. Another indicator of dehydration is able to obtain fluids on their own or who may have decreased blood pressure, especially when the disordered senses of thirst. patient is standing, or a clinically significant Individuals with DIABETES INSIPIDUS are clearly at decrease in blood pressure when the patient risk for rapid and severe dehydration, leading to changes position from lying to sitting or standing. death, if they are not properly treated. They need Laboratory tests such as the blood urea nitrogen adequate replacement of desmopressin acetate (BUN) level, creatinine, complete blood count (DDAVP), their antidiuretic hormone, to avoid (CBC), and electrolytes will often reinforce the huge losses of fluid in the urine. diagnosis.

55 56 delayed puberty

The doctor treats dehydration by first determin- girls, although the reason for this finding was ing the cause of the problem and then replacing flu- unclear. The greatest delays in breast development ids to an adequate level. Sometimes merely were seen in African-American girls with high encouraging the individual to drink fluids may solve blood lead concentrations. the problem. At other times, medical intervention is required. A severely dehydrated person may need Signs and Symptoms of Delayed Puberty fluid replacement intravenously until he or she is Delayed puberty is indicated more by a lack of signs able to take fluids in the usual manner, by drinking. than the presence of signs. For example, the child Dehydration may become a serious problem if lacks hair in the underarm or genital area. The left untreated. Dehydration may contribute to or female has not menstruated or developed breasts. exacerbate such medical problems as DIABETIC The male genitals have not developed beyond KETOACIDOSIS and even COMA. childhood. However, both males and females with delayed puberty are usually smaller in size than their peers. delayed puberty A later-than-average onset of the normal physical maturation that occurs in males and females during adolescence, or later Diagnosis and Treatment than age 13 in girls and age 14 in boys. Delayed A key determinant of delayed puberty is the child’s puberty is more common among boys than girls. BONE AGE. In a bone age study, physicians take Often it is an inherited trait and is not due to any X-rays of certain bones, such as those of the wrist. underlying endocrine disease or other illness. Physicians look at whether the bones have fused Delayed puberty that is not caused by disease is (the epiphyseal plates or growth plates at the ends also known as constitutional delay of growth and of the bones), which occurs during adolescence. maturation or simply CD. If the child has a younger bone age than his or In one study of 158 boys and 74 girls with her chronological age, physicians should also note delayed puberty, published in a 2002 issue of the the child’s hormonal levels to check for a deficien- Journal of Clinical Endocrinology & Metabolism, cy. In boys, testosterone levels should be checked, researchers found that the majority of children and in girls the estradiol level should be taken. The studied (53 percent) had CD. In the other children, thyroid levels of both boys and girls with delayed many different medical problems were identified, puberty should also be checked since the underly- including a growth hormone deficiency, HYPOTHY- ing problem may be hypothyroidism. ROIDISM, poor nutrition, seizure disorders, The treatment for delayed puberty depends on KALLMANN’S SYNDROME,KLINEFELTER SYNDROME, the underlying cause. If an illness is identified, that PRADER-WILLI SYNDROME,TURNER SYNDROME, sickle medical problem is treated and the delayed puber- cell anemia, ANOREXIA NERVOSA, and other causes. ty may then resolve. If no cause is found, physi- As a result, even though most children with cians must decide whether to treat the child. delayed puberty are merely late bloomers, physi- Some physicians may treat patients with cians should rule out other potential causes for the delayed puberty with growth hormone, although delay in physical maturation. pediatricians disagree on whether growth hormone In a study reported in a 2003 issue of the New should be administered at all as well at what age it England Journal of Medicine, the researchers studied should be considered. Others may treat males with 600 Caucasian girls, 805 African-American girls, delayed puberty with intramuscular injections of and 781 Mexican-American girls and considered testosterone, given every four weeks for a period of their onset (or lack of onset) of puberty. The about four to six months. Hormonal treatment for researchers found there was a significant relation- females with delayed puberty is considered contro- ship between high blood lead concentration and versial. However, some physicians treat girls with delayed puberty in the African-American and low doses of oral estrogen or estradiol daily for Mexican-American girls but not in the Caucasian three to four months. DEXA scan 57

If treatment does occur, it should be started or at Most physicians consider depression highly least monitored by an endocrinologist rather than treatable, and many patients respond very well to by an internist or family practitioner. antidepressant medications. Most of the modern selective serotonin reuptake inhibitors (SSRIs) Effects of Delayed Puberty on the Child have response rates in the 80 percent range. Many different types of antidepressants are available. Delayed puberty can cause emotional problems Consequently, even if the first medication does not such as DEPRESSION in some children and adoles- work, another medication may be efficacious. cents, who may feel shunned and ridiculed by their Patients may also need to receive short-term ther- peers. Especially during their early adolescent apy, such as cognitive-behavioral therapy (CBT), in years, children are likely to be verbally abused and which the therapist teaches the patient how to sometimes physically abused by others, particular- identify and challenge irrational beliefs that are ly if they are males. Said Sharon Travers and self-defeating and destructive. Robert Slover in their discussion of the disorders of For further information, contact the following puberty, “Both boys and girls may be distressed organizations: because of their small size and sexually immature appearance. They are often treated as if they were American Psychiatric Association younger, teased by peers, and denied participation 1400 K Street NW in certain athletic activities.” Washington, DC 20005 It can also be very difficult for parents to see (202) 682-6000 their children feel humiliated and maligned due to http://www.psych.org their small size and lack of pubertal development. American Psychological Association See also EARLY PUBERTY; GROWTH HORMONE; 750 First Street NE TANNER STAGES. Washington, DC 20002 Seldmeyer, Ines L., and Mark R. Palmert. “Delayed (202) 336-5500 Puberty: Analysis of a Large Case Series from an http://www.apa.org Academic Center.” Journal of Clinical Endocrinology & Metabolism 87, no. 4 (2002): 1,613–1,620. Selevan, Sherry G., et al. “Blood Lead Concentration and desiccated thyroid Thyroid hormones obtained Delayed Puberty in Girls.” New England Journal of from animal thyroids, such as pork thyroid. These Medicine 348, no. 16 (April 17, 2003): 1,527–1,536. extracts contain thyroid hormones and thyroglob- Travers, Sharon H., M.D., and Robert H. Slover, M.D. ulin. They are inexpensive, but their potency is “Disorders of Puberty.” Endocrine Secrets, 3d ed. harder to standardize than that of other thyroid Philadelphia, Pa.: Hanley & Belfus, Inc., 2002, medications. 334–347. Desiccated thyroid hormone is available in 15, 30, 60, 90, 120, 180, 240, and 300 mg tablets. The 60 mg tablets contain about 30 mg of T4 (THYROX- depression Clinically abnormal condition of low INE) and 9 mg of T3 (TRIIODOTHYRONINE) and are mood state with the inability to enjoy life and func- equivalent to about 75 mg (or 0.075 mg) of tion at optimal levels. Depression may be caused by LEVOTHYROXINE. events in a person’s life, or it may be triggered by an endocrine disorder or other illness. In some cases, depression is misdiagnosed when the under- DEXA scan (dual-energy X-ray absorptiometry) A lying problem is actually an endocrine disease, special type of X-ray used to determine the level of such as HYPOTHYROIDISM or CUSHING’S SYNDROME, bone density. Assessment of a DEXA scan can help and the patient is not truly clinically depressed. It is a physician make the diagnosis of OSTEOPOROSIS or also true that patients may have an endocrine dis- the less severe condition known as OSTEOPENIA. The order as well as depression. DEXA scan is considered by many experts as the 58 diabetes insipidus gold standard, not only in making the diagnosis of urination (typically, greater than four liters per day, osteoporosis but also in following the patient’s with very dilute urine), fatigue, and excessive thirst. response to therapy for the treatment of osteo- Unless the person with diabetes insipidus drinks porosis. copious quantities of fluid, he or she will become severely dehydrated and constipated. However, the patient will not have hyperglycemia (high levels of diabetes insipidus (DI) A rare metabolic/endocrine blood glucose), which is the hallmark feature of disorder characterized by massive losses of body flu- both Type 1 and Type 2 diabetes. Some patients ids through urination. The antidiuretic hormone with DI also have severe night sweats. (ADH), also known as vasopressin, which is made by the hypothalamus and stored in the pituitary Infants and Children with DI gland, is at a reduced level among patients with DI. If infants with the disease are not treated quickly, In a healthy person, ADH works to decrease urine they may suffer from irreversible brain damage or flow by increasing the reabsorption of salt and developmental problems, such as mental retarda- water in the kidney tubules. tion and physical delays. Symptoms of diabetes Diabetes insipidus has no relationship to DIA- insipidus in a baby are fever, vomiting, and con- BETES MELLITUS, although the twin symptoms of fre- vulsions, with high levels of sodium found in the quent urination and extreme thirst are common to blood upon laboratory examination. Infants and both diseases. Diabetes insipidus may occur abrupt- children with diabetes insipidus may also have ly in individuals of any age, although it is more FAILURE TO THRIVE and experience growth deficits. common among adults. Researchers studied 79 children with diabetes insipidus and reported on their findings in the New Types and Causes of Diabetes Insipidus England Journal of Medicine. The children had a DI is caused by damage to the pituitary gland, median age of seven years. The researchers per- which may result from a head injury, an infection, formed MAGNETIC RESONANCE IMAGING (MRI) scans a tumor, or a variety of other causes. Some experts on the children, and they found that most of the believe DI may be a form of autoimmune disorder. children had certain abnormalities. For example, Diabetes insipidus may also be an inherited disease. 18 of the patients had an intracranial tumor, two Hereditary forms of DI are called familial diabetes had skull fractures, and 12 of the children had insipidus or familial neurohypophysial diabetes Langerhans’ cells histiocytosis. insipidus. Many of the children (61 percent) showed ante- Central DI is the most common form of diabetes rior pituitary deficiencies, particularly of growth insipidus. Unless otherwise stated, researchers who hormone, within about a year from the onset of are discussing diabetes insipidus are referring to their diabetes insipidus. central DI. Another form of DI is nephrogenic DI, In about 25 percent of the children, there caused by a disorder of the kidneys in which they appeared to be a link between contracting a virus are unable to respond to the ADH that is produced. and the subsequent onset of diabetes insipidus. In Nephrogenic DI may sometimes be caused by med- about 30–50 percent of the cases, the cause for the ications such as lithium. diabetes insipidus was unknown. Dipsogenic DI, a rare form of diabetes insipidus, is caused by a disorder in the hypothalamus that affects Adults and DI the mechanism causing thirst. In rare cases, pregnant Among adults, diabetes insipidus is commonly women may develop gestational diabetes insipidus, caused by pituitary tumors of many types as well as which is caused by an enzyme in the placenta. by the surgery and/or radiation used to treat them. Typically these tumors are benign. However, they Signs and Symptoms of Diabetes Insipidus damage the pituitary gland by their mass effect, as Whether the illness is inherited or acquired, the there is very little extra room in the sella turcica symptoms of diabetes insipidus include frequent where the pituitary gland sits. Malignant tumors diabetes insipidus 59 may also metastasize to the pituitary gland and or a tablet. Physicians must be careful to prescribe cause DI. the correct dose of this medication. If excessive A significant head trauma, such as that which amounts of DDAVP are administered, patients may can be caused by motor vehicle accidents or by become water intoxicated. Patients taking this drug gunshot wounds, can also cause DI to occur. must also be reassessed several times per year. Granulomatous diseases may also cause DI. These Other drugs besides DDAVP that increase ADH diseases cause the body to respond by creating secretion are generally not very effective and, con- granulomas, which are large cells derived from sequently, are rarely used. However, in a study white blood cell monocytes and used as part of the reported in a 1999 issue of the Archives of Internal body’s immune system defense. Medicine, researchers treated 20 patients with cen- Anything that damages the hypothalamus, tral diabetes insipidus with indapamide (Lozol), an which sits directly adjacent to the pituitary gland, antihypertensive diuretic. The drug worked well on may also lead to DI. This occurs because the hypo- most patients. thalamus is where ADH is made prior to its transit In the case of nephrogenic diabetes insipidus, to the pituitary gland. recommendations of low-salt diets, thiazide diuretics, and nonsteroidal anti-inflammatory drugs Diagnosis and Treatment (NSAIDs) are often used for patients. Gestational The diagnosis of diabetes insipidus is based on the DI usually resolves when the pregnancy ends. patient’s symptoms and on blood tests of glucose For further information, contact the following levels that rule out a diagnosis of either Type 1 or organizations: Type 2 diabetes. In order to diagnose DI, the endocrinologist must document that the patient is Diabetes Insipidus Foundation, Inc. producing a large flow of urine that is quite dilute 4533 Ridge Drive and that fails to concentrate to the appropriate Baltimore, MD 21229 stimuli. In healthy people, if they do not drink (410) 247-3953 water over a period of time, appropriate hormonal National Kidney and Urologic Diseases changes will ensue that cause the urine to become Information Clearinghouse more concentrated and thus they will lose less 3 Information Way water in their urine and their lives will be sus- Bethesda, MD 20892 tained. However, in contrast, when individuals (800) 891-5390 (toll-free) with DI fail to drink water, the hormonal changes do not occur and instead, the body continues to Nephrogenic Diabetes Insipidus Foundation pour out diluted urine. As a result, the water dep- P.O. Box 1390 rivation test is used to diagnose DI. Eastsound, WA 98245 To determine the presence of diabetes insipidus, (888) 376-6343 (toll-free) a fluid deprivation test is needed on occasion, espe- http://www.ndif.org cially if the ADH deficiency is only partial. Sometimes a test known as a dehydration test is Maghnie, Mohamad, M.D., et al. “Central Diabetes used. This test is used especially if the ADH defi- Insipidus in Children and Young Adults.” New England ciency is partial or if there is a suspicion of the pres- Journal of Medicine 343, no. 14 (October 5, 2000): ence of psychogenic polydipsia, which is an 998–1,007. extreme intake of water that may stem from an Petit, William A. Jr., M.D., and Christine Adamec. The emotional or psychotic disorder such as untreated Encyclopedia of Diabetes. New York: Facts On File, Inc., schizophrenia. 2002. Diabetes insipidus is usually treated with desmo- Tetiker, Tamer, M.D., Murat Sert, M.D., and Mustafa pressin acetate (DDAVP), a hormone that is avail- Kocak, M.D. “Efficacy of Indapamide in Central able in several forms: an intravenous or Diabetes Insipidus.” Archives of Internal Medicine 159, subcutaneous preparation, a nasal spray, a liquid, no. 17 (1999): 2,085–2,087. 60 diabetes mellitus diabetes mellitus (DM) Common name for both Most people with diabetes are diagnosed in Type 1 and Type 2 diabetes. Diabetes mellitus is a adulthood. According to the CDC, only 7.2 percent complex disorder of carbohydrates, proteins, and of adults with diabetes were diagnosed between fats that leads to premature death, usually due to birth and age 19 years (see Table I). heart attack and stroke. Many experts think that The percentages of people in the United States although diabetes is commonly considered a dis- who have been diagnosed with diabetes also varies ease of sugar, it is more accurately a vascular dis- greatly from state to state according to surveillance ease that severely affects blood vessels throughout data for 2001 from the CDC. The greatest percent- the body. ages were found in Puerto Rico (9.8 percent), Type 1 diabetes is an autoimmune disorder in Alabama (9.6 percent), and Guam (9.5 percent). which all the insulin-producing beta cells in the The lowest percentages were found in Alaska (4.0 pancreas are destroyed, with patients dependent percent), Utah (4.2 percent), and Minnesota (4.4 upon taking insulin to live. With Type 2 diabetes, percent) (see Table II). patients’ bodies do make insulin but have resistance to its effects. They are unable to make adequate insulin to control their glucose levels and the result- TABLE I: DISTRIBUTION OF AGE AT DIAGNOSIS ing metabolic disarray. Most patients with Type 2 OF DIABETES AMONG ADULTS AGED 18–79 YEARS, UNITED STATES, 2000 diabetes can be treated with nutrition, exercise, and oral medications. About 7 percent of patients with Age in Years Percent Type 2 diabetes lose the ability to make insulin and, 0–9 2.4 consequently, require insulin therapy. 10–19 4.8 20–29 6.6 Risk Factors 30–39 14.4 According to the Centers for Disease Control and 40–49 24.2 50–59 24.8 Prevention (CDC), as of this writing about 18 mil- 60–69 17.0 lion people in the United States, or 6.3 percent of 70–79 5.7 the population, have diabetes. This number Source: Diabetes Surveillance System, National Center for Chronic includes about 6 million people who have the dis- Disease Prevention and Health Promotion, Centers for Disease ease but do not realize it. From 90–95 percent of all Control and Prevention. patients with diabetes mellitus have Type 2 diabetes, while 5–10 percent have Type 1 diabetes, requiring insulin injections. These figures do not Risks Are Increasing for Developing Diabetes include women with gestational diabetes, which The risk of developing diabetes mellitus is rising. refers to an estimated 135,000 pregnant women in For example, according to an article in a 2003 issue the United States who did not have diabetes prior of the Journal of the American Medical Association, to their pregnancies. researchers estimated the lifetime risk of develop- About one in every five adults over age 65 has ing diabetes among children born in 2000. They diabetes. The National Diabetes Information estimated that the risk was 32.8 percent for males Clearinghouse estimated that the direct medical and 38.5 percent for females. costs of diabetes mellitus were $92 billion in 2002. Hispanics had the highest potential risks for There are racial differences among patients with developing diabetes, or 45.4 percent for males and diabetes. African Americans and Native Americans/ 52.5 percent for females. Said the researchers, “The Alaska Natives have a greater risk for developing lifetime risk of diabetes is comparable with or high- Type 2 diabetes than Caucasians. In contrast, er than that for many diseases and conditions that Caucasians are more likely to be diagnosed with are perceived as common. For example, the life- Type 1 diabetes. time risk of diabetes is considerably higher than the diabetes mellitus 61

TABLE II: PREVALENCE OF ADULTS WHO REPORTED EVER HAVING BEEN TOLD BY A HEALTH PROFESSIONAL THAT THEY HAD DIABETES, 1991, 2000, AND 2001, AND BY SEX, 2001— UNITED STATES, BEHAVIORAL RISK FACTOR SURVEILLANCE SYSTEM

Both sexes Men Women (%) 2001 2000 1991Difference (2001) (2001)

State or Territory % 95% CI* (±) % 95% CI (±) % 95% CI (±)1991–2001 % 95% CI (±) % 95% CI (±)

Alabama 9.6 1.2 7.4 1.2 5.1 1.0 89.3 10.5 2.0 8.8 1.4 Alaska 4.0 1.0 3.8 1.4 4.3 1.3 –7.8 4.0 1.4 4.0 1.4 Arizona 6.1 1.0 5.9 2.2 3.8 1.0 60.1 7.3 1.8 4.9 1.2 Arkansas 7.8 1.2 6.2 1.0 4.8 1.2 63.9 8.4 1.8 7.2 1.4 California 6.5 1.0 6.8 1.2 4.8 0.9 36.8 5.8 1.2 7.1 1.4 Colorado 4.6 1.0 5.1 1.2 2.9 0.8 56.5 5.6 1.8 3.7 1.2 Connecticut 6.3 0.6 5.5 0.8 4.6 1.1 37.6 6.5 1.0 6.0 0.8 Delaware 7.1 1.0 6.4 1.2 4.9 1.2 43.7 7.5 1.8 6.7 1.4 District of Columbia 8.3 1.6 7.2 1.4 6.7 1.7 24.3 9.6 2.5 7.2 1.8 Florida 8.2 1.0 6.9 0.8 5.1 1.0 60.5 9.1 1.6 7.3 1.2 Georgia 6.9 0.8 6.8 1.0 5.6 1.2 23.2 6.5 1.4 7.2 1.2 Hawaii 6.2 1.2 5.2 0.8 6.5 1.2 –4.0 6.8 2.0 5.6 1.2 Idaho 5.4 0.8 4.9 0.8 3.7 0.9 45.2 5.2 1.0 5.7 1.0 Illinois 6.6 0.8 6.2 1.0 5.1 1.0 30.2 6.7 1.4 6.6 1.2 Indiana 6.5 0.8 6.0 1.0 5.4 1.0 20.8 6.3 1.2 6.8 1.0 Iowa 5.7 0.8 6.1 1.0 3.8 1.0 51.6 5.8 1.2 5.6 1.0 Kansas 5.8 0.8 5.9 0.8 -† — — 5.5 1.0 6.1 1.0 Kentucky 6.7 0.8 6.5 0.8 4.8 1.0 40.8 6.9 1.2 6.4 0.8 Louisiana 7.6 0.8 6.6 0.8 6.3 1.3 20.3 6.9 1.2 8.2 1.0 Maine 6.7 1.2 6.0 1.2 4.2 1.2 60.3 7.0 2.0 6.5 1.4 Maryland 6.9 1.0 6.4 1.0 5.2 1.2 32.7 7.1 1.6 6.6 1.4 Massachusetts 5.6 0.6 5.8 0.6 4.4 1.3 26.7 6.0 1.0 5.2 0.8 Michigan 7.2 1.0 7.0 1.0 5.4 0.9 34.3 6.8 1.4 7.6 1.2 Minnesota 4.4 0.6 4.9 1.0 3.7 0.7 18.3 4.4 1.0 4.3 1.0 Mississippi 9.3 1.2 7.6 1.2 7.0 1.4 32.1 8.8 2.0 9.7 1.4 Missouri 6.6 1.0 6.7 1.0 4.1 1.0 63.0 7.0 1.6 6.2 1.2 Montana 5.6 1.0 4.9 1.0 4.9 1.3 13.4 4.9 1.2 6.2 1.6 Nebraska 5.2 0.8 4.9 1.0 4.8 1.2 8.3 4.9 1.2 5.5 1.0 Nevada 5.7 1.4 6.8 2.0 — — — 5.2 1.4 6.2 2.2 New Hampshire 5.4 0.8 4.4 1.0 4.7 1.2 14.2 5.8 1.2 5.0 1.0 New Jersey 7.1 1.0 5.8 0.8 4.3 1.1 64.0 7.3 1.4 7.0 1.2 New Mexico 6.2 1.0 6.5 1.0 3.4 1.1 80.2 5.9 1.4 6.5 1.2 New York 6.6 1.0 6.3 1.0 5.2 1.1 27.7 6.4 1.4 6.8 1.4 North Carolina 6.7 1.0 6.4 1.0 6.3 1.2 6.2 6.8 1.4 6.7 1.0 North Dakota 5.1 1.0 5.2 1.2 4.4 1.0 16.4 4.7 1.4 5.6 1.2 Ohio 7.2 1.0 6.4 1.2 4.5 1.4 61.8 7.5 1.6 6.9 1.2 Oklahoma 7.7 1.0 5.5 0.8 4.0 1.0 91.1 8.3 1.6 7.2 1.2 Oregon 5.7 1.0 6.0 1.0 4.8 0.8 19.0 5.5 1.4 5.8 1.4 Pennsylvania 6.7 0.8 7.1 1.0 6.5 1.1 3.4 6.6 1.4 6.7 1.2 Rhode Island 6.4 1.0 6.0 0.8 5.6 1.1 14.9 7.4 1.4 5.6 1.2 South Carolina 8.1 1.0 7.1 1.0 6.5 1.2 24.8 8.4 1.8 7.7 1.4 South Dakota 6.1 0.8 5.7 0.8 3.4 0.9 79.4 6.6 1.2 5.6 0.8 Tennessee 7.7 1.2 7.2 1.2 7.2 1.1 6.4 7.6 2.0 7.9 1.4 Texas 7.1 0.8 6.2 0.8 4.7 1.1 50.7 7.0 1.2 7.2 1.0 Utah 4.3 0.8 5.4 1.2 3.9 1.0 10.3 4.3 1.4 4.2 1.2 Vermont 5.1 0.8 4.4 0.8 4.5 1.2 13.1 4.6 1.0 5.5 1.0 (continues) 62 diabetes mellitus

Both sexes(%) Men Women 2001 2000 1991Difference (2001) (2001)

State or Territory % 95% CI* (±) % 95% CI (±) % 95% CI (±)1991–2001 % 95% CI (±) % 95% CI (±)

Virginia 6.0 1.0 6.2 1.4 4.2 1.1 43.9 6.2 1.4 5.8 1.4 Washington 5.7 0.8 5.5 0.8 5.0 1.0 13.3 6.2 1.2 5.2 1.0 West Virginia 8.8 1.2 7.6 1.2 6.0 1.0 47.7 8.9 1.6 8.8 1.6 Wisconsin 5.6 0.8 6.1 1.0 4.9 1.2 15.0 5.9 1.4 5.3 1.2 Wyoming 4.5 0.8 5.0 1.0 – – – 4.1 1.2 4.8 1.0 Guam 9.5 2.5 – – – – – 9.9 3.9 9.1 3.1 Puerto Rico 9.8 1.2 8.5 1.0 – – – 9.1 1.8 10.5 1.6 Virgin Islands 7.2 1.2 – – – – – 4.3 1.6 9.5 2.0

Summary

Both sexes Men Women

2001 2000 1991 (2001) (2001) No. of states/territories 54 52 48 54 54 Median 6.6 6.2 4.8 6.6 6.5 Range 4.0–9.8 3.8–8.5 2.9–7.2 4.0–10.5 3.7–10.5 Mean 6.6 6.1 4.9 6.6 6.5 * Confidence interval. †Not available or sample size <50 . Source: Centers for Disease Control and Prevention, “State-Specific Prevalence of Selected Chronic Disease Related Characteristics—Behavioral Risk Factor Surveillance System, 2001,” Morbidity and Mortality Weekly Report 52, no. 55–8 (August 22, 2003): 39. widely publicized 1 in 8 risk for breast cancer “can uncover health beliefs, reinforce and tailor among US women.” health messages, and activate patients by opening a dialogue.” Communication Is Critical Between Patients with Diabetes and Their Doctors Poor Compliance with Treatment It is very important that people who have diabetes The National Institute of Diabetes and Digestive understand the basics about their illness as well as and Kidney Diseases (NIDDK) stated that study what they need to do in order to manage it suc- results released in 2004 showed that less than 12 cessfully. In one study, reported in a 2003 issue of percent of people with diagnosed diabetes meet the Archives of Internal Medicine, interactions were their recommended treatment goals for blood glu- observed between 38 doctors and 74 of their cose, blood pressure, and cholesterol. This occurs English-speaking patients when the physicians even though research has clearly shown that con- were explaining new concepts to their patients. trolling these conditions dramatically delays or pre- The researchers found that when patients under- vents diabetes complications. stood what their doctors were telling them, they Further, the percentage of people complying were more likely to have good glycemic control. with treatment recommendations has improved lit- This is particularly important among patients who tle in the last decade. This is discouraging because may have a poor grasp of their illness and what failure to control diabetes leads to an increased risk they need to do to control it. Of particular help is for many complications, such as heart attack, when doctors assess the patients’ understanding stroke, amputations, DIABETIC RETINOPATHY, DIABET- level. According to the researchers, doing so can IC NEUROPATHY, DIABETIC NEPHROPATHY, and death. diabetes mellitus 63

Complications from Diabetes age groups are either overweight or obese in com- Although many people can control their diabetes parison to past years. with diet, medication, exercise, and weight control, an estimated 200,000 Americans die each year TABLE III: HOSPITAL DISCHARGE RATES FOR from complications due to diabetes, making dia- DIABETES AMONG ADULTS 45 YEARS OF AGE betes the sixth leading cause of death in the United AND OLDER BY AGE, DISCHARGES PER 10,000 POPULATION: UNITED STATES: 1990–2001 States. The key cause of diabetes-related complications is heart disease. Patients with diabetes have a Year 45–54 55–64 65–74 75 years+ two to four times greater risk of dying from heart 1990–1991 121.0 270.3 487.3 648.0 disease than patients who do not have diabetes. In 1992–1993 139.4 302.9 536.9 699.5 addition, patients with diabetes have a two to four 1994–1995 140.3 307.3 561.6 746.6 1996–1997 148.5 322.1 576.1 791.1 times greater risk of suffering from a stroke than 1998–1999 151.1 347.8 628.0 831.3 nondiabetic patients. In addition, 73 percent of 2000–2001 156.6 344.0 632.4 830.6 adults with diabetes have high blood pressure or Source: Centers for Disease Control and Prevention. Chartbook on are taking medications for hypertension. Trends in the Health of Americans. Health, United States, 2003. Diabetes is also the leading cause of adult-onset blindness. Between 12,000–24,000 people in the Costs of Diabetes United States become blind each year as a result of The federal government in the United States esti- complications from diabetes. Others develop kid- mates that the direct and indirect costs of diabetes ney diseases; an estimated 38,000 people with dia- are about $130 billion per year and the average betes die from kidney failure each year in the health care cost for a person with diabetes is about United States. five times greater than that of an age-matched per- Diabetes is the leading cause of nontraumatic son without diabetes. Some experts believe that amputation in the United States. Many patients these figures are underestimated. with diabetes suffer amputations of the toes, feet, and legs. An estimated 82,000 Americans have Medications for Diabetes body parts amputated each year as a result of diabetic complications. People with diabetes are also The medications used to treat diabetes mellitus more likely to die from complications of flu or depend on whether the patient has Type 1 diabetes, pneumonia, and from 10,000–30,000 people with which invariably requires some form of insulin deliv- diabetes die of flu or pneumonia each year. Only ery, or Type 2 diabetes, which can often be treated with oral medications. The Diabetes Prevention slightly more than half of them (55 percent) get an Program studied more than 3,000 people at risk for annual flu shot although nearly all are eligible for developing Type 2 diabetes (they had impaired glu- such injections. cose tolerance/prediabetes). Researchers compared Increasing numbers of people with diabetes are the effects of diet and exercise to treatment with being hospitalized. For example, according to the medication. One group was given medication National Center for Health Statistics, in the years (metformin), and individuals in a second group 1990–91, there were 121.0 hospital discharges per (the lifestyle group) were given information and 10,000 people among those individuals ages 45–54 the goal of dropping their body weight by 7 percent years old. This rate has steadily increased. Over the by exercising. A third group was a placebo group. period 2000–01, it was 156.6 per 10,000 people. The study was ended about a year earlier than The rates of hospitalization also increased for indi- planned because the benefits of weight loss and viduals in the age brackets of 55–64 years, 65–74 medication were so clear. The lifestyle group had a years, and 75 years and older (see Table III). 58 percent lower incidence rate of diabetes than Clearly, diabetes is becoming a greater problem for the placebo group. The medication group had a 31 middle-aged and senior adults than in past years, percent reduced occurrence of developing Type 2 possibly because so many more individuals in these diabetes compared with the placebo group. Clearly, 64 diabetic ketoacidosis exercise and medication can prevent or delay Type Reducing the Health and Economic Burden of 2 diabetes in many people. Chronic Disease.” Department of Health and Human Among those who are already diagnosed with Services, 2003. diabetes, studies have shown that improving Cherry, Daniel K., Catharine W. Burt, and David A. glycemic control to reduce hemoglobin A1c blood Woodwell. “National Ambulatory Medical Care tests by even 1 percent will reduce the risk of dia- Survey: 2001 Summary.” Division of Health Care betic complications by 40 percent. Statistics, Centers for Disease Control and Prevention, no. 337, August 11, 2003. Prevention of Diabetes and Diabetic Complications Narayan, K. M., M.D., et al., “Lifetime Risk for Diabetes To date, Type 1 diabetes is a disease that is difficult Mellitus in the United States,” Journal of the American or even impossible to prevent, although it can be Medical Association 290, no. 14 (October 8, 2003): well controlled with a careful diet, exercise, and 1884–1890. insulin therapy. Ongoing clinical studies are look- National Institute of Diabetes and Digestive and Kidney ing at various means to delay or prevent the onset Diseases. “Most People with Diabetes Do Not Meet of Type 1 diabetes in susceptible individuals, such Treatment Goals.” Press Release, National Institutes of as those with impaired glucose tolerance. Health, January 20, 2004. Studies have indicated that Type 2 diabetes can be Petit, William A. Jr., M.D., and Christine Adamec. The prevented or delayed in patients at high risk. These Encyclopedia of Diabetes. New York: Facts On File, Inc., high-risk individuals are obese, have impaired glu- 2002. cose tolerance and are considered to have predia- Schillinger, Dean, M.D., et al. “Closing the Loop: betes, and are people with first-degree relatives Physicians Communication with Diabetic Patients (such as a parent or sibling) with Type 2 diabetes. Who Have Low Health Literacy.” Archives of Internal See also DIABETIC KETOACIDOSIS; GESTATIONAL Medicine 163, no. 1 (January 13, 2004): 83–90. DIABETES; HYPERGLYCEMIA; HYPOGLYCEMIA; IMPAIRED Tuomilehto, Jaako, M.D., et al. “Prevention of Type 2 GLUCOSE TOLERANCE; TYPE 1 DIABETES; TYPE 2 DIA- Diabetes Mellitus by Changes in Lifestyle Among BETES. Subjects with Impaired Glucose Tolerance.” New For further information, contact the following England Journal of Medicine 344, no. 18 (May 3, 2001): organizations: 1,343–1,350. American Diabetes Association (ADA) 1701 North Beauregard Street diabetic ketoacidosis (DKA) An acute and often Alexandria, VA 22311 severe metabolic complication that occurs to some (703) 549-1500 or (800) 342-2383 (toll-free) patients with diabetes (both TYPE 1 DIABETES and http://www.diabetes.org TYPE 2 DIABETES). DKA involves a combination of National Diabetes Information Clearinghouse HYPERGLYCEMIA (excess acid in the blood) and DEHY- 1 Information Way DRATION. Bethesda, MD 20892 DKA is so serious that it requires patients to be (800) 860-8747 (toll-free) hospitalized (usually in the intensive care unit) until http://diabetes.niddk.nih.gov they are stabilized. In the worst cases, DKA may lead to coma and death. Experts report a death rate of American Diabetes Association. “Economic Costs of 5–10 percent among patients who lapse into diabet- Diabetes in the U.S. in 2002.” Diabetes Care 26, no. 3 ic ketoacidosis. DKA may also cause cerebral (brain) (March 2003): 917–932. edema, which greatly heightens the risk of death, Bardsley, Joan K., and Maureen Passaro, M.D. “ABCs of especially among children with Type 1 diabetes. Diabetes Research.” Clinical Diabetes 20, no. 1 (2002): 5–8. Risk Factors for Developing DKA Centers for Disease Control and Prevention, Chronic The presence of diabetes is the major risk factor for Disease Prevention. “The Promise of Prevention: the development of DKA. Poor glycemic control diabetic nephropathy 65

(patients’ inadequate monitoring of blood glucose further relapses into DKA. Patients who have been levels, poor nutrition, and inadequate therapy) is hospitalized for DKA should wear a medical identi- another risk factor. However, sometimes blood lev- fication bracelet that shows they have diabetes so els can change precipitously no matter how consci- that if the condition recurs, they will be likely to entious patients are about checking their blood. obtain proper medical care in a timely manner. For One major problem is that not everyone who patients with diabetes, speed in treatment may has diabetes mellitus is actually aware that they mean the difference between life and death. have the disease. In fact, they may first discover See also COMA. their illness when they are hospitalized and diag- Glaser, Nicole, M.D., et al. “Risk Factors for Cerebral nosed with DKA. Ethnicity is another key factor in Edema in Children with Diabetic Ketoacidosis.” New DKA. African Americans are twice as likely to be England Journal of Medicine 344, no. 4 (January 25, admitted to the hospital for DKA as Caucasians. 2001): 264–269. Age is another risk factor, as DKA risks increase Rewers, Arleta, M.D. “Predictors of Acute Complications with age. in Children with Type 1 Diabetes.” Journal of the Symptoms of DKA American Medical Association 287, no. 19 (May 15, 2002): 2,511–2,518. Blurred vision, nausea, abdominal pains, and lack of appetite are all common symptoms of DKA. The individual may also experience increased urination and great thirst. Dehydration may be both a symp- diabetic nephropathy Kidney disease that stems tom and a cause of DKA. directly from DIABETES MELLITUS and that may ultimately result in kidney failure. According to the Diagnosis and Treatment National Diabetes Information Clearinghouse, in The diagnosis of DKA is based on the patient’s clin- 2001 nearly 43,000 patients with diabetes began ical presentation as well as on the results of tests, treatment for end-stage renal disease (another such as blood glucose levels and urine and/or name for kidney failure). serum acetone levels, all typically high in patients Patients who have diabetic nephropathy repre- with DKA. In addition, often an arterial blood gas sent nearly half (42 percent) of all the kidney fail- is drawn to measure the pH level in the blood, ure patients in the United States. Diabetic which shows the level of acidity or alkalinity. nephropathy is also the cause for either kidney Normal pH is 7.4, while in patients with DKA, it is dialysis or a kidney transplant among an estimated less than 7.3. 100,000 people each year. Most patients with dia- Once DKA is diagnosed, the patient is given betic nephropathy also suffer from DIABETIC aggressive fluid resuscitation as well as insulin. RETINOPATHY, a disease of the eye. Typically, short-acting insulin is administered intra- Unfortunately, patients with kidney disease usu- venously and is followed by a continuous intra- ally do not have any symptoms until less than 25 venous drip of the same insulin at a lower level. The percent of their kidney function remains. However, fluid that is usually given initially is normal saline. diligent testing by physicians, such as testing for Once the patient is producing urine, potassium gen- very small amounts of protein in the patient’s erally needs to be administered as the vast majority urine, can often detect an early onset of kidney of patients with DKA have a total body deficit of dysfunction. Blood tests to measure creatinine and potassium. Once the emergency issues are treated, blood urea nitrogen (BUN) can also be monitored the physician must determine the underlying cause by physicians every three to six months, but these of the DKA and treat that cause aggressively. tests are less sensitive than monitoring the urine Once the patient has sufficiently recovered, the for protein. Increases in creatinine and BUN levels physician will emphasize the importance of main- are also indicators of kidney disease. taining blood glucose levels that are as close to nor- The current standard of care is to monitor the mal as possible with the hope that there will be no patient first with a simple dipstick urine test. If pro- 66 diabetic nephropathy tein is present in the urine, the patient has overt betes, the federally funded Diabetes Control and proteinuria. The patient will need strict attention to Complications Trial Research Group, 1,441 subjects glycemic control, blood pressure, and lipids as well with Type 1 diabetes were studied from 1983–93. as treatment with angiotensin-converting enzyme The study definitively proved that the group that (ACE) inhibitor mediations or angiotensin receptor successfully and tightly controlled their diabetes had blockers (ARBs). a 50 percent reduced risk for kidney disease (and If no protein is seen in the urine dipstick test, a also a 60 percent reduced risk for nerve disease). second, more sensitive test for urine microalbuminuria can be obtained. Typically, this is a Signs and Symptoms radioimmunoassay that detects tiny amounts of In the early stages of the disease, there may be few protein in the urine. If patients have less than 30 or no symptoms, although there may be micro- mcg of albumin per mg of creatinine, their levels scopic levels of albumin and increased creatinine are considered normal. If the level is 30–300 mcg levels. As the illness progresses the albumin and albumin per mg of creatinine, patients have creatinine levels increase, and the proteinuria microalbuminuria. These patients are treated with becomes apparent. If the patient’s kidneys further ACE and/or ARB drugs, and strict attention is paid deteriorate, symptoms such as malaise and itchy to their glucose and lipid levels. skin may develop. Patients may show fatigue and When the level is greater than 300 mcg of albu- decreased endurance. They may also retain fluid in min per mg of creatinine, patients have macroal- the ankles and elsewhere in the body. buminuria or overt proteinuria. Once a patient has Physicians should check the urine of their a serum creatinine level greater than 1.8 mg/dl or patients with diabetes on a regular basis to detect has had greater than 1,000 mg of protein in their any early signs of diabetic nephropathy. That way, urine over 24 hours, he or she should be referred to it can be treated before the condition becomes too a nephrologist for further consultation and therapy. advanced and the patient requires kidney dialysis and a kidney transplant. Causes of Nephropathy The cause of diabetic nephropathy is often a com- Genetic Risks bination of both hypertension and diabetes. Patients with these two medical problems have a Researchers have found that the siblings of patients mortality risk that is increased by 37 times over who have both diabetes and kidney disease have that of patients with one of these ailments. Patients five times the risk of developing diabetic nephropa- with diabetes who do not have hypertension can thy themselves. In the future, doctors may be able also develop diabetic nephropathy, although their to estimate a patient’s risk by the detection of vari- risk is reduced compared with patients who have ous forms of the ACE gene. both medical problems. Because of the links connecting diabetes and Diagnosis and Treatment hypertension with kidney disease, patients with The diagnosis of diabetic nephropathy is based on the both hypertension and diabetes must comply close- patient’s symptoms and laboratory tests. Physicians ly with the medical regimens prescribed by their may order a 24-hour urine collection, a test that pro- physicians for decreasing high blood pressure. vides a good estimate of kidney function and also These regimens include taking medication, losing measures excess amounts of protein being lost in the weight (if weight loss is recommended), and fol- urine. If detected early, diabetic nephropathy can be lowing other medical advice. treated with medications. In most cases, ACE Patients with diabetes should work hard to keep inhibitors and/or ARB blockers are used to slow their glucose levels as close to normal as possible by down the progression of kidney disease. testing their blood on a regular basis and, if neces- Blood pressure is also a consideration. The goal sary, acting on the information provided by the blood pressure may be as low as 120/70 if clinical- blood tests. In a major study of people with dia- ly indicated in patients with kidney disease. diabetic neuropathy 67

See also BLOOD PRESSURE/HYPERTENSION; TYPE 1 Diagnosis DIABETES; TYPE 2 DIABETES. Physicians diagnose diabetic neuropathy based on Petit, William A. Jr., M.D., and Christine Adamec. The the patient’s medical history and physical examina- Encyclopedia of Diabetes. New York: Facts On File, Inc., tion. The most common form of neuropathy, the 2002. stocking-glove form, or peripheral sensory neuropathy, is often diagnosed based on history alone. These patients typically complain of numbness, tingling, burning, or a sense that something is in their diabetic neuropathy Nerve damage directly shoe. In addition, they note that their symptoms caused by diabetes. Diabetic neuropathy may result increase when they remove their socks and shoes in a variety of ailments, including a loss of feeling and try to go to sleep. They often complain that the in the feet or hands, the delayed digestion of food, bedclothes bother their feet. This very sensitive ERECTILE DYSFUNCTION, and many other medical feeling is called hyperesthesia. problems. About 60–70 percent of all patients with Early on in this disorder, the nerve conduction diabetes will eventually suffer from some neuropa- studies and electromyograms that are usually done thy, ranging from a mild to a severe form. are not helpful and often have normal findings. Maintaining excellent glucose control may delay or This is because they measure larger myelinated prevent the development of neuropathy. nerve fibers that are affected much later in the When the nerves of the face are affected, dia- course of the disease. On examination, these betic neuropathy can mimic symptoms of a stroke patients may have loss of ankle reflexes or changes and may also cause a facial droop similar to that in sensory testing to stimuli such as vibration and a found in Bell’s palsy. Diabetic neuropathy may also light touch with nylon microfilaments. cause an eyelid droop. These types of neuropathies are caused by nerve attacks, a sudden blockage of blood flow to the nerve. This problem is similar to Treatment that of a heart attack or a stroke. Syndromes affect- Diabetic neuropathy may also cause chronic and ing the cranial nerves are called cranial mononeu- sometimes severe pain. People with diabetes may ropathies. need medications or creams. The first therapy is to A radiculopathy is a painful neuropathy in tighten glucose control to as near-normal levels as which a nerve root is directly affected. If the nerve possible. Patients are also counseled to stop smok- root supplying the area is located just below the ing and to normalize their blood pressure and lipid right lower ribs of the patient, it can mimic a gall- levels. Often medications are given at bedtime, bladder attack. If the radiculopathy is located in the when patients’ symptoms are typically the worst. nerves of the lower legs, it can cause sciatica. Simple analgesics such as acetaminophen (Tylenol) may be given to patients. The drug tra- madol (Ultram), which is a nonnarcotic and not a Other Focal Neuropathies nonsteroidal anti-inflammatory medication (NSAID), Patients with diabetes are more commonly affected is given if acetaminophen provides insufficient pain than nondiabetics by carpal tunnel syndrome (in relief. Many people do not wish to take narcotics or the fingers) and tarsal tunnel syndrome (in the NSAIDs because of their side effects. The next med- foot, typically in the heel). These syndromes may ication usually tried is in the class of antiseizure or occur because of a deposit of carbohydrates and antidepressant medications. Antidepressants such as proteinlike material in the canals where the nerves amitriptyline (Elavil) or nortriptyline (Aventyl or run. The problem may also be caused by medica- Pamelor) or the antiseizure drug gabapentin tions as well as by blood flow problems. (Neurontin) may be used. Damage to the peroneal nerve in the foot can When a patient has a lancinating (shooting) form lead to foot drop. This is the inability to extend the of pain, carbamazepine (Tegretol) is also very helpful. foot, causing it to drag when walking. Memantine (Namenda and Axura), a medication 68 diabetic retinopathy currently indicated to treat Alzheimer’s disease, has The National Diabetes Eye Examination Program also been found to be effective in reducing neuro- offers free eye examinations to patients with dia- pathic pain for patients. betes who are over age 65 and on Medicare. If the neuropathy is in a very localized area, topical medications such as capsaicin or lidocaine can Risk Factors be used. As a last resort, narcotics have been used People with TYPE 1 DIABETES are at greater risk for with success. developing retinopathy than patients with TYPE 2 See also TYPE 1 DIABETES; TYPE 2 DIABETES. DIABETES. In fact, almost all patients who have had Type 1 diabetes for 15 or more years have some The Diabetes Control and Complications Trial Research degree of retinopathy. Patients with Type 2 diabetes Group. “The Effect of Intensive Diabetes Therapy on who require insulin are also likely to develop the Development and Progression of Neuropathy.” retinopathy. Annals of Internal Medicine 122, no. 8 (April 15, 1995): African Americans who have Type 1 diabetes are 561–568. particularly at risk for developing diabetic retinopa- Petit, William A. Jr., M.D., and Christine Adamec. The thy. In fact, African Americans with diabetes face a Encyclopedia of Diabetes. New York: Facts On File, Inc., 40–50 percent greater risk than Caucasians with dia- 2002. betes of developing diabetic retinopathy. Hispanics with diabetes, especially Mexican Americans, are also at high risk for developing the condition. It is also diabetic retinopathy Disease of the retina of the possible for children who have diabetes to suffer eye, directly stemming from diabetes mellitus. from diabetic retinopathy, although the risk appears Diabetic retinopathy is the most common eye dis- to be low, especially prior to the onset of puberty. ease found among people diagnosed with diabetes. The people with diabetes who are the most like- According to the National Institutes of Health ly to suffer from diabetic retinopathy include those (NIH), diabetic retinopathy causes from who: 12,000–24,000 new cases of blindness each year and is estimated to cause 12 percent of all new • Did not control their diabetes in the first years cases of blindness each year. It is also the leading after diagnosis cause of adult-onset blindness. • Have had diabetes for 17 or more years Diabetic retinopathy is at least partially caused by • Experience high blood pressure high levels of glucose that result in varying levels of harm to the blood vessels in the retina. Other fac- • Are African American, Native American, or tors, such as a genetic predisposition to developing Hispanic the disease, hypertension, smoking, hyperlipidemia, • Have high cholesterol levels and kidney disease, may worsen the retinopathy. • Have had gestational diabetes An early diagnosis, determined by a dilated eye • Are smokers examination and followed by appropriate treatment, could prevent the loss of sight for over 90 • Abuse alcohol percent of patients with diabetes. Because the early • Have other illnesses, such as kidney disease stages of the disease produce no symptoms, only an • Have a genetic risk for eye disease early eye examination will detect possible problems. However, according to the National Institutes of Health, less than half (47 percent) of all patients Indications of Diabetic Retinopathy diagnosed with diabetes have annual eye examina- Few symptoms of early diabetic retinopathy are tions. In its Healthy People 2010 plan, the federal detectable to the patient. This is why screening government has set a goal that 75 percent of all examinations are so critical. Some early symptoms adults with diabetes have a dilated eye examina- may be a worsening of peripheral (side) vision or tion each year. worse color vision. A dilated eye examination per- dwarfism 69 formed by an ophthalmologist (a medical doctor American Academy of Ophthalmology who specializes in eye diseases) or an optometrist P.O. Box 7424 should reveal the problem. Symptoms may often San Francisco, CA 94120-7424 be mistaken by the patient as minor problems or as (415) 561-8500 signs of aging. http://www.eyenet.org

Diagnosis and Treatment National Eye Health Education Program 2020 Vision Place A dilated eye examination will detect diabetic Bethesda, MD 20892-3655 retinopathy, which is why annual eye examina- http://www.nei.nih.gov/nehep tions are crucial for all adults who have been diagnosed with diabetes. Patients with Type 1 diabetes The Diabetes Control and Complications Trial Research should begin annual eye examinations after having Group. “Early Worsening of Diabetic Retinopathy in diabetes for five years. In contrast, those with Type the Diabetes Control and Complications Trial.” The 2 diabetes should have a yearly examination Archives of Ophthalmology 116, no. 7 (1998): 874–886. beginning the year they are diagnosed. This is due Fong, Donald S., M.D., and Robin Demi Ross, M.D. The to the fact that many patients with Type 2 diabetes Diabetes Eye Care Sourcebook. Los Angeles, Calif.: Lowell have had metabolic derangements for seven to 12 House, 1999. years prior to diagnosis. Petit, William A., Jr., M.D., and Christine Adamec. The Encyclopedia of Diabetes. New York: Facts On File, Inc., Treatment of Diabetic Retinopathy 2002. If diabetic retinopathy is in the early stages, tight glycemic control may help. This means that the person with diabetes must carefully note glucose dwarfism A skeletal deformity, usually inherited, levels and respond to significant changes. that causes below-normal height (usually the indi- When the retinopathy is advanced, laser sur- vidual is less than four feet, 10 inches in height) gery, which is also known as photocoagulation, and often results in other characteristic features, may help the patient. The physician uses a special such as a broad forehead, a large head compared laser to make tiny burns over the surface of the with the body, and disproportionately short arms retina and to destroy blood vessels that are growing and legs. (Individuals with pituitary dwarfism, over the surface of the eye or stop leakage from however, have arms and legs that are proportional retinal vessels. to their bodies.) In rare cases, dwarfism is caused Laser photocoagulation is very successful in by a growth hormone deficiency. There are an esti- most patients who have diabetic retinopathy. This mated 200 different types of dwarfism. However, procedure also reduces the risk of blindness in peo- the most common form is achondroplasia, which ple with diabetic retinopathy by approximately 50 represents about 50 percent of all cases. percent. The advantages of laser therapy are that It should be noted that some individuals with no incision is required and that it can be performed dwarfism are offended by the term dwarf, and they on an outpatient basis. The procedure is best done prefer to be known as little people or as a person of when the patient’s eyesight is still normal or near- short stature. Others, however, do not have a prob- ly normal. A disadvantage of the surgery is that it lem with the words dwarf or dwarfism. does not always resolve the problem. Sometimes surgery requiring an incision must Achondroplasia be performed to preserve vision. The vitrectomy is The most common form of dwarfism is achon- a surgical procedure that removes old blood and droplasia, which occurs in about one in 15,000 to scar tissue from within the eye, all of which have one in 40,000 births. (Researchers have been resulted from the disease. unable to narrow the incidence any more precisely See also EYE PROBLEMS. than this range.) Most people with achondroplasia For further information, contact: are about four feet in height and were born to 70 dwarfism nondwarf parents of average size. Nearly all (97 two or three years old, when their growth lags percent) of individuals with achondroplasia have a behind that of other children their own age. mutation in their fibroblast growth factor receptor (FGFR) 3 gene. Individuals with achondroplasia Diseases That May Cause Short Stature usually have small stature, large heads, flattened Some medical problems, such as MCCUNE- bridges of the nose, short upper arms and legs, and ALBRIGHT SYNDROME, TURNER SYNDROME, and CON- incomplete elbow extensions. Children with GENITAL ADRENAL HYPERPLASIA, may result in achondroplasia are at risk for obstructive apnea (a dwarfism and short stature. Treatment may help breathing disorder) and hydrocephalus (enlarge- mitigate the growth outcome if the child is treated ment of the brain). early enough. Children who experience EARLY It is important to note, however, that despite PUBERTY are also at risk for short stature. OSTEOGE- these variations from the appearance of the aver- NESIS IMPERFECTA, an inherited condition of brittle age person, many people with achondroplasia lead bones, may also cause dwarfism, and individuals normal lives. Additionally, most of them are fertile. with this condition usually do not exceed three feet in their final height.

Other Forms of Dwarfism Treatment of Dwarfism Although achondroplasia is the most common Treatment depends on the nature of the dwarfism. form of dwarfism, there are other types as well. Growth hormone may be used in children whose These include hypochondroplasia, thanatophoric bones have not yet fused. In a study reported in a dysplasia (TD), and severe achondroplasia with 1996 issue of the Journal of Clinical Endocrinology & development delay and ACANTHOSIS NIGRICANS Metabolism, Shohat and colleagues reported on (SADDAN). their study of 15 children with achondroplasia and People with hypochrondroplasia are of small hypochondroplasia who were treated with growth stature and have bowed limbs. They may have nar- hormone. The children’s ages ranged from three to rowed spines and lumbar lordosis. 12 years. The children showed significant growth, Thanatophoric dysplasia is so severe that it is particularly the children with hypochondroplasia. usually fatal. This form of dwarfism occurs in an The body disproportion did not increase with estimated one of every 60,000 births, and most of growth as the researchers had feared it might. these babies die as newborns. Children and adults with dwarfism may require Individuals with SADDAN suffer from chronic joint replacement because of early wear and tear on seizures and hydrocephalus during infancy. Both the joints. Some adults have back fusion or neck their intellectual and motor development is much fusion surgery to strengthen that part of their spine. delayed. Limb lengthening is a controversial form of treat- Pituitary dwarfism, which is also known as ment, in which the bones are cut and pins are insert- growth hormone deficiency dwarfism, is caused by ed to cause new bone growth and lengthening. It is a growth hormone deficiency rather than by an a very painful process that takes at least two years inherited defect. (People with pituitary dwarfism and has not been evaluated as of this writing. were formerly called midgets; however, that term is considered particularly offensive by most people of Daily Living short stature.) Individuals of short stature need to make many About 10,000–15,000 people in the United daily adaptations. For example, they may need spe- States have pituitary dwarfism. People with pitu- cial tools to help them reach light switches and itary dwarfism have arms and legs that are propor- other common devices. The child or adult may tionately sized to their short stature. Sometimes need an expandable wand to enable her to reach children with pituitary dwarfism are treated with the toilet paper holder in bathrooms. Simple stools growth hormone. Children born with pituitary will enable the child or adult to reach many areas dwarfism may grow normally until they are about that are too high for their arms. Adaptations will dwarfism 71 need to be made to cars so that adults can drive. Francomano, Clair A., M.D. “The Genetic Basis of Some experts recommend that air bags be removed Dwarfism.” New England Journal of Medicine 332, no. 1 from the car, because if activated, they can be very (January 5, 1995): 58–59. dangerous to adults of small stature. Shohat, M., et al. “Short-Term Recombinant Human There are also emotional and psychological pres- Growth Hormone Treatment Increases Growth Rate sures upon persons of short stature. Children and in Achondroplasia.” Journal of Clinical Endocrinology & adults must face staring from children and adults as Metabolism 81, no. 11 (1996): 4,033–4,037. well as questions and sometimes negative com- Vajo, Zoltan, Clair A. Francomano, and Douglas J. ments from others. Some people treat persons of Wilkin. “The Molecular and Genetic Basis of short stature as if they were children. During Fibroblast Growth Receptor 3 Disorders: The school years, physical education with other chil- Acondroplasia Family of Skeletal Dysplasias, Muenke dren or adolescents may be difficult or even dan- Craniosynostotis, and Crouzon Syndrome with gerous. Instead, the individual’s other talents, in Acanthosis Nigricans.” Endocrine Reviews 21, no. 1 music, art, or other abilities, should be encouraged. (2000): 23–39. See also GROWTH HORMONE. For further information on dwarfism, contact: Little People of America, Inc. 5289 Northeast Elam Young Parkway Suite F-700 Hillsboro, OR 97124 (888) LPA-2001 (toll-free) http://www.lpaonline.org

E early puberty An earlier-than-normal onset of demonstrated that often African-American girls the body changes that normally occur during ado- experience normal puberty before Caucasian girls.) lescence. Early puberty is generally defined as The researchers found that bone ages were occurring in girls younger than age eight and boys advanced by as much as five years in the girls who younger than age nine. However, early puberty can had at least two signs of pubertal development. occur in children as young as two or three years old. Some girls with breast development alone had a Early puberty is also known as precocious puberty. bone age that was well advanced for their years. Some children are at particular risk for develop- Early puberty is problematic because it means the ing early puberty, such as boys with KLINEFELTER child’s growth will end prematurely and, conse- SYNDROME and girls with MCCUNE-ALBRIGHT SYN- quently, these children will attain a height much DROME, follicular cysts, or stromal cell ovarian lower than that of their peers. Though it is not a tumors. Early puberty can also be seen in children form of DWARFISM, the short stature of individuals who have cerebral palsy, NEUROFIBROMATOSIS TYPE 1, with an early puberty may be in the similar range CONGENITAL ADRENAL HYPERPLASIA, or fetal alcohol of individuals who are diagnosed with dwarfism. syndrome. In boys, precocious puberty is often due to tumors, radiation therapy, or a hypothalamic dis- Early Puberty and Internationally Adopted Girls order with increased secretion of gonadotropin- In several cases, some children (especially girls) releasing hormone (GnRH). who were adopted from orphanages in poor coun- If children are under the age of five or six years tries by parents in North America or Europe have old, hormones that are administered may help to evinced an early puberty. Physicians speculate that suppress the puberty. After that age, the physical the child who was living in an orphanage at a sub- changes may be difficult or impossible to reverse, sistence level and who was then adopted and given although studies have shown that growth in height all the food she or he needed experienced a surge can be stimulated by medications for at least sever- of growth that may have triggered a change to the al years. brain that caused the onset of the early puberty. In a study of 105 female patients with preco- In a 1998 study reported in the Archives of Disease cious puberty, reported in a 2003 issue of Pediatrics, in Childhood, Italian researchers studied 19 girls researchers found that about 12 percent of the adopted from India by Swedish families and who patients had other endocrine diseases or disorders, all experienced an early puberty. The researchers including McCune-Albright syndrome, growth found that hormone treatment to suppress the hormone deficiency, hyperinsulinism, HYPOTHY- puberty, which sometimes started at age four, was ROIDISM, neurofibromatosis, and PITUITARY ADENO- largely unsuccessful. In general, girls adopted MAS. The researchers in this study identified before the age of three are less likely to experience precocious puberty in girls as occurring before age an early puberty than girls adopted at an older age. seven or eight years in Caucasian girls and before In addition, girls who have a very dramatic growth age six to eight years in African-American girls. spurt within two years of adoption are more likely (The reason for the discrepancy is that research has to experience an early puberty.

73 74 early puberty

Pediatrician and international adoption expert for girls to rule out an ovarian tumor or cyst or Jerri Ann Jenista, M.D. has stated that children McCune-Albright syndrome. with even subtle indications of an early puberty, Boys with suspected early puberty should be such as body odor, any pubic or underarm hair, or tested for androgen levels. If they are elevated, this acne, should be seen by a pediatric endocrinologist may indicate the boy has congenital adrenal hyper- as soon as possible to determine if the child has plasia or a tumor of the adrenal glands. The thyroid experienced an early puberty or another illness level of the child should also be tested. In some and what, if anything, can be done to help the cases, hypothyroidism is the cause for early puber- child. ty in girls, and treatment with thyroid hormone causes a remission and, for example, the regression Signs and Symptoms of breast development. The signs of early puberty are the appearance of Treatment is aimed at maximizing final adult body hair in males and females (pubarche), enlarg- height, avoiding premature menstruation and sexual ing testicles in males, and breast budding (thelarche) activity, and treating associated psychosocial issues. in females. Other signs such as menstruation may Some physicians treat children with early puberty develop. In boys, a variety of tests are taken, includ- with medications such as luteinizing hormone- ing a pituitary computerized tomography (CT) scan releasing hormone (LHRH) agonist drugs. or a magnetic resonance imaging (MRI) scan as well In a study reported in a 2001 issue of the as tests to ascertain bone age and human chorionic Journal of Clinical Endocrinology & Metabolism by the gonadatropin (HCG) level. HCG can be secreted by a National Institutes of Health, researchers found Leydig cell tumor. In girls, a pelvic ultrasound is that treatment with LHRH agonist medications in taken. In all children, thyroid function is measured. girls before the age of eight years and in boys Pseudoprecocious puberty can also be caused by before age nine was effective at improving their the use of exogenous sex steroid hormones. final height. The 98 children, including 80 girls and 18 boys with precocious puberty, were treat- Psychological Consequences of Precocious Puberty ed with deslorelin for two or more years. As might be expected, it can be very difficult for a Although most of the children did grow, they child to experience an early puberty. A 12-year-old were still shorter than the norm. The researchers girl has enough difficulty coping with menstrual also found that even girls with a bone age of 13 periods, but at least many of her peers will be going years when treatment had started showed through the same situation at about the same time. improved growth. In contrast, it is not at all normal for a four- or five- See also DELAYED PUBERTY. year-old girl to have breasts and menstrual cycles. People can make cruel comments to such children. Adamec, Christine, and William L. Pierce. The Encyclopedia Children may also need to undergo therapy to help of Adoption, 2d ed. New York: Facts On File, Inc. 2000. them deal with the behaviors of others. Family Kaplowitz, Paul B., M.D., Sharon E. Oberfield, M.D., and therapy may help family members learn how to the Drug and Therapeutics and Executive Committees cope with the actions of others. of the Lawson Wilkins Pediatric Endocrine Society. “Reexamination of the Age Limit for Defining When Diagnosis and Treatment Puberty is Precocious in Girls in the United States: In most cases of precocious puberty, the diagnosis is Implications for Evaluation and Treatment.” Pediatrics not difficult because a physical examination of the 104, no. 4 (October 1999): 936–941. child reveals a sexual maturity beyond the norm Midyett, L. Kurt, M.D., Wayne V. Moore, M.D., and Jill for the child’s age. In addition, the physician may D. Jacobson, M.D. “Are Pubertal Changes in Girls order a gonadotropin-releasing hormone (GnRH) Before Age 8 Benign?” Pediatrics 111, no. 1 (January stimulation test. If the test results are greater than 2003): 47–51. seven to 10 IU/l, the diagnosis of precocious puber- Oerter Klein, Karen, et al. “Increased Final Height in ty is made. A pelvic ultrasound is usually ordered Precocious Puberty after Long-Term Treatment with eating disorders 75

LHRH Agonists: The National Institutes of Health Diagnosis and Treatment Experience.” Journal of Clinical Endocrinology & Eating disorders are diagnosed via the patient’s his- Metabolism 86, no. 10 (2001): 4,711–4,716. tory and physical examination. The history (often Raffaele, Virdis, et al. “Precocious Puberty in Girls given by others) that reveals symptoms such as Adopted from Developing Countries,” Archives of excessive eating or refusal to eat, anorexia, nausea, Disease in Childhood 78, no. 2 (1998): 152–154. fatigue, and constipation may point to an eating disorder. Physical signs, such as the loss of enamel on the teeth, bruises on the knuckles of the hands, eating disorders Generally refers to either weight loss, the growth of lanugo hair (very fine ANOREXIA NERVOSA (self-starvation) or bulimia body hair), and the presence of carotene in the nervosa, a condition in which the patient binges urine (carotenemia) may suggest an eating disorder and then self-induces vomiting. Some patients such as anorexia nervosa. abuse laxatives. Binge eating disorder is another Treatment is individualized but usually involves form of an eating disorder, in which patients eat the patient’s primary care provider, an endocrinol- large quantities of food several times a week, far ogist, a gastroenterologist, and a psychiatrist. In beyond when they feel full. They may be obese or severe cases, patients require hospitalization. Some may be of normal weight. Binge eating disorder is patients need long-term residential treatment. different from bulimia nervosa in that the patients See also IMPAIRED GLUCOSE TOLERANCE. do not induce vomiting. Eating disorders can be For further information on eating disorders, difficult to diagnose and treat. Some experts also contact the following organizations: characterize OBESITY as an eating disorder, while Academy for Eating Disorders most consider it to be a separate medical problem 60 Revere Drive in its own right. Suite 500 One unique eating disorder is hyperphagia, an Northbrook, IL 60062 uncontrollable desire to continue eating because of (847) 498-4274 a continuously ravenous and insatiable appetite. http://www.aedweb.org This medical problem is rare and is primarily found among individuals with PRADER-WILLI SYNDROME. Harvard Eating Disorders Center Some experts report that such patients have 55 Fruit Street extremely elevated levels of GHRELIN, a hormone YAW 6900 that controls appetite. The parents or caregivers of Boston, MA 02114 patients with Prader-Willi syndrome actually have (617) 726-8470 to lock up the refrigerator and kitchen cabinets or http://www.hedc.org the patient would eat everything in there. These National Eating Disorders Association patients are obese. 603 Stewart Street Eating disorders may cause or worsen existing Suite 803 endocrine problems, such as making diabetic Seattle, WA 98101 patients more ill. Eating disorders that lead to severe (206) 382-3587 weight loss may also cause AMENORRHEA as well as http://nationaleatingdisorders.org OSTEOPOROSIS. There is a fairly high incidence of eating disor- Becker, Anne E., M.D., et al. “Eating Disorders.” New ders in young patients with TYPE 1 DIABETES, espe- England Journal of Medicine 340, no. 14 (April 8, 1999): cially females. Early on, these patients realize that 1,092–1,098. by omitting their insulin doses and allowing their National Center on Addiction and Substance Abuse at glucose levels to run very high, this action puts Columbia University. Food for Thought: Substance Abuse them in a catabolic state with significant weight and Eating Disorders. National Center on Addiction and loss. Often this manipulation is subtle and vehe- Substance Abuse at Columbia University, December mently denied by the patient. 2003, New York, N.Y. 76 elderly

Zipfel, Stephan, et al. “Osteoporosis in Eating Disorders: the patients were taking melatonin compared with A Follow-Up Study of Patients with Anorexia and when they took the placebo. The researchers con- Bulimia Nervosa.” Journal of Clinical Endocrinology & cluded, “Melatonin deficiency may have an impor- Metabolism 86, no. 11 (2001): 5,227–5,233. tant role in the high frequency of insomnia among elderly people. Controlled-release melatonin therapy effectively improves sleep quality in this population.” elderly Generally defined as individuals who are Although it is often true that the first and most age 65 and older. Older people have an increased obvious diagnosis of a patient is usually the right one, risk for some endocrine diseases and disorders, when a patient does not improve with treatment, such as TYPE 2 DIABETES, OSTEOPOROSIS, and thyroid physicians should explore other possible causes of disease (especially HYPOTHYROIDISM), as well as for the medical problem. Many illnesses experienced by some endocrine cancers, such as OVARIAN CANCER older people can be diagnosed and treated. and PANCREATIC CANCER. Undiagnosed endocrine diseases can present Ageist Attitudes May Blind Some serious risks to elderly individuals. For example, Physicians to Existing Disease the majority of patients experiencing a MYXEDEMA Ageist attitudes, that older people are supposed to COMA (a thyroid crisis) are older people who were feel ill and that it is normal and acceptable for them previously not diagnosed with hypothyroidism. to feel sick, may sometimes prevent otherwise This disease may be brought on by the administra- competent physicians from exploring a variety of tion of sedating/hypnotic drugs that are given in causes of medical complaints from older people. If the hospital to previously undiagnosed elderly, elderly patients or their caregivers (such as family hypothyroid patients. members) feel that ageist attitudes are preventing the patient from receiving a proper diagnosis and Diagnosis of Endocrine Diseases in treatment, other physicians should be sought. the Elderly May Be Difficult Sometimes physicians do not realize the signifi- Multiple Medical Problems cance of signs and symptoms found among older Sometimes the diagnosis of an endocrine disease people. For example, patients may complain of means that older patients have an increased risk for joint pain and weakness. Many doctors may experiencing other medical problems. Elderly indi- attribute these problems to arthritis and aging viduals with diabetes are at risk for thyroid dis- when they may instead be caused by more unusu- eases, kidney diseases, eye disorders, cardiac al diseases and disorders, such as hyperparathy- ailments, and other disorders. In one study report- roidism. ed in a 2000 issue of Clinical Endocrinology, Older patients may have serious sleep disorders researchers found that older subjects with subclin- that have gone unidentified. These disorders may ical hyperthyroidism were at an increased risk for be caused by pineal gland insufficiency, which can developing dementia. be treated with controlled-release melatonin. In a Researchers have also found that older women study in Israel of 12 elderly individuals, all of whom with HYPERTHYROIDISM have a three times greater complained of chronic insomnia, researchers found risk of suffering from FRACTURES than women of below-normal blood levels of the main melatonin the same age with normal THYROID-STIMULATING metabolite, 6-sulphatoxymelatonin. The subjects HORMONE (TSH) levels. These findings were based were treated for three weeks with controlled- on a study of 686 white women older than age 65 release melatonin and then for three weeks were at four clinical centers in the United States. All the given a placebo. The patients’ sleep efficiency was patients had hyperthyroidism, and the patients measured with a wrist actigraphy device. were a subset of a much larger study of nearly The researchers found that the sleep efficiency 10,000 patients, the Study of Osteoporotic was significantly improved during the period when Fractures Research Group. The study was reported elderly 77 in a 2001 issue of the Annals of Internal Medicine. presence of hypothyroidism. Another laboratory The fracture risk was based on actual fractures test, of free T4 levels, may indicate the presence of experienced by the women over nearly six years hypothyroidism. and was verified by X-rays. Tests for thyroid-releasing hormone (TRH) may also be useful in older women but are not usually Medications May Act Differently on Older People valid to diagnose thyroid disease among older men. Physicians should realize that medications that In general, the older the patient, the less well the may work well in younger people can sometimes pituitary gland responds to a variety of stimuli. This cause harm to older people. Additionally, some- is truer for men than for women. times older people need a different dose of a med- Other laboratory tests may help to diagnose thy- ication than do younger people. roid disease present in senior citizens, such as a The kidneys and livers of elderly people often check of the creatine phosphokinase (CPK) levels, are less efficient than those of younger people, and which are elevated when thyroid disease is present their overall metabolisms may be much slower, in older people. Some older people also have ane- even when no evidence exists of thyroid disease. In mia with hypothyroidism, which responds to treat- addition, some drugs may further exacerbate other ment with LEVOTHYROXINE (L-thyroxine), a thyroid existing medical problems. For example, met- supplement. formin, a medication often used to treat diabetes, can cause lactic acidosis, which is dangerous in Treatment May Be Different for Older People patients with renal insufficiency or heart disease. Once illness is determined, the treatment for the medical problem may not be the same as for Signs and Symptoms of Endocrine younger people. For example, doctors may decide Disorders May Be Different that surgery for thyroid disease is too dangerous or Sometimes when older people have endocrine dis- not indicated in an older patient. However, it is eases and disorders, they do not have the same important to distinguish between whether treat- symptoms or signs as seen among younger people ments may be unsafe, and thus should be avoided, who have the same disease. For example, older and the presence of ageist attitudes among some people with hypothyroidism may present with few doctors, who may assume that older people should or no symptoms or with symptoms that are easily accept illness as a part of aging. overlooked, such as fatigue and general achiness as well as various vague complaints. Older people with Older People and Diabetes thyroid disease often do not have GOITERS, whether An estimated 11 percent of all Americans ages six to they have hyperthyroidism or hypothyroidism. 74 years have diabetes. Among Americans age 65 Older patients with hyperthyroidism may not be and older, an estimated 20 percent have diabetes, hyperactive but, instead, may appear apathetic and although only about half are aware that they have depressed (apathetic thyrotoxicosis). Physicians the disease. Among some racial groups, such as need to realize that the symptoms of older people African Americans and Native Americans, diabetes is with thyroid disease may be much more subtle among the top five causes of death of older people. than those found in younger individuals. According to John R. White Jr. and R. K. Campbell, authors of the chapter on managing Laboratory Tests and Values May Differ in Elderly Type 2 diabetes in the book Diabetes Mellitus in the When older people have endocrine diseases, some Elderly, “The [older] patient with diabetes is 25 of the laboratory tests used to diagnose them times more likely to become blind, 17 times more should be different than those used to diagnose likely to develop kidney disease, 20 times more younger people. For example, when hypothy- likely to develop gangrene, and 2 times more like- roidism is present among older people, often the ly to suffer a stroke or a heart attack than aged TSH values may be in the normal range despite the matched cohorts without diabetes. However, 78 elderly recent studies have demonstrated a tight correla- older individuals are unable to test their own blood, tion between development and progression of most a caregiver (a family member, a staff person at an of the chronic complications of diabetes and strict assisted living facility or nursing home, or another glycemic control.” person) should do the tests for the patient and act Despite the seriousness of diabetes among older upon the information that the test provides. individuals, as mentioned earlier, as many as half of all seniors with diabetes do not know they have the disease. Part of the reason is that the signs and Osteoporosis and Seniors symptoms of diabetes in elderly individuals may Middle-aged and younger people may develop not be the same as found among younger people. OSTEOPOROSIS. However, it is the most dangerous For example, intense thirst is not always present in when present among elderly individuals because of older people with undiagnosed diabetes. the increased risk for bone fractures. In addition, In addition, rather than frequent urination, the rate of hospitalization for vertebral fractures which is a common symptom among nonelderly caused by osteoporosis increases dramatically with patients with untreated diabetes, older people with age. For example, among people between the ages diabetes are more likely to experience urinary of 65–74 in the United States, 6.7 people per 1,000 incontinence. Rather than experiencing intense are hospitalized because of an osteoporotic verte- hunger, older people with undiagnosed diabetes bral fracture. This rate nearly quadruples for people are more likely to have a lack of appetite and to age 75–84, to a rate of 26 people per 1,000. The experience weight loss. In addition, older people rate of hospitalization for vertebral fractures rises with undiagnosed diabetes may also present with still higher for people ages 85 and older, with a rate psychiatric features such as mental confusion, that of 39 people per 1,000. are misconstrued by physicians and others. Many people believe that only older women are When diabetes is diagnosed in older people, it at risk for osteoporosis. However, older men are at may also be treated differently by doctors than when risk as well. In some studies, such as the Rotterdam the illness is diagnosed in younger people. Study, bone loss in men ages 70–75 was actually Physicians may not insist on as tight a glycemic con- worse than the bone loss found among same-aged trol because very tight glycemic control may be dif- women. ficult or impossible to achieve in some older Some experts believe that bone loss is linked to individuals. Doctors may also not press patients to declining levels of growth hormone among elderly lose weight unless they are truly obese. However, as individuals, but studies to date have not borne out with all other patients, physicians usually urge older this hypothesis. Further studies are needed to patients with diabetes to get regular exercise, partic- determine if administering growth hormone could ularly recommending walking on a regular basis. improve bone density levels in older individuals. Older patients with Type 2 diabetes may be able However, studies on providing another substance, to control their illness with oral medications. vitamin D, to elderly individuals who were defi- However, sometimes insulin and other drugs are cient in vitamin D have demonstrated that bone required to treat the disease as well, depending on density can improve with this supplementation. In its severity. It is also possible for an older person to one study, femoral bone density increased 2–7 per- be diagnosed with Type 1 diabetes (which always cent over 18 months in elderly women given vita- requires insulin), although the disease presents in min D, while it declined 4–6 percent in the group the senior years only very rarely. that received the placebo. People with diabetes (or their caregivers) should Osteoporosis is considered primary osteoporosis test their blood at least several times each day to if no illness or cause can be found for it. It is usual- obtain information that lets them know whether to ly treated with medications such as alendronate increase or decrease their glucose levels. This is (Fosamax) to build up the bones. Other drugs that important for elderly people who may develop are prescribed for osteoporosis are risedronate hypoglycemia (low blood sugar), which can itself be (Actonel), raloxifene (Evista), and calcitonin dangerous, and could lead to falls and injuries. If (Miacalcin). elderly 79

Osteoporosis is considered to be secondary if roidism, which is not seen in middle-aged or other factors have caused this medical problem. younger adults with hyperthyroidism. Weakness is Many older people have secondary osteoporosis that another sign of hyperthyroidism among the aged. was originally caused by hypogonadism, THYROTOXI- The older person with hyperthyroidism may COSIS, and HYPERPARATHYROIDISM. Some medications, appear listless and depressed, unlike the younger such as GLUCOCORTICOIDS and anticonvulsants, can individual with the same disease, who is overac- also cause secondary osteoporosis. Some lifestyle tive, nervous, and even manic. choices, such as alcohol abuse and smoking, can Elderly women with hyperthyroidism have a induce secondary osteoporosis as well. three times greater risk of having fractures than With secondary osteoporosis, a variety of treat- women of the same age with normal TSH levels. ment recommendations can be made based on the Even a history of having hyperthyroidism is associ- underlying cause of the osteoporosis. For example, ated with twice the risk of developing fractures. people who smoke should immediately stop smok- In general, physicians should treat patients ing. Endocrine diseases and disorders such as based on their physiological age rather than their hypogonadism, thyrotoxicosis, and hyperparathy- chronological age. Some patients who are 70 years roidism can and should be treated. If medications old may have no illness, and may be physically fit, are inducing secondary osteoporosis, physicians at an ideal body weight, and able to tolerate most may change the drug or lower the dose. For exam- medications and/or procedures. These patients are ple, if glucocorticoid drugs have caused secondary what physicians refer to as 70 going on 50. osteoporosis, physicians may decide to prescribe Obviously, the opposite is also true. A 40-year- thiazide diuretics to correct this problem. old patient may have diabetes mellitus with multiple complications, such as diabetic nephropathy Thyroid Disease and the Elderly and diabetic neuropathy, and may be unable to tol- Thyroid disease, particularly hypothyroidism, is erate certain medications and/or procedures well. common among older people. However, as men- This patient is considered by doctors to be age 40 tioned earlier, the signs and symptoms in older going on age 70. people may be different from those of younger See also DIABETES MELLITUS; FRACTURES; TYPE 1 people. In addition, elderly individuals may present DIABETES. with signs and symptoms commonly associated with other diseases of aging, such as mental confu- Bauer, Douglas C., M.D., et al. “Risk for Fracture in sion and paranoia (often associated with Women with Low Serum Levels of Thyroid- Alzheimer’s disease or dementia), muscle stiffness Stimulating Hormone.” Annals of Internal Medicine 134, (associated with arthritis), and heart irregularities. no. 7 (2001): 561–568. Older people may also present with depression, Boonen, S., J. Aerssens, and J. Dequeker. “Age-Related which may be masking the underlying problem of Endocrine Deficiencies and Fractures of the Proximal hypothyroidism. (Depression may also coexist with Femur. I. Implications of Growth Hormone Deficiency thyroid disease.) in the Elderly.” Journal of Endocrinology 149, no. 1 Hypothyroidism in the elderly may also coexist (1996): 7–12. with hypertension and hyperlipidemia. In its most Boonen, S., J. Aerssens, and J. Dequeker, “Age-Related severe manifestation, hypothyroidism presents as a Endocrine Deficiencies and Fractures of the Proximal myxedema coma, a clinical syndrome with a rapid Femur. II. Implications of Vitamin D Deficiency in the onset that is potentially fatal to the patient. Almost Elderly.” Journal of Endocrinology 149, no. 1 (1996): all individuals who lapse into myxedema are elder- 13–17. ly people with hypothyroidism. Cooper, James W., ed. Diabetes Mellitus in the Elderly. New Hyperthyroidism (excessive levels of thyroid York: The Haworth Press, 1999. hormone) is also a problem for some elderly indi- Garfinkel, D., M. Laudon, and N. Zisapel. “Improvement viduals. It too may present differently in older indi- of Sleep Quality in Elderly People by Controlled- viduals than in younger people. For example, Release Melatonin.” Lancet 346, no. 8,974 (August 26, mental decline may be one indicator of hyperthy- 1995): 541–544. 80 empty sella syndrome

Kalmijn, S., et al. “Subclinical Hyperthyroidism and the Autoimmune disorders can be difficult to diagnose Risk of Dementia. The Rotterdam Study.” Clinical and treat in their early stages. Endocrinology 53 no. 6 (2000): 733–737. Some studies have shown a linkage between an Kandel, Joseph, M.D., and Christine Adamec. The environmental factor and an endocrine autoimmu- Encyclopedia of Senior Health and Well-Being. New York: nity. For example, a study reported in a 2000 issue Facts On File, Inc., 2003. of Archives of Internal Medicine compared 132 same- Kane, Robert L., M.D., Joseph G. Ouslander, and Itamar sex twins (264 individuals) and found a significant B. Abrass. Essentials of Clinical Geriatrics, 4th ed. New relationship between smoking and the subsequent York: McGraw-Hill, 1999. development of either Graves’ disease or autoimmune thyroiditis (Hashimoto’s thyroiditis). empty sella syndrome The syndrome that occurs when the sella turcica, the bony area of the skull Brix, Thomas, M.D., Kyvik, K. O. and Hegedus, L., that provides the support for the pituitary gland, is “Cigarette Smoking and Risk of Clinically Overt not completely filled with pituitary tissue. Empty Thyroid Disease.” Archives of Internal Medicine 160, no. 5 sella syndrome is divided into primary and second- (March 13, 2000): 661–666. ary types. Ductless glands in the With primary empty sella syndrome, it is endocrine glands endocrine system that secrete hormones needed for believed that there is a defect in the diaphragm by normal functioning as well as for the sustaining of the pituitary gland, allowing cerebrospinal fluid to life. These glands work via hormones that are typi- enter and to push the gland aside. No common cally secreted into the bloodstream and travel to endocrine abnormalities are seen with primary other organs to have their effects. If the hormones empty sella syndrome, and it is an X-ray abnor- act upon nearby cells, even upon other cells within mality without significant hormonal sequelae. the same gland, they display the paracrine effect. However, almost all types of pituitary dysfunction The endocrine glands are the following: the have been reported, ranging from single hormone adrenal glands, hypothalamus, ovaries, pancreas, deficiencies to the loss of all anterior pituitary hor- parathyroid glands, pineal gland, pituitary gland, monal function. testes, thyroid gland, and the thymus. As In the case of secondary empty sella syndrome, researchers learn more and more about the human the pituitary has been destroyed by surgery, a body, all organs in the body can clearly act as tumor, an infiltrative process, or radiation therapy. endocrine glands, which is to say, they secrete hor- In this syndrome, partial or complete loss of pitu- mones. For instance, the gastrointestinal tract is itary function often occurs. now known to synthesize and secrete over 40 hor- See also POSTPARTUM PITUITARY NECROSIS. mones, many of whose function and operation are Kaufman, B. “The Empty Sella Turcica: A Manifestation still unknown. The heart makes a hormone called of the Intrasellar Subarachnoid Space.” Radiology 90, atrial natriuretic factor or peptide that is involved no. 5 (1968): 931–941. in the body’s salt and water balance. endocrine autoimmunity A condition in which endocrinologist A medical doctor with special- the body mistakenly interprets the actions of an ized training who concentrates on treating people endocrine organ as those of an outside invader and with endocrine diseases and disorders such as attacks the organ. Sometimes the cause for what DIABETES MELLITUS, thyroid diseases, and the full triggers an endocrine immunity is known, while array of other common or rare endocrine prob- other times physicians as well as researchers lems. A pediatric endocrinologist generally treats are unable to identify the cause. GRAVES’ DISEASE patients under the age of 18 years who have and HASHIMOTO’S THYROIDITIS are two examples endocrine diseases or disorders. of autoimmune disorders of the thyroid gland. Endocrinologists who treat adults typically com- DIABETES MELLITUS is also an autoimmune disorder. plete a three-year post–medical school internship erectile dysfunction 81 and a residency in internal medicine before train- Aging Study found that more than half (52 percent) ing for an additional two to three years in an of men over age 40 had some level of erectile fail- endocrinology-metabolism-diabetes fellowship ure. Erectile dysfunction affects a man’s quality of program. Pediatric endocrinologists follow a similar life, and many studies have shown that effective course of education and training, but they have a treatment of ED significantly improves life quality. three-year internship and residency in pediatrics. Erectile dysfunction is a distressing problem for Many endocrinologists who treat adults see some most men. Some experts believe that the psycho- children with endocrine disorders, just as many logical impact of having erectile dysfunction is pediatric endocrinologists will follow their patients more severe than whatever medical problem has into adulthood and past the age of 18 years. actually led to the ED. Even when the erectile Physicians who complete endocrinology training problem is solely caused by a medical problem, it may sit for board certification for endocrinology/ still has an emotional effect on the man. metabolism/diabetes if they have previously passed According to Dr. Andre Guay and his colleagues their internal medicine board examination. This is in their article on medical guidelines for treating typically a two-day long examination that tests the male sexual dysfunction, published in 2003 in physician in all areas of endocrinology and is admin- Endocrine Practice, “Every man who has some prob- istered by the American Board of Internal Medicine lem with erectile function develops performance and its subsidiary boards. anxiety, and determining whether psychological There is great concern that the current number factors are the main problem or merely a minor of endocrinologists practicing in the United States accompaniment may be difficult.” is insufficient. In fact, as of this writing, only about 275 physicians are in fellowship training for endocrinology. These new doctors can barely Causes of ED replace the numbers of endocrinologists who are There are many causes of erectile dysfunction, retiring or leaving their practices for other reasons. including medications, an excessive temporary or At the same time, the United States faces a pan- chronic consumption of alcohol, or diseases such as demic of diabetes as well as a rapidly aging popula- DIABETES MELLITUS, hypertension, stroke, prostate tion that is more susceptible to endocrine disorders surgery, Parkinson’s disease, hyperlipidemia, spinal such as thyroid disease and osteoporosis. How this cord disease and/or surgery, coronary artery dis- situation can be successfully resolved over the ease, and seizure disorders. Smoking cigarettes may short term is unclear. also impede a man’s ability to have an erection. The two main clinical and research societies that Some medications can cause or contribute to the support the endocrinology community are the development of erectile dysfunction, such as drugs American Association of Clinical Endocrinologists for hypertension, antidepressants, and many oth- and the Endocrine Society. ers. Even nonprescription medications, such as decongestants or antihistamines, may impede an erection. According to the 2003 update on male epinephrine See ADRENALINE. sexual dysfunction, published in Endocrine Practice, prescription and nonprescription medications erectile dysfunction (ED) The consistent difficul- cause about 25 percent of erectile problems men ty in achieving or retaining an erection sufficient to experience in the United States. achieve a completed act of sexual intercourse. Men taking hormone therapy for advanced Erectile dysfunction is best viewed as a couple’s prostate cancer may experience erectile dysfunc- problem. The patient’s partner often prompts the tion until they no longer take the drug, at which patient to seek medical attention. time normal sexual functioning will often resume According to a 2002 article on erectile dysfunc- (if they did not have ED before they started taking tion in Urology, 10–20 million men in the United the hormones). Often the hormones are used after States have ED. In addition, the Massachusetts Male a surgical procedure. 82 erectile dysfunction

A PROLACTINOMA, or benign tumor of the pituitary check for obvious signs of testosterone effect gland, may also cause erectile dysfunction, as may (beard, pubic and underarm hair, scalp hair reces- rare medical problems such as KALLMANN’S SYN- sion, and normal muscle mass) as well as check the DROME or KLINEFELTER SYNDROME. Hypogonadism testicular size and shape. Most men are embar- (low testosterone levels) can cause ED but usually rassed by such an examination, but they should be causes only decreased libido and mild ED. However, reassured that urologists commonly perform many some men have very low levels of testosterone and such examinations in a single day. have no problems with erectile dysfunction at all. A rectal examination will also be performed to When diabetes is the cause of ED (whether it is determine if there is a possible problem with the Type 1 or Type 2 diabetes), the problem is often due prostate gland. Problems may include prostatitis, to nerve damage caused by diabetic neuropathy as which is an inflammation of the prostate gland that well as premature atherosclerosis, which is more may be caused by an infection, or benign prostatic common among men whose levels of glucose are hyperplasia (BPH), a tissue overgrowth. Both con- not well-controlled. ditions are often treated with prescribed medica- Men who have undergone a transurethral resections. Doctors will also check for indications of tion of the prostate due to benign prostatic hyper- prostate cancer with the digital rectal examination plasia (BPH) may also experience erectile and may also order a prostate specific antigen dysfunction. This occurs because of nerve damage (PSA) blood test. that occurred during the procedure. The PSA test may be ordered routinely because There is often an emotional component to erec- the man is over age 50 and/or he is at risk for tile dysfunction, and problems such as depression prostate cancer or has family members who have can lead to ED. Even when the underlying cause had prostate cancer. It may also be ordered if the for the ED is physical, the man may develop prob- physician notes the presence of any nodules or lems with performance anxiety. The combined excessive tissue growth of the prostate gland. If there emotional and physical aspects then make it more is a possibility of cancer, a biopsy will be performed. difficult for him to attain or maintain an erection. The physician may also order laboratory tests, such as a complete blood count, tests of the man’s testosterone level, and a urinalysis to check for Diagnosis and Treatment infection or blood in the urine. If blood testos- Primary care doctors typically diagnose and treat terone levels are low, the physician may order tests erectile dysfunction but may refer the patient to an of prolactin, luteinizing hormone, and serum-free endocrinologist or urologist. Men with erectile dys- testosterone to provide further information. For function are aware that they are having trouble example, high levels of prolactin indicate a pro- with achieving an erection, and they may seek help lactinoma, or pituitary tumor. The doctor may also from their doctor. However, many men are too order tests of glucose level, serum creatinine, cho- embarrassed to discuss this problem with their doc- lesterol, and triglycerides. An ultrasound may be tors, not realizing how common this problem is or ordered as well as other specialized tests, depend- that it is often reversible with treatment. ing on the patient and the doctor. The doctor will take a complete medical history If any medical problems are identified in the to try to ascertain if there may be medical causes of physical examination or by laboratory testing, the erectile dysfunction. Some doctors prefer to treating these problems may resolve the erectile speak with both the man with erectile dysfunction dysfunction. For example, low testosterone levels and his sexual partner to obtain a view of the prob- (HYPOGONADISM) may be treated with topical or lem from the perspective of both parties. injected testosterone to normalize the testosterone During the physical examination, the physician levels. Better glycemic control may improve erec- will also examine the man’s penis to determine if tile function in patients with diabetes. Changing there are any obvious abnormalities (most com- the medications that the patient takes for hyper- monly, Peyronie’s disease). The doctor will also tension may also help to resolve the ED. erectile dysfunction 83

Viagra and Other Medications Mechanical Devices If a man is diagnosed with erectile dysfunction that To achieve an erection, some men rely upon is not resolved by treating underlying medical mechanical devices such as the vacuum constric- problems, there are many different ways for most tion device. It is placed over the penis and pumped men to achieve potency again. up. If the device helps the man achieve an erection, As of this writing, three phosphohodiesterase a rubber band–like device is placed around the base inhibitors are available on the market to treat erec- of the penis and will help the man to maintain the tile dysfunction. They include Viagra (sildenafil), erection for about 30 minutes. Many men find vac- Levitra (vardenafil), and Cialis (tadalafil). All three uum devices to be effective, although some com- drugs work via the same mechanism. They inhibit plain that it causes their penis to feel cold and phosphodiesterase (PDE5), and, by doing so, strange. Others say that the constriction band hurts enable an erection. These drugs affect only blood them. The man must remove the band after inter- flow and have no direct effect on sexual drive. course in order to avoid damage to the penis, up to These medications work within 30–60 minutes and and including gangrene. last for four to 12 hours. The drugs cause headaches and flushing in 10–15 percent of the Penile Implants men who use them and also cause nasal congestion If other methods for resolving ED are unsatisfacto- in 4–5 percent of men. ry, some men consider a penile prosthesis that is None of these drugs should be used if the man is surgically inserted while the man is under anesthe- on any medication that contains nitrates (topical, sia. Several different varieties of prostheses are cur- sublingual, or oral). If a man develops chest pains rently available as of this writing, and they vary after using one of these drugs and needs medical considerably in their complexity. attention, the treating emergency medical techni- With the semirigid or malleable prosthesis, the cians and physicians must be advised that the man man will manually change the angle of his penis, used the medication so that they can order med- depending on whether he wants to have sex or not. ications other than nitrates for the first 24–36 When in the down position, the prosthesis is not hours of treatment. noticeable unless the man wears very tight-fitting When phosphodiesterase inhibitors are ineffec- clothes. When he wants to have sex, he simply tive in helping the man to achieve erections, some moves the penis to the up position. According to doctors may prescribe injectable drugs, such as urologist Paul H. Lange in his chapter on erectile Caverject (alprostadil), Genabid (papaverine), or a dysfunction in his book Prostate Cancer for Dummies, combination of three drugs mixed up by the urol- this device is the easiest to use and the most popular ogist, commonly referred to as trimix. These drugs type of penile implant among many post–prostate are injected directly by the man into his penis, cancer patients. which is said to feel like a brief pinch. Urologists Another surgically inserted prosthesis uses an teach men how to perform these simple injections. inflatable pump that is connected to a cylinder that The drug must be injected about 15 minutes fits into the penis. The patient presses on his penis before the man anticipates having sex. The erec- to cause the pump to inflate and to achieve an tion induced by an injectable drug lasts about erection. Yet another prosthesis is the three-piece an hour. prosthesis, which includes inflatable cylinders and Another form of alprostadil is available in a pel- a fluid reservoir. It is activated by the man pressing let called MUSE (Medicated Urethral System for on an area near his scrotum. This type of implant is Erection), a drug that is manually inserted into the the most costly, and it is also considered to be the urethra of the penis and that causes no pain. It is most effective device. self-dissolving. If the pellet works, the erection will Penile prostheses can be very expensive (as of occur within five to 10 minutes of the injection and this writing, the surgical procedure costs at least will last about an hour. $10,000), and they are not always covered by 84 estradiol health insurance. In addition, they may last for • For postmenopausal women: 5–25 pg/ml only five to 10 years, depending on the manufac- • For males: 10–60 pg/ml turer, the type of prosthesis that is implanted, and other factors. If the prosthesis breaks down, a new Some diseases impair the release of estradiol, one can usually be inserted. The area where the such as premature ovarian failure and TURNER SYN- prosthesis was inserted can become infected, which DROME. Rarely, above-normal levels of estradiol usually requires the removal of the entire prosthe- may be detected with an ovarian tumor. Estradiol sis. After healing occurs, a new prosthesis can then levels are also important in fertility, and physicians be inserted. measure these levels when evaluating infertile The key advantage of the penile prosthesis is individuals. that it can often enable the patient to have a nor- Estradiol is also available as a medication in oral mal sex life without the need for taking any drugs tablets, skin patches, topical creams, and an such as Viagra. The key disadvantage is that once injectable form. It is used to treat women with estro- the penile prosthesis has been inserted, the other, gen deficiency from a variety of causes. Generally, noninvasive methods available to resolve impo- estradiol is given for the following reasons: tence will no longer work. See also INFERTILITY; MALE REPRODUCTION; TESTOS- • To reduce menopausal symptoms such as HOT TERONE. FLASHES Althof, Stanley, E. “Quality of Life and Erectile • As replacement therapy in women who are Dysfunction.” Urology 59, no. 6 (2002): 803–810. prematurely hypogonadal Guay, Andre T., M.D., et al. “American Association of • To prevent OSTEOPOROSIS Clinical Endocrinologists Medical Guidelines for • To treat vaginal dryness caused by menopause Clinical Practice for the Evaluation and Treatment of Male Sexual Dysfunction: A Couple’s Problem—2003 • To treat some prostate cancers (rare) Update.” Endocrine Practice 9, no. 1 (January/February • To create female characteristics in biological 2003): 77–95. males prior to and after sexual reassignment Lange, Paul H., M.D., and Christine Adamec. Prostate surgery. Cancer for Dummies. New York: Wiley Publishing, 2003. Lue, Tom F., M.D. “Erectile Dysfunction.” New England Journal of Medicine 342, no. 24 (June 15, 2000): Risks of Exogenous Estradiol 1,802–1,813. In addition to its usual physiological effects, estradiol and other forms of estrogen can lead to a pro- estradiol The most important form of estrogen thrombotic state, making the patient more released by the body. Estradiol is responsible for susceptible to blood clots. Such clots may occur in female breast development, the growth of the the legs or pelvis and can lead to a pulmonary uterus, the placement of body fat, and other func- embolism in the heart, in turn leading to a myocar- tions. Estradiol is secreted from the adrenal cortex, dial infarction (heart attack) or an embolism in the ovarian follicle, and, in a pregnant woman, the pla- brain, leading to a stroke. Breast cancers that are centa. Both males and females synthesize estradiol, present in women but that are not yet clinically which can be measured in the blood. detectable may have their growth stimulated by According to the National Institutes of Health, the use of exogenous estradiol and other estrogens. normal estradiol levels are as follows: These major adverse effects of estrogens, especially after the report of the Women’s Health • For premenopausal women: 20–400 picograms Initiative, have led to more limited use of estradiol per milliliter (pg/ml); the measurement varies and other estrogens for hormone replacement. according to the time of the menstrual cycle These risks are accentuated among smokers. euthyroid sick syndrome 85

Estradiol can also increase blood pressure as it who is menopausal either due to the natural onset stimulates the production of angiotensinogen from of MENOPAUSE (usually after the age of 45 years or the liver, thus leading to increased levels of so) or because of the removal of both of her angiotensin (a very potent constrictor of blood ves- ovaries. Each woman must decide for herself sels). Estradiol also increases the risk of the devel- whether to take estrogen, or another type of opment of gallstones and can increase the female hormone replacement medication, after frequency of headaches, especially in women who consulting with her physician and considering both are predisposed to migraine headaches. There are the risks and benefits of the medications. some nuisance side effects to estradiol, such as Some studies have indicated that women who breast tenderness and fluid retention. take LEVOTHYROXINE (l-thyroxine) for their Estradiol should not be used in an attempt to HYPOTHYROIDISM may need to increase their decrease macrovascular complications (such as dosage if they also take estrogen replacement heart attack and stroke) as they may actually therapy. increase the risk slightly, especially in the first sev- See also ESTRADIOL; ESTROGEN; HORMONE eral years. Estradiol should also not be used in REPLACEMENT THERAPY. women with a prior history of breast cancer and Arafah, Baha M., M.D. “Increased Need for Thyroxine in should be used only with caution in women at high Women with Hypothyroidism During Estrogen risk of developing breast cancer. Therapy.” New England Journal of Medicine 344, no. 23 See also ESTROGEN. (June 7, 2001): 1,743–1,749. estrogen Female hormones, released by the ovaries, that are responsible for female secondary sexual characteristics, hair growth, and other fea- euthyroid Refers to the physiological state in tures. Like TESTOSTERONE, estrogens are steroid individuals whose thyroid hormone levels are hormones. in balance. In other words, these individuals are When estrogen levels decline, with advancing neither hyperthyroid (with excessive levels of age and the onset of MENOPAUSE, some women circulating thyroid hormone) or hypothyroid experience signs and symptoms such as HOT FLASH- (with inadequate levels of thyroid hormone). ES (vasomotor symptoms), insomnia, mood swings, Some individuals have normal levels of thyroid in and irritability. These women may consult with their blood and yet are ill with thyroid disease, a their physicians about the advisability of taking condition known as EUTHYROID SICK SYNDROME. ESTROGEN REPLACEMENT THERAPY (estrogen alone) or HORMONE REPLACEMENT THERAPY (a combination of estrogen and progesterone). Some women experi- euthyroid sick syndrome A condition in which ence an early menopause because their ovaries fail THYROID BLOOD TESTS reveal abnormal results, such or because they have had the ovaries surgically as low levels of T3 (triiodothyronine) or T4 (THY- removed because of a disease such as ovarian cysts ROXINE) and typically, but not always, normal levels or ovarian cancer. of thyroid-stimulating hormone (TSH) while the See also ESTRADIOL; FEMALE REPRODUCTION. thyroid gland is actually functioning appropriately. Gruber, Christian J., M.D., et al. “Production and Actions The individual with euthyroid sick syndrome of Estrogens.” New England Journal of Medicine 346, no. generally has another serious underlying illness 5 (January 31, 2002): 340–352. such as CANCER, AIDS, ANOREXIA NERVOSA, DIABETIC KETOACIDOSIS, or malnutrition. Some medications, such as corticosteroids, lithium, amiodarone, and estrogen replacement therapy (ERT) Synthetic propranolol, may affect thyroid blood levels in the or natural estrogen hormones given to a woman absence of thyroid disease. Some patients may 86 exercise be recovering from surgery or from a transplant Losing a significant amount of weight with exer- procedure. cise alone is difficult. However, exercising helps to Euthyroid sick syndrome is common among eld- decrease the overall body fat, including both vis- erly individuals who are hospitalized with a severe ceral fat and abdominal obesity. illness. The treatment for euthyroid sick syndrome is Tuomilehto, Jaako, M.D., et al. “Prevention of Type 2 oriented to the underlying disease, and thyroid Diabetes Mellitus by Changes in Lifestyle Among blood tests may be repeated at a later date. Thyroid Subjects with Impaired Glucose Tolerance.” New hormone treatment is generally not begun unless England Journal of Medicine 344, no. 18 (May 3, 2001): the patient exhibits apparent symptoms of 1,343–1,350. hypothyroidism. In fact, use of thyroid hormone replacement therapy has increased mortality (death) in several clinical trials where it has been eye problems Disorders of the eye. Some administered to gravely ill patients who had abnor- endocrine diseases and disorders cause or con- mal results on their thyroid function tests. tribute to the development of eye diseases. For See also GRAVES’ DISEASE; HYPERTHYROIDISM. example, long-term TYPE 1 DIABETES may lead to DIABETIC RETINOPATHY or other eye diseases, up to Camacho, Pauline M., M.D., and Arcot A. Dwarkanathan, and including blindness. As many as 24,000 people M.D. “Sick Euthyroid Syndrome.” Postgraduate Medicine lose their eyesight in the United States because of 105, no. 4 (April 1999): 215–228. diabetic eye disease. Yet experts report that as Umpierrez, Guillermo E., M.D. “Euthyroid Sick much as 90 percent of these cases of blindness Syndrome.” Southern Medical Journal 95, no. 5 (2002): could have been prevented by regular screening for 506–513. eye disease. Only about 60 percent of patients with diabetes have an annual dilated eye examination. exercise Regular physical activity to maintain or Other diseases may cause eye problems. For achieve good health. Nearly all physicians consider example, a key feature of GRAVES’ DISEASE is regular exercise to be an important part of main- bulging of the eyes, or exophthalmos. Not all taining good health. Even individuals who are dis- patients with Graves’ disease have this feature of abled and weak can usually master some simple the illness, but many have mild signs or symptoms exercises. Exercise is important to help individuals and do exhibit it. avoid obesity or to resolve obesity if it is already a Patients with DIABETES MELLITUS and/or a history problem. Simply walking several times a week may of thyroid disease are more likely to suffer from dry be sufficient to improve the health of many eye syndrome (keratoconjunctivitis sicca), as are patients with OBESITY and other endocrine diseases women in MENOPAUSE. The illness can cause severe and disorders. pain and should be treated by an ophthalmologist In the Diabetes Prevention Program, the study (medical doctor who specializes in eye disease). The group that walked briskly approximately 150 min- ophthalmologist may treat dry eye syndrome with utes per week decreased their risk of progressing specialized eyedrops and environmental recommen- from IMPAIRED GLUCOSE TOLERANCE (PREDIABETES)to dations (such as advising patients to avoid having overt DIABETES MELLITUS by 31 percent. heating or air-conditioning vents near their faces Exercise decreases INSULIN RESISTANCE and and limiting caffeine consumption). Sometimes improves the glucose levels in patients who have surgical procedures are also needed. This condition diabetes mellitus. For patients with HYPERLIPIDEMIA, should not be ignored because it can lead to worsened exercise will decrease their triglyceride levels and symptoms and even blindness. also increase their high-density lipoprotein (HDL or For further information on eye diseases, contact good CHOLESTEROL) levels. the following organization: eye problems 87

American Academy of Ophthalmology Moss, Scot E., Ronald Klein, M.D., and Klein, Barbara E., P.O. Box 7424 M.D. “Prevalence and Risk Factors for Dry Eye San Francisco, CA 94120-7424 Syndrome,” Archives of Ophthalmology 118, no. 9 (415) 561-8500 (September 2000): 1,264–1,268. http://www.aao.org

Bartalena, Luigi, Aldo Pinchera, and Claudio Marcocci. “Management of Graves’ Ophthalmopathy: Reality and Perspectives.” Endocrine Reviews 21, no. 2 (2000): 168–199.

F failure to thrive (FTT) A phrase used to describe be diagnosed with FTT than children of other the condition of infants or small children up to the socioeconomic classes. age of two years who are not eating adequately and who show markedly poor growth. Such children Symptoms of Failure to Thrive will rank lower than the fifth percentile for weight Infants with FTT generally present with listlessness at two or more checkups, or show no growth at all and apathy and have poor muscular development. while evincing an overall development that is Certain behaviors are typical among babies with much slower than expected of other children of the FTT. For example, according to The Encyclopedia of same age. Child Abuse, “Infants suffering from the sensory Some children with failure to thrive not only do deprivation associated with FTT often maintain a not grow but may actually lose weight. Untreated posture in which the arms are held out, flexed at FTT may lead to further health problems such as the elbow with the hands up and legs drawn in. developmental delays. This position of apparent surrender is held for long An estimated 1–5 percent of children younger periods of time.” than age two who are admitted to hospitals are diagnosed with failure to thrive. Children living in Diagnosis and Treatment orphanages may also experience FTT, especially FTT is diagnosed based on its clinical presentation when they receive the bare minimum of care (such as well as a comparison of the child’s weight and as brief washing, feeding, and changing) and when height with the weight and height expected for a the caregivers constantly change. child of the same age. Past weights of the child, if Organic and Nonorganic Failure to known, are also used for a comparison basis. Thrive Problems Physicians also use laboratory tests to screen for infections and metabolic diseases, such as hypothy- There are two primary categories of failure to thrive, roidism, that may cause the patient to become organic and nonorganic FTT. Organic failure to thrive lethargic. is caused by a severe chronic medical problem, such If the underlying cause of FTT is organic, the ill- as cystic fibrosis, untreated HYPOTHYROIDISM, infection ness is treated. If it is nonorganic, physicians seek with the human immunodeficiency virus (HIV), or to identify and rectify the problem. For example, if heart disease. Nonorganic failure to thrive is caused abuse or neglect is suspected, the child may need to by a severe, externally induced factor, such as starva- be removed from the family. tion, maternal drug addiction, or other causes. See also CACHEXIA; INFANTS. Extreme cases of abuse and neglect may cause failure to thrive in some children. Clark, Robin E., Judith Freeman Clark, and Christine Adamec. The Encyclopedia of Child Abuse, 2d ed. New Risk Factors York: Facts On File, Inc., 2000. Mothers who are malnourished and/or who are Zenel, J. A. Jr. “Failure to Thrive: A General Pediatrician’s drug abusers are more likely to have children diag- Perspective.” Pediatric Review 18, no. 11 (1997): nosed with FTT. Poor children are more likely to 371–378.

89 90 familial combined hyperlipidemia familial combined hyperlipidemia An inherited advised to limit their fat consumption to less than form (autosomal dominant inheritance) of hyper- 30 percent of their caloric intake and limit their lipidemia with elevated levels of serum CHOLES- cholesterol intake to less than 300 mg per day. This TEROL and/or triglycerides. Familial combined generally means that they will eat less beef, chick- hyperlipidemia has a variable clinical presentation. en, pork, and lamb. Weight loss will also decrease One person with the condition may have normal triglyceride levels a bit more than cholesterol lev- lipid levels, while the next may have elevated cho- els. Weight loss will typically decrease the total lesterol levels and normal triglycerides, and a third cholesterol levels by 5–20 percent, but typical person may have elevated levels of both. decreases are 10 percent. Familial combined hyperlipidemia is linked to Ingestion of plant stanol esters, now available as an increased risk for cardiovascular disease and for spreads, will lower the total cholesterol by 12–17 heart attacks if it is not controlled. This condition is percent. Alcohol intake should be minimized or also exacerbated by the presence of other illnesses, prohibited. Exercise is helpful, especially in such as HYPOTHYROIDISM, DIABETES MELLITUS,or decreasing VLDL and thus triglyceride levels. alcoholism. In addition, alcoholism may also wors- When therapeutic life changes fail to lower the en the condition. Both men and women are at risk patient’s levels to the goal (as often happens, even for familial combined hyperlipidemia. Patients may with the most motivated of patients), pharmaco- develop this condition in adolescence, and treat- logical therapy is generally initiated. ment should not be delayed. When the triglycerides are less than the desired The gene or genes that cause this condition are levels, a statin drug such as simvastatin (Zocor) or unknown as of this writing, but researchers have pravastatin (Pravachol) is prescribed. If the LDL is found familial patterns of occurrence. In the not controlled after titration, a second drug, such as Frederickson classification, this disorder is labeled nicotininc acid (Niaspan) or ezetimibe (Zetia), is hyperlipidemia type IIb. added. This additional drug will provide an 18–26 percent reduction in LDL and a 3–5 percent Signs and Symptoms increase in high-density lipoproteins (HDL). Patients who are obese and who have had attacks If the triglycerides are not at goal after beginning of angina (chest pain) at a young age are suspects the statin drug, nicotinic acid or a fibric acid deriv- and should be screened for familial combined ative such as gemfibrozil (Lopid) or fenofibrate hyperlipidemia. In addition, a family medical histo- (Tricor) is added. Nicotinic acid can decrease the ry of early heart attacks or HYPERLIPIDEMIA is anoth- LDL (by 5–20 percent) and the triglycerides (20–50 er indicator of the possible presence of this condition. Typically, there are no cutaneous mani- percent reduction), and it can also increase the festations. HDL by 10–20 percent. The physician and patient must be vigilant for adverse effects, especially Diagnosis and Treatment myositis and rhabdomyolysis, when these agents Patients are diagnosed based on their blood test (statins and nicotinic acid) are combined. This is results as well as a complete medical history. especially true among patients with kidney disease Patients with familial combined hyperlipidemia or decreased muscle mass and among patients who may have high levels of serum low-density lipopro- are elderly. teins (LDLs) or very low-density lipoproteins Bile acid sequestrants such as cholestyramine (VLDLs), a predominant component of triglyc- (Questran) and colestipol (Colestid) are used occa- erides. Thus these patients may have elevated lev- sionally. However, they have weak effects on LDL els of total cholesterol and/or elevated triglycerides. unless used at high doses and may increase triglyc- They may also have increased apolipoprotein B100 eride levels. concentrations. Treatment is usually for the remainder of the Treatment is aimed at decreasing the levels of patient’s life. cholesterol and triglycerides. Patients are often See also ATHEROSCLEROSIS/ARTERIOSCLEROSIS. familial hypercholesterolemia 91

Athyros, V. G., et al. “Atorvastatin Versus Four Statin- treated to achieve levels as close to normal as possi- Fibrate Combinations in Patients with Familial ble. Patients are directed to change their diet and Combined Hyperlipidemia.” Journal of Cardiovascular reduce the amount of ingested saturated fats and Risk 9, no. 1 (2002): 33–39. cholesterol. If dietary changes do not cause cholesterol and triglyceride blood levels to drop, physicians may prescribe cholesterol-lowering medications familial dysbetalipoproteinemia A condition such as HMG CoA reductase inhibitors (statins), also known as type III hyperlipoproteinemia that nicotinic acid, fibrates, ezetimibe, or some combina- causes ATHEROSCLEROSIS in the coronary arteries tion of several drugs. and can lead to coronary artery disease and peripheral vascular disease. It is exacerbated by diabetes, OBESITY, and HYPOTHYROIDISM. These other clinical familial hypercholesterolemia (FH) An inherited problems often need to be present to increase the predisposition to high levels of blood cholesterol, production of the lipoproteins and to lead to the first described by C. Muller in 1939. The heterozy- full clinical scenario of familial dysbetalipopro- gous form of familial hypercholesterolemia is com- teinemia. This condition occurs in an estimated one mon, and it affects an estimated one in 500 in 10,000 individuals and usually does not present individuals. According to an article on cardiovascu- until a patient is 20 years old or older. If it is lar disease in a 2003 issue of the New England untreated, familial dysbetalipoproteinemia can lead Journal of Medicine, over 600 mutations in the low- to heart attack, strokes, and blocked arteries to the density lipoprotein (LDL) receptor gene have been lower extremities and to the brain (peripheral vas- linked to this disorder. In contrast, the severe cular disease). homozygous form of familial hypercholesterolemia Familial dysbetalipoproteinemia, which is inher- affects only one per 1 million individuals. Most of ited as an autosomal dominant defect, is caused by a these individuals die in childhood from a heart genetic defect that causes accumulations of rem- attack (myocardial infarction). nants of very low-density lipoprotein (VLDL) and Individuals with heterozygous FH have an chylomicrons with triglyceride and cholesterol con- increased risk for heart attacks at an early age (by centrations greater than the 90th percentile. Patients age 20) because of their severe ATHEROSCLEROSIS have two apo E2 lipoprotein genes that are present. (clogged arteries). Men with this condition are They have lipoproteins that are not appropriately more likely to have early heart attacks than removed from the circulation, as they are abnormal. women with familial hypercholesterolemia. According to Dr. Evan Stein and his colleagues in Signs and Symptoms an article on hypercholesterolemia in a 1999 issue Patients with familial dysbetalipoproteinemia may of the Journal of the American Medical Association, have fatty skin deposits called XANTHOMAS. among males with untreated FH, 5 percent have Specifically, they may have a tuberoeruptive xan- clinically overt coronary artery disease by age 30. thomata and palmar xanthoma known as xan- The risk increases to 20 percent by age 40 and more thomata palmare striatrum, which are fatty than doubles to 50 percent by age 50. deposits in the creases of the palms. In most cases, changing the diet has only a minimal effect on people with FH. These individuals Diagnosis and Treatment must also take cholesterol-lowering medications to A physical examination will reveal the presence of control the condition. xanthomas. Laboratory tests will show elevated Men and women are both at risk for FH. levels of serum total cholesterol and low-density Children and adolescents can also present with this lipoproteins (LDLs) as well as triglycerides. medical problem. Stein and his colleagues studied Angiograms will show atherosclerosis. adolescent boys ages 10–17 years with FH at 14 Patients with concomitant DIABETES MELLITUS pediatric outpatient clinics in the United States and and/or hypothyroidism should be aggressively Finland. In one group, there were 63 intervention 92 familial hypertriglyceridemia subjects (patients who took lovastatin to lower their require several medications. Typically, patients are cholesterol levels) and 59 who took the placebo. In treated with high doses of statin medications as another group, there were 61 intervention subjects well as with bile acid sequestrants or cholesterol and 49 who took the placebo drug. The researchers absorption inhibitors. found that lovastatin was effective at lowering cho- See also CHOLESTEROL; FAMILIAL COMBINED HYPER- lesterol and did not impair growth and develop- LIPIDEMIA; FAMILIAL DYSBETALIPOPROTEINEMIA; FAMIL- ment among the boys who took the medication. IAL HYPERTRIGLYCERIDEMIA. The researchers also looked at the family histo- Nabel, Elizabeth G., M.D. “Cardiovascular Disease.” New ry of their study subjects. They found that the England Journal of Medicine 349, no. 1 (July 3, 2003): mother passed on the FH in 56 percent of the cases 60–72. and the father in 44 percent. They also found that, Ronzio, Robert A. The Encyclopedia of Nutrition and Good among the parents, the average age of onset of Health. New York: Facts On File, Inc., 1997. coronary artery disease was 37. Eight of the sub- Stein, Evan A., M.D. “Efficacy and Safety of Lovastatin in jects had fathers who had died of CAD, and their Adolescent Males with Heterozygous Familial average age of death was 39 years. Hypercholesterolemia: A Randomized Controlled Signs and Symptoms Trial.” Journal of the American Medical Association 281, no. 2 (January 13, 1999): 137–144. The presence of XANTHOMAS (lipoprotein deposits under the skin) is one sign of hypercholesterolemia, as are cholesterol deposits that are found familial hypertriglyceridemia An inherited auto- in the eyelid area (xanthelasmas). However, many somal dominant disorder that causes moderately patients with xanthelasmas also have normal cho- high levels of very low-density lipoprotein (VLDL) lesterol levels. in the blood and occurs in an estimated one in 300 Diagnosis and Treatment individuals in the United States. Familial hypertriglyceridemia is also known as type IV hyper- Diagnosis is made by taking a careful medical histo- lipoproteinemia in the Frederickson classification. ry, including any early-age heart attacks in close This elevation of VLDLs causes an increased risk family members, such as among parents or siblings. for patients to develop PANCREATITIS, heart disease, Laboratory testing will show that patients with and OBESITY. It is also associated with hypertension, familial hypercholesterolemia have elevated levels hyperuricemia, HYPERGLYCEMIA, and INSULIN RESIST- of total cholesterol that are greater than 300 mg/dl ANCE. The condition may be worsened by HYPOTHY- in adults and greater than 250 mg/dl in children. ROIDISM, DIABETES MELLITUS, and the use of estrogen They also have elevated levels of low-density therapy in an affected postmenopausal female. lipoproteins (LDLs), typically greater than 200 Familial hypertriglyceridemia does not usually mg/dl. In addition, the patients have normal or become apparent until after puberty or young mildly increased triglyceride levels. In addition, pro- adulthood. Patients are at risk for this dyslipidemic tein electrophoresis may be abnormal, as may the syndrome if either parent was diagnosed with results of heart function studies, such as stress tests. hypertriglyceridemia or if there is a history of pre- Although changing the diet alone will probably mature heart disease (clinical heart disease occur- not resolve FH, it can help improve the situation. ring before age 50). The condition is caused by a As a result, patients with FH are urged to decrease mutation in the lipoprotein lipase enzyme. their consumption of fat to less than 30 percent (less than 10 percent as saturated fat) of all the calories consumed. Patients are also encouraged to Diagnosis and Treatment exercise, which will help them lose weight and by Hypertriglyceridemia is easily diagnosed by obtain- doing so, lower their cholesterol levels. ing a fasting lipid profile from the patient. This Diet and exercise will not bring the hypercho- should include total cholesterol, high-density lesterolemia under control, and these patients will lipoprotein, and triglycerides levels. feedback loops 93

Patients typically have elevated triglyceride lev- The basic cause of familial hypocalciuric hyper- els in the 200–500 mg/dl range with lower-than- calcemia is an inactivating mutation in the calcium- normal high-density lipoproteins (a condition sensing receptor gene, which typically causes fewer called hypoalphalipoproteinemia). They also have calcium receptors that are expressed on parathyroid normal or modestly elevated total cholesterol or tissue and in the kidney. Thus, in the parathyroid LDL cholesterol. Typically, LDL levels cannot be glands, which are the glands located behind the measured accurately as is done with most standard thyroid, this defect causes the gland to be exposed lipid profiles but, instead, must be measured direct- to higher-than-normal levels of calcium to the ly with radioimmunoassay. appropriately suppressed parathyroid hormone The first therapy is good medical nutrition ther- secretion. At the same time, in the kidney, exces- apy, with attention to lowering the carbohydrate sive calcium is absorbed. content in meals. Alcohol is removed from the diet. Most people with familial hypocalciuric hypercal- Exercise will help tremendously as well. The intent cemia have no signs or symptoms at all and do not of the nutrition and exercise is to have patients get require any treatment. Doctors must carefully differ- their weight as close to ideal as possible. However, entiate these patients from those with true primary often diet and exercise are inadequate and phar- hyperparathyroidism, as patients with familial macological therapy is employed as well. hypocalciuric hypercalcemia do not require surgery. The first-line medication therapy is usually a fib- If the physician does not measure the urinary calci- ric acid derivative, such as gemfibrozil (Lopid) or um levels, he or she could misdiagnose patients with fenofibrate (Tricor) or a form of nicotinic acid, such FHH, as patients may have high-normal or even as an intermediate-release product like Niaspan. If slightly elevated intact parathyroid hormone levels. the patient’s triglyceride level is in the lower range See also HYPERCALCEMIA; HYPERPARATHYROIDISM; of 200–350, then HMG CoA reductase inhibitors PARATHYROID CANCER. are often employed, such as simvastatin (Zocor), pravastatin (Pravachol), atorvastatin (Lipitor), lovastatin (Mesvacor), or fluvastatin (Lescol-XL). feedback loops A complex process, key to the Bile acid sequestrants are to be avoided in these functioning of endocrine glands, in which sensors patients, because they may actually increase the recognize changes to the individual or to the envi- triglyceride levels. ronment and, as a result, cause higher or lower lev- In postmenopausal women, estrogen therapy may els of hormones to be secreted. need to be discontinued. Younger woman taking Feedback loops are analogous to a thermostat or ORAL CONTRACEPTIVES may need to discontinue them. other device that seeks to maintain a certain home- The aim of the doctor is for the patient to have ostatic level. For example, say a thermostat in a the condition corrected as much as possible. house is set at 70 degrees. When the inside temper- Patients with diabetes need to attain a normal ature falls below that temperature, the change caus- hemoglobin A1c, and patients with hypothy- es a sensor to order the heat to turn on. If a home roidism need to achieve normal thyroid-stimulat- has both heat and air-conditioning, the thermostat ing hormone (TSH) levels. was set at 70 degrees, and the temperature rose to 71 degrees, the air-conditioning would come on. Similarly, if the blood levels of hormones rise to familial hypocalciuric hypercalcemia (FHH) A a given level, feedback loops will send a message to hereditary (autosomal dominant) form of hyper- the body to cut back on their production. If they calcemia in which the individual has high blood fall below a certain level, feedback loops enable an levels of calcium, while at the same time, he or she increase in their production. For instance, cells with- has low urinary calcium levels and normal levels of in the pancreas measure or sense the ambient glu- parathyroid hormone in the blood. Parathyroid cose concentration in the blood. Then the beta cells hormone is produced by the parathyroid glands of the pancreas secrete an appropriate amount of and it regulates calcium levels in the bloodstream. insulin while the alpha cells secrete an appropriate 94 female reproduction amount of glucagons to maintain the glucose level at situation. However, amazing progress has been the appropriate level for that person. With damage made in reproductive technologies, allowing many to the beta cells, resulting in diabetes mellitus, this women to achieve pregnancies once thought to be loop is disrupted and the blood glucose level rises. impossible. Women may be advised to take med- Feedback loops control the increase and decrease ications to stimulate ovulation or other drugs need- of such HORMONES as T4 and T3 (thyroid hor- ed to achieve pregnancy, or they may become mones), cortisol, estradiol, and others. The usual pregnant by way of in vitro fertilization. hierarchy is as follows. If the cortisol levels dip to a Endocrine diseases can impede the course of a less-than-adequate level, the hypothalamus per- normal pregnancy. For example, some women ceives this drop. The production of corticotropin develop GESTATIONAL DIABETES, which is diabetes releasing hormone (CRH) is then increased, which that occurs only during pregnancy. Such women in turn increases the synthesis of adrenocorticotrop- must be carefully followed by their physicians dur- ic hormone (ACTH) from the pituitary gland. This ing their pregnancies to help ensure a normal action stimulates the adrenal gland to produce and pregnancy and the delivery of a healthy child. release more cortisol. The reverse process also Some endocrine diseases, such as untreated occurs. If the cortisol levels rise too high, this feed- HYPOTHYROIDISM, can cause an otherwise healthy back travels back to the hypothalamus, which woman to have great difficulty achieving a preg- decreases the production of CRH and so on. nancy. Once her thyroid levels are normalized, the When patients have hypothyroidism, there are woman may be able to become pregnant. inadequate levels of T3 and T4 in the bloodstream. See also AMENORRHEA; BREAST-FEEDING; FERTILITY; These low levels of thyroid hormones are perceived INFERTILITY; MALE REPRODUCTION; PREGNANCY; REPRO- by the hypothalamus, which decreases the levels of DUCTIVE ENDOCRINOLOGY. thyrotropin-releasing hormone (TRH). This, in turn, causes a decrease in the level of thyroid-stimulating hormone (TSH) that the pituitary gland fertility The ability to create a pregnancy that produces. Thus, damage to the hypothalamus or results in the delivery of a live child. If they have the pituitary gland can dramatically upset these normal fertility, an estimated 93 percent of couples normal feedback loops and lead to endocrine dis- should be able to achieve a pregnancy after 12 eases. This is also why physicians usually order the months of unprotected intercourse. The inability to laboratory levels of several hormones to be tested achieve a pregnancy is the definition of INFERTILITY. at the same time. In a healthy person, hormonal For most women, fertility declines markedly after levels all exist in balance with each other. age 35–40 years. They may require assisted reproductive techniques from specialized clinics, such as in vitro fertilization or donated embryos, to achieve a female reproduction The process of creating a pregnancy and a birth. Unfortunately, these tech- pregnancy and, about nine months later, bearing a niques do not always succeed. Fertility also declines live child. Reproduction can be impaired by a wide in men as they age, although many men can contin- variety of conditions affecting the endocrine glands ue to father children well beyond the age of 40. as well as other organs in the body. For example, Sometimes infertile couples or single individuals who the ovaries must produce an egg for a pregnancy to desire to parent a child but cannot create a pregnan- occur, and some woman do not ovulate regularly cy will hire a surrogate mother. Others will adopt a or at all (ANOVULATION). Some women do not have child from their own country or another country. a uterus that can carry a child. Sometimes, even Sexually transmitted diseases, heavy drug or when the woman’s and the man’s reproductive alcohol use, and other factors may impair fertility systems appear healthy to their respective physi- for both men and women. Endocrine diseases such cians, no pregnancy occurs. as HYPOTHYROIDISM,CUSHING’S DISEASE, HYPOGO- Couples seeking to attain pregnancy report that NADISM, and POLYCYSTIC OVARY SYNDROME can also unexplained infertility is an extremely upsetting impair fertility. fractures 95

See also FEMALE REPRODUCTION; MALE REPRODUC- rience a greater risk of developing fractures than do TION; PREGNANCY; REPRODUCTIVE ENDOCRINOLOGY. others. In addition, individuals with OSTEOMALACIA, another low-density BONE DISEASE, also have an increased risk for suffering from bone fractures. follicle-stimulating hormone (FSH) A hormone Endocrinologists differentiate between fragility released by the anterior pituitary gland as directed fractures and other fractures. Fragility fractures are by the HYPOTHALAMUS GLAND. In women, this hor- those that occur with minimal or no trauma and mone stimulates ovulation to occur and also caus- are clearly a sign of decreased bone strength. This es the release of ESTRADIOL. In men, FSH stimulates decreased bone strength is typically due to the production of sperm. Estradiol in women and decreased bone density usually associated with testosterone in men are the hormones that feed microarchitectural abnormalities of the bone. back to the pituitary and hypothalamus and help to Radiographic fractures are those seen on X-rays but maintain an appropriate balance. that are not clinically significant to the patient. In Like other pituitary hormones, FSH is secreted in contrast, a broken arm or leg that occurs in an acci- a pulsatile fashion. Levels of FSH need to be assessed dent is usually severely painful to the patient, who by physicians who have knowledge of the clinical actively seeks treatment for the problem. situation of the patient as well as the concurrent Some endocrine diseases are linked to a greater estradiol or testosterone levels or semen analysis. risk for fractures. For example, a large study, the When adult women present with menstrual dif- Study of Osteoporotic Fractures, demonstrated that ficulties, such as the failure to menstruate (AMEN- elderly women with HYPERTHYROIDISM have a three ORRHEA) or with infrequent menstruation times greater risk of having fractures than women (oligomenorrhea), physicians will measure levels of the same age with normal thyroid-stimulating of FSH, LUTEINIZING HORMONE (LH), and possibly hormone (TSH) levels. A past history of having other hormone levels. The normal FSH blood lev- hyperthyroidism, among women who currently els of a premenopausal woman, according to the had normal thyroid levels, was associated with NATIONAL INSTITUTES OF HEALTH, is five to 30 inter- twice the risk of developing fractures. national units per liter (IU/l), although the midcy- Research has shown that women taking 3- cle peak may range from 10–60 IU/l. hydroxy-3-methylglutaryl coenzyme A (HMG Physicians may also decide to test the FSH levels CoA) reductase inhibitor medications, also known if a woman has (or is suspected of having) OVARIAN as statins, for hyperlipidemia have a lower risk of CYSTS or MULTIPLE ENDOCRINE NEOPLASIA, type 1 suffering from hip and nonspine fractures. Statins (MEN 1). With primary ovarian or testicular fail- apparently stimulate bone formation and enhance ure, the FSH level will be increased and the estra- bone strength. diol or testosterone levels will be elevated. When a See also ELDERLY; OSTEOPENIA. hypothalamic or a pituitary problem is present, the Bauer, Douglas C., M.D., et al. “Risk for Fracture in FSH level will be inappropriately low. Women with Low Serum Levels of Thyroid- Some endocrine disorders associated with Stimulating Hormone.” Annals of Internal Medicine 134, abnormal FSH blood test results include the follow- no. 7 (2001): 561–568. ing: HASHIMOTO’S THYROIDITIS, HYPOPITUITARISM, Bauer, Douglas, M.D., et al. “Use of Statins and Fracture: POLYCYSTIC OVARY SYNDROME, POSTPARTUM PITUITARY Results of 4 Prospective Studies and Cumulative NECROSIS (pituitary failure after childbirth), and Meta-Analysis of Observational Studies and TURNER SYNDROME. Controlled Trials.” Archives of Internal Medicine 164, no. 2 (January 2004): 146–152. fractures Breaks in the bones. People who have OSTEOPOROSIS have a low bone density and also expe-

G galactorrhea Breast milk production in nonnurs- their diabetes after the weight loss caused by the ing women. Hyperprolactinemia, the excess pro- surgery. The remaining 17 percent showed marked duction of prolactin from the lactotrophs in the improvements of their glucose levels. anterior pituitary gland, is the most common cause Most patients who choose gastric bypass surgery of galactorrhea. are females. Many physicians who perform gastric PROLACTINOMA is a benign cause of hyperpro- bypass surgery require prospective patients to lactinemia that can lead to galactorrhea. Other undergo psychological evaluations. This is done to causes of excess prolactin can also lead to breast ensure that patients are emotionally stable and that milk production, for example, HYPOTHYROIDISM, the they understand that the procedure is not chronic excessive stimulation of the breast or nip- reversible, should they be unhappy with their new ple, or drugs that reduce the production of inability to eat large quantities of food. In addition, dopamine in the brain, such as certain antipsycho- these patients require a comprehensive evaluation, tic drugs (haloperidol and risperidone) and the including, but not limited to, cardiac stress testing, antiemetic drug metoclopramide. The galactorrhea pulmonary function testing, sleep studies, and usually resolves with successful treatment of the complete laboratory evaluations. underlying illness. In general, physicians restrict weight reduction See also PROLACTIN. surgery to adult patients with a BODY MASS INDEX (BMI) of 40 or greater. However, in some cases, the procedure will be performed in patients whose gastric surgery for weight loss An elective sur- BMI is 35 or greater when they have other signifi- gery and the most effective form of weight reduction cant health problems (such as diabetes) that would surgery (also known as bariatric surgery). It is per- be improved with extensive weight loss. formed on some morbidly obese patients who have Gastric bypass surgery allows digestion to occur. failed to lose weight with diet and exercise regimens However, patients can eat only small quantities and whose health is seriously compromised. Many because of the shrunken size of the stomach. If patients who have gastric bypass surgery also have they revert to past habits of consuming large TYPE 2 DIABETES and hypertension prior to the proce- amounts of food, they become severely nauseated dure. They are also at risk for developing heart dis- and experience stomach upset and vomiting. ease and stroke. The surgery usually improves these conditions, in many cases bringing glucose and Benefits of Surgery blood pressure levels to normal. In addition to the general benefits of a considerable In a study reported in a 2003 issue of the Annals weight loss in obese individuals, these patients usu- of Surgery, the researchers evaluated 191 patients ally show an improvement in their menstrual reg- with Type 2 diabetes and who underwent laparo- ularity, FERTILITY, and overall hormonal balance. scopic Roux-en-Y gastric bypass surgery. Most Women can become pregnant after having gastric patients lost about 100 pounds. A dramatic per- bypass surgery, although physicians recommend centage (83 percent) experienced a normalization that women wait at least a year after surgery before of their blood glucose levels and thus a reversal of they seek to conceive a child.

97 98 gastrinomas

Of interest is that some patients who have had compared with an estimated 100,000 adults who gastric surgery experienced a change in their GHRE- have weight reduction surgery in a year. LIN levels. Ghrelin is a hormone released by the Physicians who perform gastric bypass surgery stomach that affects hunger and a feeling of full- generally require adolescents to be more obese ness after eating (satiety). In a study reported in a than their adult counterparts in order to be consid- 2002 issue of the New England Journal of Medicine, ered for this surgery or to have a BMI of greater researchers compared the ghrelin levels of individ- than 40 accompanied by a serious medical prob- uals who lose weight through dieting after six lem, such as diabetes mellitus or hypertension. months on a low-calorie, low-fat diet, with patients See also OBESITY. who lost weight from gastric surgery. They found For further information on gastric bypass sur- that the gastric surgery patients had significantly gery, contact the following organizations: lower levels of ghrelin. In a seemingly self-defeating American Society for Bariatric Surgery manner, the dieters’ ghrelin levels actually went up 7328 West University Avenue when they dieted. Suite G Said the researchers, “In summary, 24-hour Gainesville, FL 32607 plasma ghrelin levels increase in response to diet- (352) 331-4900 induced weight loss, suggesting that ghrelin may http://www.asbs.org play a part in the adaptive response that limits the amount of weight that may be lost by dieting. We American Society of Bariatric Physicians also found that ghrelin levels are abnormally low 5453 East Evans Place after gastric bypass, raising the possibility that this Denver, CO 80222 operation reduces weight in part by suppressing (303) 770-2526 ghrelin production.” http://www.asbp.org

Disadvantages to Gastric Bypass Surgery Cummings, David E., M.D., et al. “Plasma Ghrelin Levels After Diet-Induced Weight Loss or Gastric Bypass Gastric bypass surgery comes with disadvantages. Surgery.” New England Journal of Medicine 346, no. 21 For example, patients may develop serious vitamin (May 23, 2002): 1,623–1,630. and mineral deficiencies, particularly of vitamin Minocha, Anil, M.D., and Christine Adamec. The B12, as well as of iron, folate, and calcium. Some Encyclopedia of Digestive Diseases and Disorders. New patients develop gallstones after surgery as well as York: Facts On File, Inc., 2004. other digestive ailments. Schauer, P. R., et al. “Effect of Laparoscopic Roux-en Y The surgery is a serious one, and some fatalities Gastric Bypass on Type 2 Diabetes Mellitus.” Annals of have occurred. However, with proper preoperative Surgery 238, no. 4 (2003): 467–485. selection and evaluation of patients, operative and Winslow, Ron, and Rhonda L. Rundle. “For Obese Teens, perioperative mortality should be less than 1 per- A Radical Solution: Stomach Surgery.” Wall Street cent. This percentage needs to be contrasted with Journal CCXLII, no. 69 (October 7, 2003): A1, A15. the nearly 33 percent death rate over 10 years in those obese patients who do not have the surgery. gastrinomas Tumors that typically occur in the Adolescents and Gastric Bypass Surgery pancreas or duodenum and that secrete excess gas- Some adolescents are severely obese, and they may trin, a hormone necessary for the production of seek gastric bypass surgery. However, this proce- acid in the stomach. The excessive gastrin triggers dure is controversial in adolescents, and most an overproduction of digestive acids. Gastrinomas health insurance companies will refuse to pay for are a characteristic feature of Zollinger-Ellison syn- it. According to an article in a 2003 issue of the drome, a condition first discovered by Drs. Wall Street Journal, an estimated 150 adolescents in Zollinger and Ellison in 1955. One or multiple the United States have had gastric bypass surgery, tumors may be present. gestational diabetes 99

Patients with gastrinomas usually present with poses. Chemotherapy may also be employed if the excessive peptic ulcer disease (in about 90 percent cancer has spread. of cases). However, very few patients with peptic ulcers have gastrinomas. Patients also present with malabsorption plus weight loss and dumping syn- genetic risks The probability of inheriting a dis- drome, a condition that occurs when food enters ease because it is present in other family members the small intestine too rapidly. Common symptoms such as parents and/or siblings. If a disease is partic- are abdominal pain and diarrhea as well as large ularly linked to a genetic risk, it will often have the amounts of fat in the stool. word “familial” as part of the name of the medical Gastrinomas also sometimes contain and secrete problem, such as with FAMILIAL HYPERCHOLES- other hormones, including adrenocorticotropic TEROLEMIA or FAMILIAL COMBINED HYPERLIPIDEMIA. hormone (ACTH), INSULIN, GLUCAGON, vasoactive The likelihood of becoming ill with many diseases intestinal peptide (VIP), 5-hydroxyindole-acetic and disorders, such as DIABETES MELLITUS, hyperten- acid (HIAA), and melanocyte-stimulating hormone sion, and thyroid disease, includes genetic compo- (MSH). About 40–50 percent of gastrinomas are nents. However, in most cases, people who have malignant (cancerous), and about 25 percent are genetic risks for a disease can mitigate the chances associated with MULTIPLE ENDOCRINE NEOPLASIA of developing the disease. For example, people at (MEN) syndrome. Many gastrinomas are multifo- risk for developing hypertension can exercise, cal. Of those that are malignant, greater than 50 maintain a healthy weight, and eat a nutritious diet. percent have already metastasized (spread) by the People at risk for TYPE 2 DIABETES can maintain a time the condition is diagnosed. normal weight and eat a balanced diet, which will Gastrinomas are most common in individuals often stave off diabetes permanently or until the 35–65 years of age. They occur slightly more com- individual is elderly. monly in males than in females. When gastrinomas are suspected, serum levels of gastrin and gastric acid output are both meas- genetic short stature The attainment of below- ured. The patient’s medical history is extremely normal height but with proportional features, such important as other conditions (such as kidney fail- as arms and legs that are proportional to the per- ure, antral G cell hyperplasia, retained antrum syn- son’s height. Genetic short stature occurs because drome, and some medications) can also lead to the individual was born to individuals who were of elevated gastrin levels. short stature themselves or who carry a gene for Once the biochemical diagnosis is performed, short stature. Thus the person has inherited a attempts are made to localize the tumor. Often genetic predisposition to a small size. Genetic short nuclear medicine studies with octreotide are used. stature is not the same as dwarfism, which brings An endoscopic ultrasound may be useful in locat- other characteristic facial features, such as a large ing tumors. Computerized tomography (CT) scans head and high forehead. and magnetic resonance imaging (MRI) scans can Sometimes physicians will administer GROWTH be used to look for metastases, but they are not HORMONE to individuals who would not otherwise usually sensitive enough to locate the small, pri- reach the norm for height among their peers. mary tumors. However, this is considered controversial therapy Patients with gastrinomas can be treated with a by many physicians. combination of medications (histamine-2 blockers See also DWARFISM. and proton pump inhibitors) and octreotide. The indications for surgery have become more controversial. Surgery is used for early and easily local- gestational diabetes (GDM) Diabetes that is diag- ized disease, when medical therapy has failed, or in nosed during pregnancy, typically in the second or metastatic disease for palliative (pain relief) pur- third trimester. 100 gestational diabetes

The cause of gestational diabetes is unknown, All women should be rescreened for GDM although experts speculate that the many hormon- between the 24th and 28th weeks of pregnancy, al changes that are experienced during pregnancy unless they lack all risk factors for GDM. are a factor. Women who develop GDM may also have a genetic predisposition to the development Diagnosis and Treatment of diabetes mellitus and the stress of the pregnancy The diagnosis is made either by an in-office glucose may be allowing the problem to manifest itself. test if the glucose levels are very high or by a formal Another argument in favor of a genetic component glucose tolerance test performed by a laboratory. to GDM is that women who were born to mothers The screening test done at 24–28 weeks of preg- who had GDM will present with GDM more fre- nancy is followed by a formal glucose tolerance test quently than women born to mothers not afflicted to make the diagnosis of gestational diabetes. with the condition. If testing confirms GDM, women should be Women with gestational diabetes have a dra- referred to a diabetes care team within 48 hours of matically higher risk of developing Type 2 diabetes the initial diagnosis so they can receive complete 15–20 years after the onset of GDM. This risk is the information and recommendations on their partic- highest among Hispanic, Native-American, and ular cases. This team should include, at a minimum, African-American women who have had gesta- the obstetrician, an endocrinologist, and a regis- tional diabetes. tered dietitian. Most women with GDM should also Other risk factors for developing GDM are age learn how to test their own blood and use the infor- (women over age 30 have a greater risk than mation from blood glucose testing to make appro- younger woman) and the number of children that priate meal-planning and health decisions. In very a woman has borne (the risk increases with each mild cases of GDM, changes in caloric and carbohy- subsequent pregnancy). drate intake can control the diabetes. In other cases, Other risk factors for experiencing GDM INSULIN is required. Most experts believe that include: women with GDM who require insulin should test their blood at least two to four times per day. • A family history of diabetes In other cases (about 30–60 percent) insulin is • Gestational diabetes with previous pregnancies required. As the pregnancy progresses, women may • Previous births of very large infants (heavier need higher doses of insulin. Several studies have than 9 pounds) shown the efficacy of oral hypoglycemia medica- • Prior problem pregnancies (either stillbirths or tions in the treatment of GDM. However, as of this miscarriages) writing, none of the oral medications have been approved by the Food and Drug Administration (FDA) for use in pregnancy; thus, the only Screening Pregnant Women for GDM approved therapy other than nutrition and exercise All pregnant women should be screened for risk is injected insulin. factors for GDM in their first prenatal visit, accord- Lifestyle changes will also be recommended to ing to the AMERICAN DIABETES ASSOCIATION. women with GDM. Nearly all women with GDM Physicians should consider if risk factors such as need to eat three meals and three snacks per day at obesity, a previous history of GDM, or a family his- regular intervals, with a small breakfast to avoid tory of the disease are present. If a woman is developing a midmorning HYPERGLYCEMIA. The believed to be at high risk, she should be screened physician may also prescribe an exercise plan that prior to any planned pregnancy or very early in the includes non-weight-bearing types of exercises, pregnancy as well as at intervals throughout the such as walking or bicycling. pregnancy, at the discretion of the obstetrician. Typically, this screening is performed by measuring After Delivery the woman’s blood glucose levels or with a glucose In most cases, women with GDM are no longer tolerance test. diabetic after the delivery of their babies. Only gigantism 101 about 10–15 percent of women with GDM have have undergone GASTRIC BYPASS SURGERY, ghrelin persistent diabetes immediately after delivery. levels are decreased. This may be part of the reason Despite this, women who have had GDM must why this procedure has the best track record in continue to monitor their blood glucose levels for terms of patients maintaining their weight loss over at least several weeks after being discharged from years. Some studies indicate that people with the hospital. All women with GDM should have a PRADER-WILLI SYNDROME have abnormally high lev- follow-up glucose tolerance test six to eight weeks els of ghrelin, which may account for their raven- postpartum to ensure that they no longer have dia- ous and uncontrollable appetites. betes and to gauge their current and future risk of Experts and clinical researchers are studying the the development of diabetes. impact of ghrelin and hope to develop an antighrelin Women with GDM are also usually encouraged type of medication that will help combat the epi- to breast-feed their babies. In addition to the many demic of OBESITY currently seen in the United States, known benefits of BREAST-FEEDING accruing to both Canada, and other developed countries. the mother and the infant, breast-feeding may also See also GROWTH HORMONE. help to improve the mother’s own insulin status. In Ariyasu, Hiroyuki, et al. “Stomach Is a Major Source of addition, it may also help her to lose weight, which Circulating Ghrelin, and Feeding State Determines should further decrease her future susceptibility to Plasma Ghrelin-Like Immunoreactivity Levels in developing Type 2 diabetes. Humans.” Journal of Clinical Endocrinology & Metabolism See also DIABETES MELLITUS; PREGNANCY; TYPE 2 86, no. 10 (2001): 4,753–4,758. DIABETES. Cummings, D. E., et al. “Plasma Ghrelin Levels after Diet- Kjos, Siri L., and Tomas A. Buchanan, M.D. “Gestational Induced Weight Loss or Gastric Bypass Surgery.” New Diabetes Mellitus.” New England Journal of Medicine England Journal of Medicine 346, no. 21 (2002): 341, no. 23 (December 2, 1999): 1,749–1,756. 1,623–1,630. Langer, Oded, M.D., et al. “A Comparison of Glyburide Wren, A. M., et al. “Ghrelin Enhances Appetite and and Insulin in Women with Gestational Diabetes Increases Food Intake in Humans.” Journal of Clinical Mellitus.” New England Journal of Medicine 343, no. 16 Endocrinology & Metabolism 86, no. 12 (2001): (October 19, 2000): 1,134–1,138. 5,992–5,995. Petit, William A. Jr., and Christine Adamec. The Encyclopedia of Diabetes. New York: Facts On File, Inc., 2002. gigantism A condition caused by excessive secretion of growth hormone, usually due to a tumor of the pituitary gland. The tallest man ever recorded ghrelin A protein hormone discovered in 1999 in was the late Robert Wadlow, at 8 feet, 11 inches in Japan. It is synthesized in the stomach and duode- height. The tallest woman (who is still alive, as of num and consists of 28 amino acids. Ghrelin is the this writing) is 7 feet, 5.5 inches. A photograph of first hormone that clearly links the gastrointestinal the tallest living woman is provided in a 1999 issue tract, the pituitary gland, and the hypothalamus. of the Journal of Clinical Endocrinology & Metabolism. Ghrelin, which increases food intake in rats and For gigantism to occur, the excess growth hor- humans, is the first hormone that has been found mone must be secreted prior to the closing of the to stimulate appetite and appears to be involved growth plates (epiphyses) in the bones. The excess with the regulation of appetite and weight. Ghrelin growth hormone can result from a pituitary tumor, levels can be measured in the bloodstream. In addi- hypersecretion of growth hormone-releasing hor- tion, ghrelin seems to bind to the growth hormone- mone (GHRH) from the hypothalamus, or a defi- releasing receptor and to have a role in the ciency of SOMATOSTATIN in the neural pathways in secretion of growth hormone. the hypothalamus leading to the pituitary gland. After standard dieting, ghrelin levels increase Gigantism can accompany the following endocrine and again decline with refeeding. In patients who disorders: MCCUNE-ALBRIGHT SYNDROME,CARNEY 102 glucagon

COMPLEX, NEUROFIBROMATOSIS, and MULTIPLE increase the glucose level in the blood by stimulat- ENDOCRINE NEOPLASIA (MEN) syndrome type 1. It ing stored glycogen to break down as well as by can also occur with optic nerve tumors. stimulating the synthesis of new glucose from The symptoms of gigantism are similar to those other precursors. However, some individuals, such seen with acromegaly, in which the excess growth as those who are severely alcoholic and/or mal- hormone is secreted after the growth plates in the nourished, do not have stored glycogen readily bones have closed, causing patients to have available to them, and thus the glucagon cannot act enlarged hands and feet, excess sweating (hyper- properly in their cases. hydrosis), coarse facial features, and prognathism Patients who have had Type 1 diabetes for five (jaw protrusion). Most children with increased or more years will still have glucagon in their pan- growth do not have gigantism and are more likely creas. However, they will lose the ability to secrete to have genetic tall stature, HYPERTHYROIDISM,or glucagon when they become hypoglycemic, thus genetic abnormalities such as Soto, Weaver, rendering them more likely to develop hypo- Marshall-Smith, and XYY syndromes. glycemia again. To diagnose gigantism, initially insulin-like In an emergency, glucagon may be administered growth factor 1 (IGF-1) is measured as well as IGF by intramuscular injection to patients with diabetes binding protein 3. The gold standard is the glucose and severe hypoglycemia who cannot eat or drink. suppression test. In this test, the patient is given The injected glucagon will work within 15–20 min- oral glucose, and then serial growth hormone lev- utes to increase the blood glucose level. Thus, the els are measured. In patients with normal growth glucagon injection is a critical tool for use at home, hormone physiology, the growth hormone will in the field, and even in the hospital if an intra- decrease to a level of less than 2 ng/dl. If ectopic venous line cannot be placed to give glucose. The GHRH secretion is suspected, this can be measured one side effect of a glucagon injection is mild-to- in the blood. As with all endocrine disorders, once moderate nausea. there is biochemical evidence of a disorder, imaging On very rare occasions, the pancreas can pro- of the pituitary and hypothalamus with MAGNETIC duce tumors—glucagonomas—that secrete exces- RESONANCE IMAGING (MRI) or COMPUTERIZED sive glucagon that can cause HYPERGLYCEMIA, TOMOGRAPHY (CT) is indicated. If imaging reveals nausea, and rash. Cancerous tumors can also, the presence of a pituitary or hypothalamic tumor rarely, produce glucagons. An antidiabetic medica- or structural lesion, surgical intervention is the best tion, pramlintide (Symlin) exerts part of its effect approach. This can be followed by medication and by suppressing the surge in endogenous glucagon radiotherapy. that occurs after meals in patients with diabetes. BROMOCRIPTINE (Parlodel), octreotide (Sandostatin See also DIABETES MELLITUS; HORMONES. and Sandostatin LAR), lanreotide, and pegvisomant may be utilized to treat patients with gigantism, and combinations of medications are often used. glucagonoma An extremely rare, slow-growing Radiotherapy in children often leads to pituitary fail- neuroendocrine tumor, usually malignant (in 80 ure and the need for multiple hormone replacement percent of the cases), of the alpha 2 islet cells of the therapies. pancreas, the organ that secrets both INSULIN and See also ACROMEGALY; PITUITARY GLAND. GLUCAGON. It is most likely to occur after the age of 55. Since Dr. S. W. Becker’s first description of a Eugster, Erica A., and Ora H. Pescovitz. “Gigantism.” glucagonoma in 1942, fewer than 300 glucagono- Journal of Clinical Endocrinology & Metabolism 84, no. 12 mas have been described worldwide. (1999): 4,379–4,383. Individuals with MULTIPLE ENDOCRINE NEOPLASIA, type 1 have an increased risk for developing glucagonomas, although they are rare in these glucagon A hormone secreted by the alpha cells individuals as well. This type of tumor may also of the pancreas. Glucagon acts in the liver to spread to the liver. The tumor may also cause goiter 103 impaired glucose tolerance or overt HYPERGLYCEMIA. DROME, with increased blood pressure and glucose, It also causes a special type of skin lesion called a centripetal redistribution of body fat (especially necrolytic migratory erythema, in which the skin is around the abdominal area), and a “moon face.” hypersensitive to pressure and friction. The term glucocorticoid was devised when these Symptoms of a glucagonoma include the follow- compounds were first being analyzed and segregat- ing: ed by their abilities to maintain blood glucose levels (glucocorticoids) or to maintain blood pressure • A skin rash present on the face, abdomen, but- and salt and water balance (mineralocorticoids). tocks, or legs, which may be scaly and crusty Most of these compounds have both glucocorticoid • Inflammation of the tongue and mouth and mineralocorticoid capabilities, with the exception of dexamethasone, which has no mineralocor- • Unexplained weight loss ticoid effect. • Frequent urination (polyuria) Other examples of oral glucocorticoid medica- • Extreme thirst tions include: • Nighttime urination (nocturia) • Betamethasone (Celestone) • Increased appetite • Methylprednisone (Meprol) • Thromboembolic disorders (blood clots, pulmonary embolism) • Triamcinolone (Aristocort)

Doctors who suspect that a patient may have a glucagonoma will measure blood levels of glucagon glucose intolerance Refers to a condition in with a concurrent glucose level. The patient will which glucose levels are higher than normal but also have an abnormal result on the glucose toler- lower than the level used to determine DIABETES ance test and will have an elevated fasting glucose MELLITUS. Glucose intolerance is determined by the level. Once the biochemical diagnosis of a gluco- two-hour ORAL GLUCOSE TOLERANCE TEST. In this gonoma is made, imaging studies may be done to test, the patient’s blood is assessed after one hour try and localize the tumor for the surgeon. and then again an hour later. Glucose intolerance Computerized tomography (CT) will often show is defined as a glucose level greater than 140 mg/dl the presence of the tumor within the pancreas. but less than 199 mg/dl. The only treatment as of this writing is surgery Often patients with glucose intolerance have because glucagonomas do not respond to HYPERLIPIDEMIA or OBESITY. Women with this condi- chemotherapy or radiation treatment. Octreotide tion may also have POLYCYSTIC OVARY SYNDROME. (Sandostatin) may be used to decrease symptoms. Patients may progress to diabetes. They also have an increased risk for cardiovascular disease such as heart attack and stroke. glucocorticoids The name given to the steroids that help to maintain blood glucose levels. It is often used interchangeably with the term steroid. goiter A general term that implies an enlarge- Glucocorticoid medications such as prednisone ment of the thyroid gland without any determina- (Deltasone, Metiorten, Sterapred, Pediapred), dex- tion as to the cause for the enlargement or whether amethasone (Decadron), and cortisone acetate the thyroid function is low, normal, or high. (Cortef) are used to treat many inflammatory con- Goiters may be seen in patients with HYPOTHY- ditions such as asthma, ulcerative colitis, and ROIDISM (below-normal levels of thyroid hor- rheumatoid arthritis. They are also used to treat mone), HYPERTHYROIDISM (excessively high levels of ADDISON’S DISEASE. thyroid hormone), and even sometimes among When glucocorticoids are given in excess quan- patients who have a completely normal thyroid tity for any reason, it can lead to CUSHING’S SYN- function. 104 gonadal disorders

A symmetrical goiter (an enlargement on both Each patient’s evaluation should take place after sides of the neck) is common among patients with a medical history is taken and a physical examina- hypothyroidism, THYROIDITIS, or GRAVES’ DISEASE. tion is performed. This way the appropriate tests An asymmetrical goiter is typically due to multiple may be done in the appropriate order to avoid nodules and/or thyroiditis. Elderly patients with wasting the patient’s time and money and to lead thyroid disease are less likely to have goiters than to an expedient diagnosis. younger patients with thyroid problems. See also HASHIMOTO’S THYROIDITIS. Before the twentieth century, goiters were often caused by a severe deficiency in iodine, which then led to hypothyroidism. Today, iodine deficiency is gonadal disorders See HYPOGONADISM. very rarely a cause of thyroid disease in the United States, Canada, and other developed countries. However, iodine deficiency continues to cause goi- gonadotropin deficiency See HYPOGONADOTRO- ters and thyroid disease in developing countries PISM. around the globe.

Signs and Symptoms Graves’ disease The most common cause of HYPERTHYROIDISM, an excessive level of thyroid hor- Often there are no symptoms of goiter other than mone circulating in the body. This thyroid disease an enlarged neck, a sign that is often overlooked by was named after Irish physician Robert Graves in patients and even by some medical doctors if the 1835. Graves’ disease is an autoimmune disease, enlargement is not prominent. Other symptoms which means that the immune system mistakenly that may occur are dysphagia (difficulty swallow- attacks the body rather than foreign invaders such ing) and a change in the patient’s voice, which as bacteria or viruses. In addition to hyperthy- becomes weaker and more hoarse. Some patients roidism/THYROTOXICOSIS, Graves’ disease may cause may also have difficulty breathing because of the exopthalamos (severely bulging eyes) or other eye size of the goiter. findings. Rarely, it may cause a rash. Researchers have demonstrated that the cause Diagnosis and Treatment of Graves’ disease is the stimulation of the thyroid Goiters are evaluated for two reasons. The first is gland by a thyroid-stimulating immunoglobulin. structural. If a dominant nodule is present within a Some researchers have also noted that extremely goiter, the next best step is a fine-needle aspiration stressful events (such as a death in the family, los- to check for malignancy. If a patient has a diffuse ing a job, or another extreme stressor) may some- goiter causing structural symptoms, such as prob- times precede the development of Graves’ disease. lems with swallowing (dysphagia) or pain, often This has led experts to speculate that stress may surgery is the best option, unless an underlying trigger the disease to develop among susceptible cause can be treated. The second reason for evalu- individuals. However, most studies that have care- ating a goiter is functional. If a gland is enlarged fully looked at this issue have failed to show a con- due to primary hypothyroidism, with decreased vincing link between stress and the subsequent thyroid hormone and increased thyroid-stimulat- development of Graves’ disease. ing hormone (TSH) levels, it is best treated with Graves’ disease also has a strong genetic compo- thyroid hormone replacement therapy. This thera- nent. The illness may be discovered because of the py will normalize the TSH levels and lead to shrink- characteristic GOITER (thyroid enlargement), which age of the goiter. Thus, a variety of tests are used in causes the patient’s neck to become noticeably this diagnostic process, including blood tests for swollen and disproportionate to the head and the thyroid hormone levels, ultrasound, and radionu- rest of the body. In addition, the patient’s wide- clide scan. All tests do not have to be performed in open staring gaze and bulging eyes are other com- all patients. mon indications of the disease. Graves’ disease 105

Risk Factors mine whether Graves’ disease or THYROIDITIS may Graves’ disease is much more common in females; be causing the patient’s hyperthyroidism. women have about five times the risk of develop- Treatment is often first given in the form of ing the disease as do men. Children and adoles- antithyroid medications, such as propylthiouracil cents can also develop Graves’ disease, although it or Tapazole (methimazole). If these drugs fail to is more frequently seen among adults. Often coex- bring the patient’s thyroid levels down to within isting diseases and medical conditions are also seen normal levels, radioactive treatments may be given in patients who have Graves’ disease, including to the patient. Surgery, which usually involves a TYPE 1 DIABETES,ADDISON’S DISEASE, and pernicious nearly total removal of the thyroid gland, may anemia. become necessary, although surgery is not generally used as a common treatment for Graves’ disease Signs and Symptoms of Graves’ Disease in the United States. The following signs and symptoms are usually seen Ophthalmologists treat the eye complications in patients with Graves’ disease (some of these are that are caused by Graves’ disease, often with glu- also seen in patients with hyperthyroidism but who cocorticoid medications or with external X-ray ther- do not have Graves’ disease): apy. Barbara Bush, former first lady, suffered from eye complications caused by Graves’ disease and • A goiter that is visible and palpable (can be felt she was treated with orbital radiation therapy and by a physician) glucocorticoid medications. The late actor Marty Feldman, also noted for his extremely bulging eyes, • Eye problems (feeling of grittiness or irritation suffered from Graves’ ophthalmopathy. in the eye or other eye symptoms) Patients with severe eye problems caused by • Bulging, eye-popping appearance Graves’ disease may need surgery. Fortunately, • Heat intolerance severe eye disease is rare. Older men have a high- • Weight loss (when the patient is not seeking to er risk than other patients for developing serious lose weight); however, about 10 percent of eye complications of the disease, and Caucasians patients gain weight have a higher risk of developing eye complications than individuals of other races. In addition, • Itching skin patients with Graves’ disease who smoke have a • Excessive thirst greater risk for developing eye complications of the • Rapid heartbeat disease. • AMENORRHEA (no menstrual periods) in women Pregnancy and Graves’ Disease • Loss of sex drive Graves’ disease is the most common form of hyperthyroidism identified during pregnancy, representing about 85 percent of all cases found during that Diagnosis and Treatment period. When present, the signs and symptoms of If the physician suspects that Graves’ disease is Graves’ disease usually appear in the first trimester present, based on the patient’s appearance and the or after the delivery of the baby. Graves’ disease presence of hyperactive symptoms (such as an ele- must be treated in the pregnant woman because vated blood pressure and pulse and overall extreme she is at risk for excessive weight loss and for the nervousness), the doctor will almost invariably development of congestive heart disease. The fetus order a thyroid-stimulating hormone (TSH) test to is also at risk, for premature birth, fetal tachycardia, check for the levels of thyroid in the patient’s and severely slowed growth. bloodstream. Unusually low levels of TSH are Treatment of Graves’ disease during pregnancy indicative of hyperthyroid disease. is generally in the form of beta-blocker drugs rather Unless the patient is pregnant, doctors will also than radioiodine, which can be dangerous to the usually order thyroid radionuclide studies to deter- developing fetus. Doctors may also treat the preg- 106 growth disorders nant woman or new mother with propylthiouricil secreted decreases as individuals age. Most of the (PTU). It is less likely to cross into the placenta than effects of GH are mediated by insulin-like growth other drugs, and it is also less likely to appear in factor 1. breast milk than are other antithyroid medications. In addition to leading to the linear growth of a See also HASHIMOTO’S THYROIDITIS; THYROID child, growth hormone also helps with the break- BLOOD TESTS; THYROID-STIMULATING HORMONE; THY- down of fat (lipolysis), stimulates protein synthesis, ROID STORM. and helps the body to retain needed sodium and For further information on Graves’ disease, con- water. Growth hormone is produced by individuals tact the following organization: at all ages because it is also needed for the body to repair microscopic tissue damage properly. Peak National Graves’ Disease Foundation levels of growth hormone production usually occur P.O. Box 1969 in the evening, when individuals are asleep. Brevard, NC 28712 A tumor of the pituitary gland may cause an (828) 877-5251 excessive production of growth hormone, resulting http://www.ngdf.org in GIGANTISM if it occurs before puberty and is not Imrie, Helen, et al. “Evidence for a Graves’ Disease treated and ACROMEGALY if it occurs after puberty. Susceptibility Locus at Chromosome Xp11 in a United An insufficiency of growth hormone, on the other Kingdom Population.” Journal of Clinical Endocrinology hand, may cause short stature or may cause some & Metabolism 86, no. 2 (2001): 626–630. rare cases of DWARFISM. (Dwarfism is usually Rivkees, Scott A., Charles Sklar, and Michael Freemark. caused by a genetic mutation rather than by a lack “The Management of Graves’ Disease in Children, of growth hormone.) With Special Emphasis on Radioiodine Treatment.” It is controversial, but some children—especial- Journal of Clinical Endocrinology and Metabolism 83, no. ly males—who are below normal in height have 11 (1998): 3,767–3,777. been treated with growth hormone. Although Weetman, Anthony P., M.D. “Graves’ Disease.” New growth hormone does not make them become tall, England Journal of Medicine 343, no. 17 (October 26, it generally allows them to achieve a greater height 2000): 1,236–1,248. than they otherwise would have attained. If administered, growth hormone must be given to children prior to the onset of puberty and before growth disorders Medical problems that are the endplates in their bones (the epiphyses) close often caused by either inadequate or excessive lev- for the best effect. els of growth hormone. The underlying cause is Some examples of growth hormones that are often a problem with the pituitary gland. used include: Growth hormone deficiency refers to lower- than-normal levels of circulating growth hormone • Genotropen and results in short stature, such as DWARFISM. • Norditropen When ACROMEGALY occurs before puberty, it leads • Humatrope to excessive growth and GIGANTISM. See also GENETIC SHORT STATURE; GROWTH HOR- • Serostim MONE. Growth hormone is also sometimes used in adults who have growth hormone deficiency. It growth hormone (GH) A protein hormone syn- will help to increase their strength and muscle thesized by the PITUITARY GLAND that enables indi- mass, decrease their percentage of body fat, viduals to grow to an adult height. Of the seven increase their bone density, and in general, anterior pituitary hormones, GH is produced in the increase their overall sense of well-being. greatest amounts. Growth hormone is secreted See also AIDS; DELAYED PUBERTY; EARLY PUBERTY; throughout life, although the amount that is GROWTH DISORDERS; GROWTH HORMONE DEFICIENCY. growth hormone deficiency 107

For further information, contact the following other pituitary hormones can also cause growth organization: hormone deficiency. However, isolated GH deficiency can also occur. Thus, in adults, the causes of Human Growth Foundation GHD include trauma, vascular accidents, surgery 997 Glen Cove Avenue Suite 5 (for trauma, pituitary tumors, or other tumors), Glen Head, NY 11545 and radiation therapy. (800) 451-6434 (toll-free) Diagnosis http://www.hgfound.org Growth hormone deficiency should be suspected in Cohen, Pinchas, et al. “Effects of Dose and Gender on the all patients with pituitary failure or pituitary Growth and Growth Factor Response to GH in GH- tumor. The usual screening test is a measurement Deficient Children: Implications for Efficacy and of fasting levels of insulin-like growth factor 1 Safety.” Journal of Clinical Endocrinology & Metabolism (IGF-1). If this level is abnormally low, further test- 87, no. 1 (2002): 90–98. ing can be performed to attempt to stimulate the Drake, W. M., S. J. Howell, and S. M. Shalet. “Optimizing anterior pituitary gland to produce GH. Typically, GH Therapy in Adults and Children.” Endocrine drugs such as clonidine, L-dopa, growth hormone- Reviews 22, no. 4 (2001): 425–450. releasing factor (GHRH or GHRF), and the amino acid L-arginine can be used. The gold standard test for growth hormone defi- growth hormone deficiency (GHD) A condition ciency is the insulin tolerance test. In this test, a that exists when the pituitary gland fails to produce graded amount of intravenous insulin is given to sufficient growth hormone, either due to a primary induce hypoglycemia purposely. Growth hormone pituitary lesion or a problem with the hypothala- is one of the counterregulatory hormones, and the mus. When GHD occurs in children, growth failure anterior pituitary should produce increased levels and short stature occur. of growth hormone in response to the induced All humans, including even elderly adults, hypoglycemia. A lack of this response would indi- require some level of growth hormone to function cate GHD. This test is typically done in an outpa- at optimal levels. Growth hormone (GH) helps to tient area of the hospital or may be done in an maintain normal protein synthesis and thus helps endocrinologist’s office. It must be performed with maintain normal muscle and bone mass. Adults caution, however, especially among patients who with GHD have decreased muscle mass and may be at risk for heart problems. Hypoglycemia increased fat mass. They have poor lipid profiles, could provoke angina or even a heart attack in a low high-density lipoprotein (HDL) levels, and person with pituitary insufficiency or even an iso- high low-density lipoprotein (LDL) levels. These lated growth hormone deficiency. persons also appear to have increased mortality from cardiovascular causes. Treatment Measurements of heart function are improved Growth hormone deficiency in adults can be treat- with GH replacement therapy. In addition, markers ed with the use of daily recombinant growth hor- of endothelial inflammation, such as C-reactive mone via subcutaneous injection. The doses used protein, are higher in patients with GHD than in are often less than those used to treat children with controls. Adults with GHD have more psychologi- growth hormone deficiency and short stature. cal distress and depression that seems to decrease Progress is monitored by evaluating the patient’s when their GH is replaced. Thus, even in adults, sense of well-being, muscle and fat mass, IGF-1 GHD can be treated with recombinant subcuta- levels, bone density, and other parameters. neous growth hormone. GHD treatment among adults is controversial. As The cells that make GH in the anterior pituitary, of this writing, experts feel that not all adults with the somatotrophs, are perhaps the most sensitive to GHD should be treated. However, treatment is cer- damage. The causes of deficiencies in all of the tainly a consideration in patients with GH deficiency. 108 gynecomastia

Each case should be evaluated by the patient’s pri- mother. It can also be seen in pubertal teenage boys mary care physician, in conjunction with an and is transient. endocrinologist, to determine what is best for the As a true pathological condition, gynecomastia individual. is most common in men ages 50 and older. It can Overtreatment with growth hormone can lead affect one or both breasts. The hormonal causes to signs and symptoms of acromegaly and a wors- typically involve a disruption of normal hormone ening of diabetes. In patients with previous malig- balance. There are generally below-normal levels nancies, the use of growth hormone is of male hormone (androgen) production or controversial and typically is not used. increased female hormones (estrogen). These hor- See also DELAYED PUBERTY; DWARFISM; GROWTH mones are synthesized in both the male testes and HORMONE. the adrenal glands. Thus, in men, primary or secondary gonadal (testicular) failure, hyperthy- Cook, David M., M.D. “Shouldn’t Adults with Growth roidism, and hormonal enzyme abnormalities Hormone Deficiency Be Offered Growth Hormone (increased aromatase activity) may each lead to the Replacement Therapy?” Annals of Internal Medicine development of gynecomastia. 137, no. 3 (2002): 197–201. Tumors of the testes (germ cell/Leydig’s DeBoer, H., et al. “Clinical Aspects of Growth Hormone cell/Sertoli’s cell tumors), adrenal tumors (benign Deficiency in Adults.” Endocrine Review 16, no. 1 adenomas and carcinomas), and tumors elsewhere (February 1995): 63–86. can also cause gynecomastia. Severe liver disease, Frohman, L. A. “Controversy About Treatment of kidney failure, and starvation can lead to gyneco- Growth Hormone-Deficient Adults: A Commentary.” mastia. Multiple drugs can also cause gynecomas- Annals of Internal Medicine 137, no. 3 (2002): 202–204. tia, including but not limited to estrogens, Isley, William L., M.D. “Growth Hormone Therapy for antiandrogens (used to treat cancers), antiulcer Adults: Not Ready for Prime Time.” Annals of Internal drugs (cimetidine, ranitidine, and omeprazole), Medicine 137, no. 3 (2002): 190–196. alcohol, narcotics, marijuana, digtoxin, some angiotensin-converting enzyme (ACE) drugs, and spironolactone. Some syndromes, such as gynecomastia The benign enlargement of the Kallmann’s syndrome, as well as rare tumors and male breasts, which may be painful, and may be enzyme deficiency disorders can also lead to caused by a hormonal imbalance or by hormone gynecomastia. Gynecomastia is very common therapy, such as that taken to combat advanced among males with KLINEFELTER SYNDROME. prostate cancer. Gynecomastia is the development Treatment is aimed at removing the stimulus of true breast tissue that extends out from the that led to the breast development. Treatment of nipple. It must often be differentiated from the underlying cause will often resolve the gyneco- pseudogynecomastia, which is often secondary to mastia. For example, when males with Klinefelter obesity, and is a condition of increased fatty syndrome are treated with testosterone replace- deposits in and around the nipple area, suggesting ment therapy, the gynecomastia often abates. If the appearance of gynecomastia. treatment is impossible and the breast tissue is If gynecomastia is suspected, the physician must uncomfortable or cosmetically disturbing, mastec- first be sure that it is not male breast cancer, which tomy surgery may be performed. does occur. If the tissue is hard and nonmovable, See also HORMONES; HYPOGONADISM. the patient generally needs a mammogram and a surgical consultation for a biopsy and/or excision. Braunstein, G. D. “Diagnosis and Treatment of Gynecomastia is sometimes seen in newborns Gynecomastia.” Hospital Practice (Office Edition) 28, for two to four weeks, as they have been exposed no. 10A (1993): 37–46. to high levels of circulating estrogens from the H

Hashimoto’s thyroiditis An autoimmune form of percent of first-degree relatives (parents and sib- hypothyroidism in which the immune system lings) of individuals with Hashimoto’s thyroiditis attacks the thyroid gland. This disorder is also also have thyroid autoantibodies and may develop known as chronic thyroiditis, chronic lymphocytic the disease. thyroiditis, struma lymphomatosa, lymphadenoid Often the patient is not diagnosed for years after goiter, and autoimmune thyroiditis. the onset of Hashimoto’s thyroiditis. This occurs Hashimoto’s thyroiditis is the most common because the initial symptoms are subtle and can be cause of below-normal thyroid levels in areas of the easily confused with those of many other conditions. world with adequate iodine in the diet. In countries Graves’ disease is another autoimmune thyroid where there is inadequate iodine in the diet, it is the disease, but it causes HYPERTHYROIDISM (excessive iodine deficiency that causes the hypothyroidism levels of thyroid) rather than hypothyroidism. (without iodine, thyroid hormone cannot be pro- Individuals who have Hashimoto’s thyroiditis usu- duced naturally). Hashimoto’s thyroiditis is a slow- ally have the symptoms and signs of hypothy- ly progressive form of thyroid failure that may or roidism, although some individuals have no may not be associated with a GOITER. Other variants symptoms until the disease is more advanced. of Hashimoto’s thyroiditis are painless lymphocytic When symptoms are present, they may include thyroiditis or postpartum thyroiditis, both of which some or all of the following: can progress to HYPOTHYROIDISM that is indistin- guishable from Hashimoto’s thyroiditis. • Cold intolerance Japanese physician H. Hashimoto first described • Slowed movements Hashimoto’s thyroiditis in 1912. Other researchers • Lethargy/fatigue subsequently identified the specific autoimmune antibodies causing the condition in 1956. • Unexplained weight gain • Constipation Risk Factors • Presence of a goiter There is a genetic predisposition to Hashimoto’s • Dry skin thyroiditis. In addition, individuals with other autoimmune conditions, such as GRAVES’ DISEASE • Heavy menstrual periods or irregular periods and TYPE 1 DIABETES, have an increased risk for • Greater difficulty with thinking developing Hashimoto’s thyroiditis, as do individu- • Joint stiffness/muscle aches and cramps als with TURNER SYNDROME and Down syndrome. • Brittle nails and dry, coarse hair Women have a five to 10 times greater risk than men of developing the disease, and women between the ages of 50 and 60 years are the most In almost all cases of Hashimoto’s thyroiditis, at risk. Hashimoto’s thyroiditis occurs in up to 5 with or without the presence of a goiter, the percent of adults in the United States and other changes in the thyroid are painless. If pain occurs, developed countries. Sometimes the disease is the physician must consider other diagnoses, such linked to a familial predisposition. An estimated 50 as subacute thyroiditis or de Quervain’s thyroiditis.

109 110 hermaphroditism

Diagnosis and Treatment sequence (Graves’ disease first, then Hashimoto’s Physicians who suspect the presence of Hashimoto’s thyroiditis later) but is much more rare. thyroiditis will order laboratory tests of thyroid Patients with Hashimoto’s thyroiditis are usual- functioning, including a free T4 test and a serum ly treated with levothyroxine in a dose that is suf- thyroid-stimulating hormone (TSH) test. These tests ficient to maintain normal functioning. However, if will reveal if the patient is hypothyroid. Generally, there is no indication of hypothyroidism (in a an elevated TSH serum level and a low-normal or patient who has antiperoxidase antibodies and nor- below-normal free T4 level indicate hypothy- mal thyroid function tests), doctors may instead roidism. follow the patient on a regular basis. Ultimately, If early enough in the course of the disease, a the patient will need to take levothyroxine as the blood test can measure the levels of antibodies to disease progresses further. peroxidase, antiperoxidase, or anti-thyroid peroxi- Endocrinologists will usually treat all of the fol- dase (TPO) antibodies. Peroxidase is an important lowing patients: those who have an abnormal TSH enzyme in the thyroid gland. It is the protein to level, those with a borderline TSH level and no which the immune system reacts in some cases. symptoms, those with an enlarged thyroid with the Thus, the anti-TPO antibodies damage the thyroid presence of antibodies, and also sometimes those by attacking the enzyme and causing hypothy- patients with coexisting nodules even with normal roidism. Why the enzyme is attacked is unknown. thyroid function. This is a much more specific test than previously In rare cases, patients will need surgery because used to measure antimicrosomal antibodies and of the compression of the trachea caused by a goiter. antithyroglobulin antibodies. If the process has See also THRYOID BLOOD TESTS; THYROIDITIS. gone on for a long time, the level of these antibod- Dayan, Colin M., M.D., and Gilbert H. Daniels, M.D. ies may be quite low. “Chronic Autoimmune Thyroiditis.” New England The anti-TPO antibody test is not 100 percent Journal of Medicine 35, no. 2 (July 11, 1996): 99–107. specific for Hashimoto’s thyroiditis, as these anti- Rose, Noel R., M.D., and Patrizio Caturegli, M.D. bodies can also be detected in other forms of thy- “Chronic Lymphocytic Thyroiditis,” in NORD Guide to roiditis as well as Graves’ disease. However, if the Rare Disorders: The National Organization for Rare cause of the hypothyroidism is not primary (due to Disorders. Philadelphia, Pa.: Lippincott Williams & destruction of the thyroid gland) but is secondary Wilkins, 2003, 329. or tertiary, as in PITUITARY FAILURE or hypothalamic dysfunction, patients will have low levels of free T4 and inappropriately normal or low levels of TSH. Patients with the presence of anti-TPO antibod- hermaphroditism Very unusual condition in ies will progress to overt Hashimoto’s thyroiditis at which both male and female sex organs are present the rate of about 5 percent per year. If a technetium at birth. In one example of such a condition, Dr. thyroid scan is done, patchy or heterogeneous Eric M. Pachter and his colleagues described a “true uptake is typically seen. Usually iodine uptake hermaphrodite” in a 1998 issue of Urology. The studies are not ordered, however, as the blood tests newborn child had an XX karyotype (normal males are usually sufficient to confirm the diagnosis. have both an X and a Y chromosome). The child Because the thyroiditis or inflammation in the had a vagina, partial uterus, and tissue that resem- thyroid gland occurs at different rates in different bled an ovary as well as such male body parts as a areas, the gland may feel as if there are nodules vas deferens, spermatic cord, and an intrascrotal present. On ultrasound examination, nodules may testicle. Because of the XX karyotype, the female be seen. Hashimoto’s thyroiditis can coexist with gender was assigned to the child, and the doctors many other forms of thyroid dysfunction. A signif- performed a right orchiectomy (removal of the tes- icant number of patients who first develop Graves’ ticle). Feminizing genital surgery was planned for disease can go on to develop Hashimoto’s thyroidi- the future. The doctors also noted that patients tis later. This can also happen in the reverse such as this child have potential for future fertility. homocysteine 111

In past years, parents were advised to raise the Some experts estimate that as many as 10 percent child with hermaphroditism as a female. Some of all women in the United States have experienced children who were raised as females but never told hirsutism at some point in their lives. about their hermaphroditism eventually chose to Hirsutism in women is usually caused by an assert their masculine identities. The malleability of endocrine disorder. Women normally have some male/female identity may have more to do with male hormones, and hirsutism is caused by exces- DNA than with environmental influences, even sive amounts or overactivity of male hormones when the child has inherited both sexual charac- (androgens). This overproduction may stem from teristics. the ovaries or the adrenal glands. Rarely, it may be Currently, some experts suggest delaying the caused by tumors of these glands. Hirsutism is com- gender choice in children with hermaphroditism monly seen in patients with polycystic ovary syn- until the child is at least two years old, while oth- drome (PCOS). It is also sometimes seen in patients ers believe the decision should be delayed until the with congenital adrenal hyperplasia. child is old enough to participate in the decision. (It Hirsutism can also be caused by an excessive is difficult to understand how the gender choice intake of exogenous androgens, as is sometimes could be delayed much beyond early childhood seen among female bodybuilders. since gender identities are important, even to small The excessive activity of the 5-alpha reductase children.) enzyme at the hair follicle, which causes the con- According to Steven E. Lerman and his col- version of testosterone to dihydrotestosterone, may leagues in an article on ambiguous genitalia in chil- be responsible for the hirsutism. dren, “Sexual identity is thought to be largely a Women who are Asian or Native American conditioning process that is firmly established by 2 rarely develop hirsutism, while women whose years, 6 months of age. For this reason, any families stem from the southern Mediterranean are attempt to change the sex of rearing beyond this more likely to develop the problem. Patients with age should be undertaken only when the initial sex hirsutism may be treated with medications, such as assignment has clearly been wrong, and psychiatric ORAL CONTRACEPTIVES, that decrease the level of assessment unequivocally indicates that sex reas- androgens. The symptoms may also be treated with signment is in the best interest of the child; ongo- electrolysis hair removal as well as with cosmetic ing psychiatric support may be necessary.” The creams. doctors also noted that when gender reassignment See also ACROMEGALY; ANDROGEN EXCESS; CON- occurs at an age older than two-and-a-half years, GENITAL ADRENAL HYPERPLASIA; INFERTILITY; POLYCYS- there is a greater risk of maladjustment. TIC OVARY SYNDROME. See also HYPOGONADISM;KLINEFELTER SYNDROME.

Lerman, Steven E., Irene M. McAleer, and George W. homocysteine An intermediary amino acid Kaplan. “Sex Assignment in Cases of Ambiguous formed when methionine is converted to cysteine. Genitalia and Its Outcome.” Urology 55, no. 1 (2000): HOMOCYSTINURIA or severe hyperhomocystinuria is 8–12. a rare autosomal recessive organic aciduria (acid in Pachter, Eric M., Mark Horowitz, and Kenneth I. the urine) that is typically diagnosed in infancy, Glassberg. “True Hermaphrodite.” Urology 52, no. 2 causing failure to thrive and developmental delays, (1998): 318–319. premature severe ATHEROSCLEROSIS, eye problems, and OSTEOPOROSIS. Homocysteine has direct effects that accelerate atherosclerosis and clotting. hirsutism in women The excess growth in Depending upon the population that is tested, the women of the stiff, pigmented hairs that are nor- range of homocysteine can vary from about 5–15 mally found in males in areas that are androgen micromoles per liter. dependent, such as on their face, chest, and on the Mild-to-moderate elevations of homocysteine abdomen. These hairs are known as terminal hairs. occur in about 6 percent of the population in the 112 homocystinuria

United States and are an independent risk factor for homocystinuria A hereditary disorder that atherosclerosis and venous thromboembolic phe- affects the metabolizing of methionine, an amino nomenon. Deficiencies of folic acid, vitamin B12, acid. Newborns with homocystinuria may appear or vitamin B6 can lead to increased levels of homo- to have mild developmental delays or FAILURE TO cysteine. Homocysteine levels will decrease in most THRIVE. As the condition progresses further, the patients as oral folate intake is increased to the patient may resemble a person with MARFAN’S SYN- level of 400 mcg per day. DROME because of the characteristic tall and slender In one trial, 158 healthy siblings of 167 patients build with disproportionately long legs and long, with premature atherosclerosis were given 5 mg of thin fingers. folic acid and 250 mg of vitamin B6 daily. In these Homocystinuria can lead to blood clots that are patients, the homocysteine levels decreased from dangerous because they can travel to the brain and 14.7 to 7.4 micromoles per liter. cause a stroke. The condition may also lead to poor A number of retrospective studies have shown vision and even to double vision. that the patients with the highest homocysteine levels had the greatest risk of developing ischemic heart disease and stroke. In addition, in other ret- Diagnosis and Treatment rospective studies, increased levels of homocys- If physicians suspect that a patient has Marfan’s syn- teine appear to be related to an increased risk of drome, they should also screen for homocystinuria. venous blood clots and pulmonary embolism. In X-rays will show that the patient with homocystin- women, increased levels are associated with uria has OSTEOPOROSIS. An examination by an oph- preeclampsia, fetal growth problems, stillbirths, thalmologist (eye doctor) will usually show that the and delivery complications. patient has both a dislocated lens (typically, the lens As of this writing, a large number of prospective is dislocated downward rather than upward, as is studies are being conducted to determine if supple- seen in Marfan’s syndrome) and nearsightedness. menting the diet with folic acid and vitamins B6 Children with homocystinuria may have glaucoma, and B12 will decrease homocysteine levels and, cataracts, and retinal detachment, all eye diseases more importantly, decrease the risk of atheroscle- that are abnormal among children. rosis complications. Laboratory tests of the blood and urine will show Many physicians now recommend a minimum elevated levels of homocystine and methionine in supplementation of 400 mcg of folate, 3–10 mg of patients who have homocystinuria. If a liver biopsy vitamin B6, and 10–100 cg of vitamin B12 for a and enzyme assay are performed, they will show general risk reduction. the lack of cystathionine beta synthase, an enzyme. A biopsy of the skin will show the absence of Homocysteine Studies Collaboration. “Homocysteine and cystathionine beta synthase and folate-related Risk of Ischemic Heart Disease and Stroke: A Meta- enzyme levels in fibroblasts among patients with Analysis.” Journal of the American Medical Association homocystinuria. These enzymes can also be meas- 288, no. 16 (2002): 2,015–2,022. ured in blood cells. Ray, J. G. “Meta-Analysis of Hyperhomocysteinemia as a If homocystinuria is diagnosed, there is no cure Risk Factor for Venous Thromboembolic Disease.” for this condition. Despite this, many patients Archives of Internal Medicine 158, no. 19 (October 26, respond well to high doses of pyridoxine (vitamin 1998): 2,101–2,106. B6). If the patient is an infant or young child, a low Vermeulen, E. G., C. D. Stehouwer, J. W. Twisk, et al. methionine diet may help to prevent the child from “Effect of Homocysteine-Lowering Treatment with becoming mentally retarded and from developing Folic Acid Plus Vitamin B6 on Progression of other aspects of the disease as it progresses. Some Subclinical Atherosclerosis: A Randomized, Placebo- states screen newborn infants for homocystinuria Controlled Trial.” Lancet 355, no. 9,203 (2000): so that they can be treated promptly if the condi- 517–522. tion is present. hormone resistance 113 hormone replacement therapy (HRT) Typically In both the Women’s Health Initiative and the refers to the combined use of estrogen and proges- Heart and Estrogen/Progestin Replacement (HERS) terone in women who are estrogen deficient and study, hormones were not found to offer either pri- who still have an intact uterus. In women without mary or secondary protection against coronary a uterus who have had natural or surgical artery disease. Thus, in 2004, most physicians will MENOPAUSE, only estrogen is required, and this consider the use of HRT in menopausal women for replacement therapy is referred to as estrogen unremitting vasomotor symptoms only. They will replacement therapy (ERT). Hormone replacement also use the lowest possible dosages for the shortest therapy may also refer to any use of one or more possible period of time. Both osteoporosis and hormones to replace an existing deficiency. coronary heart disease can be prevented and treat- In the late twentieth century, many physicians ed with multiple other agents with fewer adverse routinely placed postmenopausal women on either effects than HRT. HRT or ERT when they experienced any symptoms Some women have chosen to try “natural” of menopause, most notably HOT FLASHES. Sometimes remedies, such as supplements of vitamin E, soy, even when women experienced few or no black cohosh, and other options for their menopausal symptoms, physicians placed women on menopausal symptoms. Women should also discuss hormones because it was believed that such treat- such supplements and medications with their ment would be beneficial to women’s health. physicians in advance to ensure they would experi- However, studies released in the early twenty-first ence no adverse effects from combining such drugs century revealed that HRT was riskier than was pre- with other medications that they already take. viously known and that it carried an increased risk See also ESTRADIOL; ESTROGEN; ESTROGEN for women developing breast cancer, heart disease, REPLACEMENT THERAPY; HORMONES. and other illnesses. As a result, many physicians Grady, D., et al. “Cardiovascular Disease Outcomes began limiting the use of HRT, and many women also During 6.8 Years of Hormone Therapy: Heart and voluntarily chose to stop taking the drugs. Estrogen/Progestin Replacement Study Follow-up One of the key studies that revealed health risks (HERS II).” Journal of the American Medical Association of hormone therapy, the Women’s Health Initiative, 288, no. 1 (2002): 49–57. was ended early in 2002 because of its findings. In Grodstein, Francine, Thomas B. Clarkson, and JoAnn E. this study, researchers followed more than 16,000 Manson, M.D. “Understanding the Divergent Data on women taking estrogen/progestin combination Postmenopausal Hormone Therapy.” New England (Prempro) combination therapy for five years. The Journal of Medicine 348, no. 7 (February 13, 2003): researchers found that the women taking hormone 645–650. therapy faced a significantly greater risk of develop- McKane, W. Roland, et al. “Mechanism of Renal Calcium ing breast cancer as well as an increased risk for Conservation with Estrogen Replacement Therapy in developing a stroke and heart attack. The women Women in Early Menopause—A Clinical Research experienced a lower than expected rate of colorec- Center Study.” Journal of Clinical Endocrinology & tal cancer and fewer fractures, but these apparent Metabolism 80, no. 12 (1995): 3,458–3,464. protective factors were insufficient to justify the Writing Group for the Women’s Health Initiative higher risks of developing other diseases. Investigators. “Risks and Benefits of Estrogen Plus Some women have continued with HRT because Progestin in Healthy Postmenopausal Women.” it rids them of distressing menopausal symptoms Journal of the American Medical Association 288, no. 3 such as hot flashes, vaginal dryness, and insomnia. (July 17, 2002): 321–333. An analysis of 21 double-blind, randomized, placebo- controlled clinical studies of 2,511 women showed that hormone replacement therapy decreased hot hormone resistance The inability of the body to flashes in women by 77 percent compared with use properly some or all of the hormones that are placebo. naturally produced by the body. This resistance 114 hormones may be partial or complete. The essential feature of risks and benefits should be carefully considered Type 2 diabetes is resistance to the effects of insulin beforehand. Men who are low in testosterone may secreted by the pancreas. Patients with Type 2 dia- consider testosterone replacement therapy. betes have structurally normal insulin receptors Individuals who are low in parathyroid hormone and near-normal numbers of receptors, yet these usually take both supplemental calcium and CAL- receptors do not function properly. CITRIOL. In some syndromes, patients have abnormal According to the National Center for Health receptors or sometimes make none at all. In FAMIL- Statistics, the number of hormones prescribed in IAL HYPERCHOLESTEROLEMIA, patients lack the recep- the United States increased by 25 percent from tors to bind and thus to metabolize low-density 1997–2000. This may be due in large part to an lipoproteins (LDL). aging population that is more likely to need hor- Most hormonal systems exist in a balance in mones to treat diabetes, hypothyroidism, and which the number and activity of receptors can declining levels of testosterone or estrogen. adjust to the amount and activity of the hormone However, because of concern over hormone that is available. replacement therapy for women, increases of hor- See also HORMONES. mone prescriptions may flatten out despite the aging population. See also ALDOSTERONE; CORTISOL; ESTROGEN; hormones Substances secreted by the endocrine GROWTH HORMONE; INSULIN; LEVOTHYROXINE; TESTOS- glands that send chemical messages through the TERONE. bloodstream, usually causing an action. Some examples of hormones are thyroxine (produced by the thyroid gland); adrenaline, aldosterone, and hot flashes A generic description of a symptom cortisol (produced by the adrenal gland); insulin complex that includes a sudden onset with a sen- (produced by the beta cells in the pancreas); testos- sation of increased body temperature (generalized terone (produced by the testicles); and estrogen or focal) at times associated with sweating, facial (produced by the ovaries). flushing/blushing, and a generalized sense of dis- Typically, these hormones exert their effects at comfort and/or anxiety. Hot flashes may last for places distant from where they are produced. For seconds and rarely last longer than a few minutes. example, one endocrine effect is that insulin goes The hot flash is also known as a hot flush or as from the pancreas to affect muscles and cells vasomotor instability and may have its onset in the throughout the body. Hormones can also exert perimenopausal period or in MENOPAUSE. Experts paracrine effects. For example, insulin produced in believe that it represents true thermoregulatory the beta cells of the pancreas also has effects on the dysfunction. The areas of the brain that control adjacent alpha and delta cells. The word endocrine heat regulation are actually located in the hypo- implies a secretion into the blood and movement of thalamus near an area that contains a large num- the secretion to another area. In contrast, paracrine ber of nerves containing gonadotropin-releasing refers to secreting directly into the surrounding hormone (GNRH). cells or tissue without going into the systemic cir- Interestingly, hot flashes are not seen in women culation—it is a local effect. with TURNER SYNDROME who have never been When the body produces an inadequate amount treated with estrogens. Some experts hypothesize or none of the needed hormone, supplements can that the cause of the hot flashes may be decreased often be taken. For example, people with Type 1 central opioid activity. diabetes are lacking in insulin, and they can take Women who have undergone the complete sur- supplemental insulin. Individuals who are gical removal of their ovaries also experience hot hypothyroid can take supplemental thyroid drugs, flashes. These hot flashes are often more severe such as levothyroxine. than those among women who are experiencing Some women who are menopausal take ESTRO- the hot flashes of menopause. This occurs because GEN REPLACEMENT THERAPY (ERT), although the natural menopause involves a steady decline in hypercalcemia 115 estrogen, while the surgical removal of the ovaries Until about 2002, many doctors routinely pre- causes a sudden shutdown of estrogen production. scribed both HRT and ERT to menopausal woman. Hot flashes are often experienced in the However, major clinical studies have shown that evening, causing difficulties with sleep, although the risks of some diseases, such as breast cancer, they may occur at any time. Hot flashes may be myocardial infarction (heart attack), and stroke minor and tolerable, or they may be extreme, wak- may be increased in women taking these medica- ing women from a deep sleep and finding them- tions. Some doctors also believe that taking HRT or selves bathed in sweat and with a rapid heartbeat. ERT for a certain period of time, such as several Chills sometimes follow hot flashes, and the years, is acceptable but that they should not be woman who had thrown off all her bed covers will taken for the rest of a woman’s life. suddenly need extra blankets. This can be a difficult Some women take supplements to deal with experience not only for the woman but also for their hot flashes, such as vitamin E, black cohosh, anyone sharing her bed. soy products, and other remedies whose manufacturers purport that their products can help to man- Diagnosis and Treatment age menopausal symptoms. However, women who Hot flashes are usually diagnosed based on the are considering taking any supplements should first woman’s report of her signs and symptoms. If discuss this issue with their physicians, despite the menopause is suspected, measurement of both her fact that some of these supplements are not pre- FOLLICLE-STIMULATING HORMONE (FSH) and ESTRADI- scription drugs. The reason for this is that some OL levels may be helpful. alternative medications may not work well with Women seeking medical assistance from their the other drugs that a woman takes. Consequently, physicians to overcome their hot flashes will usual- supplements may either weaken the other medica- ly be informed about hormone replacement thera- tions or boost their effect. Either action can be py (HRT) medications, which are a combination of problematic to an individual. estrogen and progesterone, and estrogen replace- Some women prefer to avoid taking ERT, HRT, ment therapy (ERT), which is the administration of or supplements altogether. They may be comforted estrogen only. ERT is generally prescribed only for to know that the hot flashes of menopause gener- women who have undergone complete hysterec- ally abate over time as the body adjusts and usual- tomies (removal of both the uterus and the ly end altogether within about two to five years. ovaries), because estrogen may increase the risk for See also ESTROGEN REPLACEMENT THERAPY; HOR- uterine cancer as well as ovarian cancer. MONE REPLACEMENT THERAPY. Fortunately, very small doses of estrogens will usually treat and/or prevent hot flashes. If estrogen supplementation alone does not help human growth hormone See GROWTH HORMONE. or the patient is unable to tolerate estrogens, other drugs may provide relief. Clonidine, a drug used mainly to lower blood pressure, can decrease hot hypercalcemia Excessively high levels of calcium flashes by as much as 80 percent. However, cloni- in the bloodstream. Most experts define hypercal- dine can cause low blood pressure (with dizziness cemia as blood calcium levels that are greater than and light-headedness), dry mouth, and sleepiness 10.5 mg/dl (8.5–10.5 mg/dl is the normal range). or sedation. Blood levels greater than 12.0 mg/dl may represent The antidepressant drugs Effexor and Effexor- a medical emergency requiring immediate medical XR (venlafaxine), Paxil and Paxil-CR (paroxetine), treatment. and Prozac (fluoxetine) have been shown to Because symptoms are not usually apparent decrease hot flash activity significantly. Another unless hypercalcemia is severe and has also caused medication, Neurontin (gabapentin), has been prolonged damage, the condition is often not sus- shown to decrease hot flashes by 45 percent in a pected by physicians. Instead, it is often detected 12-week trial. The data is much more limited for serendipitously when a patient has a blood profile nonprescription supplements. drawn for a routine physical examination or for 116 hypercalcemia other purposes. This eventuality has become less other nonspecific symptoms that often lead common, however, as Medicare and many man- patients to seek the counsel of their physicians. At aged care organizations will no longer pay for rou- its most severe, hypercalcemia may cause cognitive tine profiles and screening. problems and even coma. Many laboratories now measure blood levels of When hypercalcemia persists for a long period of ionized calcium. This is a far more accurate meas- time, depending upon its cause, it may lead to the urement than the total serum calcium level. Total development of kidney stones (known as calcium levels and ionized calcium levels are best nephrolithiasis/urolithiasis) and/or to OSTEOPOROSIS. measured in the early morning when the patient Hypercalcemia due to primary hyperparathyroidism has fasted, with no food or drink other than water leads to bone loss because the excess parathyroid for the prior 10–12 hours. hormone in the blood stimulates the extraction of Laboratory errors commonly occur. This is why, calcium from the bone into the bloodstream, which in the case of a person who was not previously diag- is then lost into the urine because it overwhelms the nosed with hypercalcemia, it is crucial to repeat the kidneys’ ability to conserve this calcium. test two or even three times and also to confirm an Osteoporosis is an asymptomatic disease of elevated total blood calcium level with an ionized bone loss until there is a bone fracture. With long- calcium level. Using the ionized calcium level as the standing hypercalcemia caused by primary hyper- gold standard removes the issue of a falsely elevat- parathyroidism (excessive levels of parathyroid ed calcium level due to increased or abnormal bind- hormone), a patient may develop multiple verte- ing proteins. When total calcium is assayed, it bral fractures with pain and with kyphosis or measures calcium bound to proteins, mainly albu- dowager’s hump. Rarely, a deposit of calcium in min and globulins. Thus, if the patient has abnor- the eye (band keratopathy) or tongue fascicula- mal levels of these proteins, he or she may also tions (tiny involuntary muscle contractions that appear to have an abnormal calcium level. cause the muscle to quiver) can also be noted in A less common form of hypercalcemia is known patients with hypercalcemia. as FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH). This condition can sometimes be mistaken for pri- Causes of Hypercalcemia mary hyperparathyroidism. In this syndrome, the Primary hyperparathyroidism is the most common patient’s body does not sense calcium levels prop- medical ailment leading to elevated blood calcium erly, which results in higher-than-normal calcium levels. This diagnosis represents the cause of about levels in the blood but also in low levels of calcium 70–90 percent of hypercalcemia in outpatients and in the urine. Patients suffer no ill effects and do not 20–30 percent among hospitalized patients. require any treatment. As the name implies, famil- Primary hyperparathyroidism has a prevalence of ial hypocalciuric hypercalcemia runs in families. about one in every 2,000–3,000 people. Once one person in a family is found with it, oth- Medical students are taught the phrase, “stones, ers should also be screened to avoid being misdiag- moans, bones, and groans” to describe the key ele- nosed with another illness at a later date. ments of hyperparathyroidism. This refers to kidney stones (stones) and the pain that they cause Signs and Symptoms (moans), the osteoporosis (bones), and the poten- Most people with hypercalcemia are asymptomatic. tial FRACTURES (groans) that may occur. Thus, most cases of hypercalcemia are found by The most common type of hyperparathyroidism chance. If the calcium level rises sufficiently, how- itself is caused by a single benign growth of one of ever, it can cause symptoms such as increased uri- the parathyroid glands, a parathyroid adenoma. nation during the day (polyuria) or at night However, the disease can also be caused by hyper- (nocturia). Hypercalcemia is also associated with plasia (a benign growth of all four of the parathyroid such symptoms as constipation, vague abdominal glands) and, rarely, by a parathyroid carcinoma. pain (on rare occasions, due to PANCREATITIS), mus- Many types of CANCER can cause hypercalcemia, cle weakness, lethargy, fatigue, and a variety of and as many as half of all hospitalized patients with hypercholesterolemia 117 hypercalcemia have cancer. (Hyperparathyroidism patients should consult with a gastroenterologist to and cancer together account for about 90 percent find out the underlying cause of their digestive dis- of all causes of hypercalcemia.) When a cancerous order.) tumor is identified as the cause of hypercalcemia, it Individuals who take very high levels of other is classified as either a humoral hypercalcemia of vitamins, such as vitamin A, may also induce malignancy (HHM) or as a non-HHM case. hypercalcemia. Many diseases in which the body forms granulomas can lead to hypercalcemia. A granuloma Treatment of Hypercalcemia refers to a specific clustering of white blood cell monocytes that have gone into various body tissues Typically, the treatment of hypercalcemia is aimed and have become tissue macrophages. This may at the underlying cause, once it has been identified. occur in diseases such as tuberculosis, sarcoidosis, However, if the hypercalcemia is severe and has led and histoplasmosis. to DEHYDRATION and mental status changes in the Other medical problems can sometimes cause patient, then hospitalization and immediate treat- hypercalcemia. Hyperthyroidism (overactive thy- ment is usually needed. Hospitalized patients with roid) from any cause can lead to mild hypercal- hypercalcemia are usually given intravenous fluids cemia as can simple immobilization (bed rest), in the form of normal saline (0.9 percent sodium although this is typically seen only in young chloride solution, which is basically salt water). patients (such as an adolescent with paraplegia due They are also often given a loop diuretic such as to a car crash). Inflammatory diseases may also furosemide (Lasix) and an intravenous BISPHOSPHO- sometimes cause hypercalcemia. Even silicone NATE medication, usually pamidronate (Aredia). implants may sometimes induce the condition. Patients with hypercalcemia may also be given CALCI Rare causes of hypercalcemia include ADDISON’S steroid medications, such as prednisone. - TONIN DISEASE, PHEOCHROMOCYTOMA,PAGET’S DISEASE, sar- may also be added to the therapy if the other coidosis, and rhabdomyolysis. medications fail or if the patient has pain that is Sometimes medications that are taken for other secondary to a fracture. Calcitonin will decrease medical problems can lead to the development of the patient’s blood calcium levels. Often physicians hypercalcemia. For example, drugs such as thiazide treat patients with a combination of medications. diuretics (hydrochlorothiazide) and lithium may Once the patient has stabilized from an emer- cause mild cases of the condition. Excessive doses gency condition, doctors seek to identify and treat of theophylline, taken for asthma, can also lead to the underlying cause of the hypercalcemia. hypercalcemia, as can the use of tamoxifen, which Surgical removal of a parathyroid adenoma may be is given to women with breast cancer and bone necessary as would be treatment of the underlying metastases. Retinoic acid given to cancer patients cancer or medical therapy for causal conditions may also lead to the condition. such as sarcoidosis. There are other causes of hypercalcemia. For See also CALCIUM ABSORPTION; CALCIUM BALANCE; example, an ingestion of excessive calcium and/or HYPERPARATHYROIDISM; HYPOCALCEMIA. VITAMIN D can also lead to this condition. Years ago, Bilezikian, John P. “Management of Hypercalcemia.” before more potent drugs such as the histamine Journal of Clinical Endocrinology & Metabolism 77, no. 6 2-blockers and proton pump inhibitors were avail- (1993): 1,445–1,449. able to patients with heartburn, dyspepsia, and Sanders, Leonard, R., M.D. “Hypercalcemia,” in Endocrine ulcers, these medical problems were often treated Secrets, 3d ed. Philadelphia, Pa.: Hanley & Belfus, Inc., with large doses of calcium-containing antacids. 2002, 66–71. Many of these patients subsequently developed what was known as MILK-ALKALI SYNDROME with hypercalcemia. Now this syndrome is not seen frequently, although it can occur among patients who hypercholesterolemia See CHOLESTEROL; FAMIL- chronically use calcium-containing antacids. (Such IAL HYPERCHOLESTEROLEMIA. 118 hyperglycemia hyperglycemia Abnormally high levels of blood riencing hypernatremia are infants, elderly people, sugar (glucose). Hyperglycemia is a hallmark fea- and some severely ill hospitalized patients. ture of diabetes, although an individual can be Hypernatremia may also be caused by a variety temporarily hyperglycemic and yet not have dia- of illnesses, including infections causing diarrhea betes. It is also possible for a person with diabetes and vomiting as well as by CUSHING’S SYNDROME, to develop HYPOGLYCEMIA. A normal fasting blood DIABETES INSIPIDUS, HYPERGLYCEMIA, HYPERCALCEMIA, glucose level is defined as less than 100 mg/dl. and sometimes the overtreatment of hypokalemia The key symptoms of hyperglycemia (and dia- (insufficient potassium). Hypernatremia may also betes) are as follows: result from the failure of a person to consume sufficient fluids over a given period of time or from • Increased urination an accidental excessive intake of sodium. In addi- • Increased thirst tion, some medications can cause hypernatremia, such as lithium, amphotericin B, foscaret, and • Unexplained weight loss methoxyflurane. • Blurred vision Signs and Symptoms of Hypernatremia Individuals with one or more of these symptoms Babies with hypernatremia usually exhibit some or should see their physicians for an evaluation. all of the following indicators: See also DIABETES MELLITUS; GESTATIONAL DIA- BETES; TYPE 1 DIABETES; TYPE 2 DIABETES. • Insomnia • Very high-pitched cry hyperlipidemia Excessive levels of blood fats, • Lethargy particularly low-density lipoprotein (LDL) cholesterol (bad cholesterol) and trigylcerides. This is a Children and adults who are hypernatremic dangerous condition that can lead to serious med- may have muscle weakness and confusion and ical consequences, such as a stroke or heart attack. may lapse into a coma. Elderly individuals may Patients with DIABETES MELLITUS have an increased exhibit no apparent signs or symptoms until the risk for developing hyperlipidemia. Patients with hypernatremia becomes severe or is greater than hyperlipidemia may experience ERECTILE DYSFUNC- 160 millimoles per liter. Patients may be thirsty; TION. Some elderly patients with HYPOTHYROIDISM however, thirst is not always present. present with hyperlipidemia. Physicians usually make recommendations for Diagnosis and Treatment dietary changes to patients with hyperlipidemia. If Sodium levels in the blood can be measured to the patient is obese, weight loss is recommended to determine if the patient is hypernatremic. The improve the condition. The doctor may also pre- treatment depends on the cause. For example, if scribe medications to lower CHOLESTEROL levels. the hypernatremia stems from a bacterial infection, See also APOLIPOPROTEINS; FAMILIAL COMBINED antibiotics can combat the infection and help to HYPERLIPIDEMIA: FAMILIAL HYPERCHOLESTEROLEMIA: resolve the patient’s hypernatremia. Whatever the FAMILIAL HYPERTRIGLYCERIDEMIA. cause, the hypernatremia itself must also be reversed. If possible, hypernatremia is reversed orally or hypernatremia Excessively high levels of sodium with a feeding tube. If that is not possible or feasi- in the blood or above 145 millimoles per liter in an ble, then intravenous fluids are given. The speed of adult. High blood levels of sodium may result from reversal often depends on how quickly the hyper- a severe lack of water compared with the sodium in natremia occurred. If it occurred over several the body, which is the cause of most cases of hyper- hours, it can usually be reversed fairly quickly. In natremia. Those who face the greatest risk of expe- contrast, if the hypernatremia occurred over a hyperoxaluria 119 longer period or an unknown period, reversal is PHI, although some patients with PHII will develop usually performed more slowly. kidney failure. One risk that doctors face with a rapid reversal As the kidney function declines, oxalate can be of hypernatremia is cerebral edema, which can risk deposited throughout the body, leading to other the life of the patient. Periodic reevaluations of the complications such as cardiac arrhythmias. If diag- sodium level in the blood need to be performed as nosed early, these children can be treated by forc- the patient is treated. ing fluids, placing them on a low oxalate diet (avoiding chocolate, rhubarb, spinach, and tea), Adrogue, Horacio J., M.D., and Nicolaos E. Madias, M.D. and providing high dosages of vitamin B6 (pyri- “Hypernatremia.” New England Journal of Medicine 342, doxine). Neutral phosphates, magnesium oxides, no. 20 (May 18, 2000): 1,493–1,499. and potassium citrate can also be used to protect the kidneys. In end-stage cases of kidney failure, kidney and combined kidney-liver transplantations hyperoxaluria The condition in which excessive can be undertaken. oxalic acid or oxalate is excreted in the urine. A kidney transplant will restore normal kidney Hyperoxaluria may be caused by a primary genetic function. However, the continued high production defect and overproduction of oxalate or may be an of oxalate can act to damage the new kidney. A acquired condition, generally due to excessive liver transplant is the only known cure to hyper- absorption. oxaluria as of this writing. Primary hyperoxaluria is a rare inherited meta- Patients with hyperoxaluria may also be treated bolic condition in which enzyme defects lead to with orthophosphate and pyridoxine therapy. This severe elevations of oxalate. This form of hyperox- treatment is especially important in children and aluria is usually diagnosed in children who are adolescents with hyperoxaluria. According to younger than five years old and also have kidney researchers who studied patients with primary failure. These young children often do not have hyperoxaluria, who reported on their findings in a kidney stones, although older children with the 1994 issue of the New England Journal of Medicine, condition will develop kidney stones. Children “The importance of increasing the doses of with primary hyperoxaluria are usually treated by orthophosphate during childhood and adolescence a pediatric endocrinologist. was illustrated by the development of new stones With primary hyperoxaluria type I, or PHI, the or an increase in the size of existing stones during liver generates high levels of oxalic acid that is growth spurts in five patients. When the dose was excreted into the individual’s urine. This acid com- increased, stone formation ceased.” bines with calcium filtered from the bloodstream The researchers wrote that early diagnosis and by the kidneys and subsequently results in the for- treatment was advantageous to patients. They also mation of kidney stones. If the disease further pro- said, “Treatment with orthophosphate and pyri- gresses to kidney failure, this condition is known as doxine before the onset of renal failure reduces cal- oxalosis. PHI is a hereditary disease that stems from cium oxalate crystallization in the urine and a missing liver enzyme, hepatic enzyme alanine- appears to preserve renal function.” glyoxylate aminotransferase (AGT), which is a substance that normally rids the urine of excessive Acquired Hyperoxaluria levels of oxalate. This defective gene is mapped to Some patients have no genetic cause of hyperox- chromosome 2q36-37. aluria, but the condition occurs due to other caus- There is also a primary hyperoxaluria type II, es. For example, it may be caused by a person which is called PHII. This is also a hereditary dis- eating extremely large amounts of substances con- ease, and it stems from a defective gene in the liver, taining oxalate, such as large quantities of rhubarb, known as hepatic hydroxypyruvate reductase or by ingesting substances that are converted by (HPR). This defective gene is mapped to chromo- the body to oxalate, such as massive doses (four some 9. PHII is not usually as severe a disease as is grams or more per day) of vitamin C. Acquired 120 hyperparathyroidism hyperoxaluria may also result from a deficiency of hyperparathyroidism Excessive levels of thiamine (vitamin B1). parathyroid hormone, which is produced by the Some patients develop hyperoxaluria as a result PARATHYROID GLANDS. of surgery to remove part of their bowel. In addi- Primary hyperparathyroidism refers to the con- tion, patients with chronic digestive diseases (such dition in which one or more of the four parathy- as Crohn’s disease) may also develop hyperox- roid glands located in the neck, near the thyroid aluria. In these cases, the condition is known as gland, produces an excessive amount of parathy- enteric hyperoxaluria. roid hormone in an autonomous fashion. This excess parathyroid hormone activity leads to HYPERCALCEMIA. Symptoms of Hyperoxaluria Secondary hyperparathyroidism is an appropri- The key symptom of any form of hyperoxaluria is ate physiological response of the parathyroid the presence of kidney stones. Kidney stones are glands when the body’s levels of calcium are low. extremely painful, and the patient may be initially This is often due to poor nutrition leading to vita- diagnosed and treated for kidney stones in a hospi- min D deficiency and inadequate calcium absorp- tal emergency room. After a patient is diagnosed tion from the gut. with kidney stones, physicians will normally Tertiary hyperparathyroidism generally only attempt to ascertain the cause of the stones. A 24- occurs in patients with kidney failure who have hour collection of urine from the patient is secondary hyperparathyroidism that is physiologi- obtained, and the amount of excreted oxalate is cal and then enters an autonomous phase in which measured. If the level of urine oxalate is greater the parathyroids continue to excrete excess than 1.2 millimoles (approximately 100 mg) per parathyroid hormone. This occurs even when the 1.73 meters square over 24 hours, then the diag- calcium and vitamin D levels are adequate. nosis of hyperoxaluria is likely. The risk for developing hyperparathyroidism Patients with acquired hyperoxaluria are increases with age. Among people who are over advised to ingest large amounts of fluids, particu- age 65, about one in every 1,000 men and two or larly water, and to avoid excessive amounts of the three in every 1,000 women will develop hyper- foods that are rich in oxalates. Kidney dialysis is parathyroidism. ineffective at ridding the body of the excess levels of oxalate, which is another reason why patients should be treated early on and before kidney func- Causes of Hyperparathyroidism tion deteriorates. In 90 percent or more of the cases, primary hyper- For further information, contact: parathyroidism is caused by the development of a single parathyroid adenoma. This is a benign growth Oxalosis and Hyperoxaluria Foundation that functions autonomously on one of the four 201 East 19th Street glands. It continues to secrete excess amounts of Suite 12E parathyroid hormone even when the blood calcium New York, NY 10003 is elevated. The other three parathyroid glands typi- (800) OHF-8699 (toll-free) cally respond appropriately, which is to say they www.ohf.org atrophy (stop working), making it a bit easier for the Milliner, Dawn S. “The Primary Hyperoxalurias.” NORD experienced surgeon to find the abnormal gland. Guide to Rare Disorders: The National Organization for In about 10 percent of the cases, parathyroid Rare Disorders. Philadelphia, Pa.: Lippincott Williams & hyperplasia develops with excess growth of all four Wilkins, 2003. glands and excess secretion from all four glands as Milliner, Dawn S., et al. “Results of Long-Term Treatment well. In very rare cases, the excess parathyroid hor- with Orthophosphate and Pyridoxine in Patients with mone secretion can be due to the development of a Primary Hyperoxaluria.” New England Journal of parathyroid cancer, typically involving one of the Medicine 331, no. 23 (December 8, 1994): 1,553–1,558. four glands. hyperparathyroidism 121

In some cases, lithium therapy that is given to elevated, although more frequently normocalcemic patients who are bipolar (manic-depressive) may hyperparathyroidism can be diagnosed. Increased also induce hyperparathyroidism. levels of protein that bind to calcium can falsely Secondary hyperparathyroidism is caused by a elevate the total serum calcium level, but this can decrease in calcium levels (HYPOCALCEMIA). This be sorted out by measuring the nonbound or ion- may stem from any process that impairs the body’s ized calcium. ability to absorb or retain calcium, such as an Serum phosphorus levels are often decreased in underlying kidney disease; vitamin D deficiency (as patients with primary hyperparathyroidism, while in RICKETS in children or OSTEOMALACIA in adults); serum alkaline phosphatase levels may be malabsorption syndromes due to pancreatitis, increased. The confirmatory test is measurement of ulcerative colitis, Crohn’s disease, or other gut the intact parathyroid hormone level, which is problems; or leakage of calcium from the kidneys nearly always elevated. Again, though, in very into the urine (renal hypercalciuria). early cases, it may run at the upper limits of the normal level. Signs and Symptoms Patients with hyperparathyroidism may have reduced BONE DENSITY, especially of the forearm, Most patients with primary hyperparathyroidism taken in a DEXA scan. (There is more cortical bone are asymptomatic. After they are diagnosed and in the forearm, and this bone decreases sooner treated, however, some patients in retrospect will than the other types of bone do.) realize that they had some symptoms. Individuals Primary hyperparathyroidism can be mistakenly vary in how they present with hyperparathy- diagnosed in patients with familial hypercalcemic roidism, but some common signs and symptoms of hypocalciuria. In this condition, patients have ele- this medical problem include: vated calcium levels, normal or high-normal parathyroid hormone levels, but very low excretion • Back pain of calcium in the urine. This is an inherited defect in • Joint pain which patients’ bodies do not properly sense blood • Fatigue calcium levels. They do not develop osteoporosis, • Upper abdominal pain kidney stones, myopathy, or any of the complications of hyperparathyroidism and thus do not need • Muscle weakness treatment, especially parathyroidectomy. • Increased thirst This condition is typically excluded by measur- • Increased urination ing a 24-hour urine for calcium. The patient col- • Itching skin lects all urine that is excreted over a 24-hour period, to be evaluated by a laboratory. Normally • Bone pain patients will excrete two to four milligrams per • Muscle and tongue fasciculations (tiny involun- kilogram of calcium in the urine per day. Patients tary muscle contractions that cause the muscle with hyperparathyroidism excrete at least this to quiver) much and often much more than patients with • Band keratopathy (usually noted only by a spe- familial hypercalcemic hypocalciuria, who always cial examination by an eye specialist) excrete much less.

Surgical Treatment Diagnosis and Treatment The best therapy for primary hyperparathyroidism Hyperparathyroidism is diagnosed based on the is surgery. Indications for surgery include kidney patient’s medical history and physical examination stones, bone loss (especially osteoporosis), severe as well as on laboratory tests of calcium, phospho- hypercalciuria, and total calcium levels that are rus, parathyroid hormone, and kidney function. greater than 11 to 12 mg/dl. On occasion, surgery Typically, total calcium or ionized calcium levels are may also be attempted if a patient is suffering with 122 hyperphosphatemia/hypophosphatemia aches and pains and/or cognitive dysfunction that attempted to determine which patients will require cannot be explained by any other mechanism. surgery, and both have failed to achieve that goal. Patients must find a surgeon who has significant Some patients will go for many years without experience in parathyroid surgery. Using an experi- any significant signs and symptoms of hyper- enced surgeon is essential because finding the parathyroidism, while others will progress rapidly. offending gland may be difficult and distinguishing Thus, patients are counseled to use a moderate between a small adenoma and hyperplasia at the amount of calcium and salt and to force fluids in time of surgery is often difficult. In addition, the order to keep the urine dilute and decrease the risk parathyroids’ blood supply is limited. Excess dam- of developing kidney stones. age to the area can lead to permanent hypoparathy- Patients who have secondary hyperparathyroidism, a condition that must be treated with both roidism may be treated with calcium and vitamin D calcium and vitamin D. Also, the recurrent laryn- to correct the deficiencies. They may also be treated geal nerves are in this area. Damage to one or both with cinacalcet (Sensipar, Amgen). Cinacalet is the of them can lead to chronic hoarseness or vocal first drug in a new class of agents called calcimimet- cord paralysis. ics. Cinacalcet sensitizes calcium receptors in the In the case of parathyroid hyperplasia, the sur- parathyroid glands (the parathyroid glands perceive geon will often remove three-and-one-half of the there is more calcium in the system) and causes four glands and transplant one-half of one gland into direct lowering of parathyroid hormone. It is the forearm. Some of the other parathyroid tissue approved by the Food and Drug Administration can be frozen and preserved for future use if needed. (FDA) for the treatment of secondary hyperparathy- In the rare cases of cancer, as much as possible roidism in patients with chronic kidney disease. of the cancer should be excised at the time of sur- See also CALCIUM BALANCE; PARATHYROID GLANDS. gery, as it does not respond well to radiation or chemotherapy. An experienced surgeon will locate Dang, Devra K. “Cinacalcet.” Formulary 39 (2004): the offending adenoma in about 90 percent of the 482–489. cases. Lips, Paul. “Vitamin D Deficiency and Secondary Preoperative imaging is not necessary, but it is Hypoparathyroidism in the Elderly: Consequences for being done more frequently as techniques have Bone Loss and Fractures and Therapeutic improved. As of this writing, the most sensitive imag- Implications.” Endocrine Reviews 22, no. 4 (2001): ing seems to be a nuclear medicine scan called a ses- 477–501. tamibi subtraction scan. This scan may be particularly Marx, Stephen J., M.D. “Hyperparathyroid and advisable in the cases of older and sicker patients, as Hypoparathyroid Disorders.” New England Journal of it may help to localize the surgeon’s efforts and also Medicine 343, no. 25 (December 21, 2000): shorten the duration of the operation. In addition, it 1,863–1,875. can lead to very directed and limited small incision surgery under local anesthesia with the use of intra- operative nuclear medicine probes, although this is hyperphosphatemia/hypophosphatemia Abnormally not standard therapy as of this writing. high levels of phosphorus in the blood (hyperphos- Tertiary hyperparathyroidism requires the phatemia) or abnormally low blood levels of phos- adjustment of dosages of calcium and vitamin D phorus (hypophosphatemia). Hypophosphatemia supplements and often parathyroid surgery as well. is a rare condition that is most commonly seen in patients who suffer from starvation/malnutrition Nonsurgical Therapy or alcoholism. Because phosphates are ubiquitous Patients who do not have any indications for sur- in the diets of most Americans, one meal can usu- gery can be followed conservatively with close ally restore levels to normal. In cases of primary attention paid to blood calcium levels, kidney func- hypophosphatemia in which phosphorus is lost in tion, and bone density. Two large trials have the urine, treatments become more complicated. hyperthyroidism 123

Hyperphosphatemia is most often seen in synthesized. The consequences are due to the exces- patients with end-stage kidney (renal) disease. It sive amounts of hormones that are synthesized. may also be caused by chemotherapy treatment for cancer (tumor lysis syndrome), caused by the destruction of many cancer cells with the subse- hypertension See BLOOD PRESSURE/HYPERTENSION. quent release of phosphorus from inside the cells. Hyperphosphatemia can result in long-term, dangerously decreased levels of calcium in the blood hyperthyroidism The clinical condition caused by (HYPOCALCEMIA). the metabolic effects of excessive levels of thyroid Some endocrine diseases associated with hyper- hormones in the blood. This clinical syndrome can phosphatemia include ACROMEGALY, HYPOPARATHY- range from minimal to severe. It can also be ROIDISM, PSEUDOHYPOPARATHYROIDISM, and THYRO- referred to as biochemical hyperthyroidism, in TOXICOSIS. which the hormone levels are elevated but the Treatment of hyperphosphatemia is aimed at patient has no symptoms (also known as subclinical identifying and treating the underlying cause of the hyperthyroidism). It can also be referred to as clini- problem as well as the resultant symptoms such as cal hyperthyroidism, in which the patient has both hypocalcemia. In patients with end-stage kidney abnormal thyroid hormone levels and the typical disease (also known as kidney failure), compounds clinical signs and symptoms of hyperthyroidism. called phosphate binders (which bind the dietary The most common cause of hyperthyroidism is phosphates) are used to treat or to prevent hyper- GRAVES’ DISEASE. Other causes are a multinodular phosphatemia. goiter, various forms of thyroiditis, toxic or Growing children normally have blood phos- autonomously functioning thyroid nodules, med- phorus levels that are higher than those of adults. ications, and iodine. Pseudohyperphosphatemia does exist and is usually due to excess and/or abnormal protein levels in Signs and Symptoms of Hyperthyroidism the blood (as with Waldenström’s macroglobuline- Patients with hyperthyroidism usually exhibit mia, monoclonal gammopathy, and multiple some or all of the following signs and symptoms: myeloma). Pseudohyperphosphatemia can also be caused by other blood abnormalities that interfere • Shortness of breath caused by minimal activity with the phosphorus assay, such as hyperlipidemia, excess bilirubin (a cause of jaundice), and hemoly- • Fatigue sis (the destruction of red blood cells). • Heat intolerance (patients with hypothyroidism, in contrast, have cold intolerance) • Hyperactivity • Increased perspiration (hyperhydrosis) hyperplasia The term used when more cells of an • Irritability organ are synthesized than usual. The cells are typically normal, that is, benign or nonmalignant, but • Menstrual disturbances (typically oligomenor- may cause problems due to their size or the pro- rhea (infrequent periods) or AMENORRHEA) duction of excess hormones. Hyperplasia is differ- • Nervousness ent from hypertrophy, in which the number of cells • Heart palpitations/rapid heart rate remains the same but each individual cell increases • Weight change (usually weight loss, but some in size. patients experience weight gain) Hyperplasia is seen in CONGENITAL ADRENAL HYPER- PLASIA. This occurs when enzyme abnormalities • Sleep disturbances, including nightmares cause problems with the normal feedback control • Muscle weakness (usually of the proximal systems and excessive numbers of adrenal cells are muscles) 124 hypertriglyceridemia

• Warm, moist, and smooth (velvety) skin See also HASHIMOTO’S THYROIDITIS; HYPOTHY- • Presence of a goiter (the thyroid may be small, ROIDISM; THYROID BLOOD TESTS; THYROID-STIMULATING normal, or large) HORMONE. Miller, K. K., and G. H. Daniels. “Lithium Therapy Can Elderly people with hyperthyroidism sometimes Cause Silent Thyroiditis and Hyperthyroidism.” will not present with hyperactivity and, instead, will Clinical Endocrinology 55, no. 4 (2001): 501–508. exhibit what is called apathetic hyperthyroidism or thyrotoxicosis. These patients may seem to be depressed and apathetic. They may also lose weight and may experience congestive heart failure. The hypertriglyceridemia Excessively high levels of physician then generally orders laboratory tests, sus- triglycerides in the blood, primarily composed of pecting hypothyroidism, and may be surprised to very low-density lipoproteins (VLDL). Patients with find hyperthyroidism instead. Administration of hypertriglyceridemia typically have elevated triglyc- antithyroid medication or radioactive iodine can eride levels in the 200–500 mg/dl range. Often induce a significant improvement and remission of there are no physical signs of hypertriglyceridemia. the patient’s symptoms. However, if the patient’s triglyceride levels increase above 1,000 mg/dl, the retinal blood vessels of the eye may appear as a milky-reddish yellow color. Diagnosis and Treatment This condition is known as lipemia retinalis. Hyperthyroidism may be diagnosed by taking a care- Hypertriglyceridemia may be a primary or a ful medical history and performing a physician genetic condition. It is also often seen secondary to examination, especially checking the patient’s neck other metabolic disorders such as DIABETES MELLI- for the presence of a GOITER. Then thyroid function TUS (mainly TYPE 2 DIABETES, especially if the dia- tests are obtained. Usually measurements of thyroid- betes is poorly controlled), HYPOTHYROIDISM, stimulating hormone (TSH), free T4, and in many alcohol ingestion, use of estrogens or steroids, and instances total T3 blood levels are ordered. kidney insufficiency or failure. FAMILIAL HYPER- If the diagnosis is in doubt, the physician may TRIGLYCERIDEMIA is an autosomal dominant disorder order a radioactive iodine uptake test. This test in which there is both an increased production of measures the avidity with which the thyroid gland VLDL by the liver and a decreased clearance of traps iodine to create more thyroid hormones. In VLDL. Other rare, familial forms exist, but most are most cases of hyperthyroidism, the uptake is recessive. increased above normal (usually 15–30 percent at Hypertriglyceridemia is often accompanied by 24 hours). In the various forms of thyroiditis, the low levels of high-density lipoproteins (HDL) or radioactive iodine uptake is quite low, usually less good cholesterol. Triglycerides are mainly synthe- than 3 percent and often near zero. The thyroid sized in the liver, and their synthesis is driven by can be scanned using an isotope known as tech- carbohydrate intake and flux through the liver. netium to ascertain the shape, size, and homo- The initial therapy for hypertriglyceridemia is geneity (or lack thereof) of the thyroid gland. diet. In particular, carbohydrates should be limited To treat Graves’ disease, antithyroid drugs or to decrease the synthesis of new triglycerides. radioactive iodine are used. For a multinodular goi- Exercise will also help to decrease triglycerides, as ter or toxic nodule, the best therapy is usually it will increase the production of the enzymes that radioactive iodine therapy. For thyroiditis, the help to metabolize the triglycerides. symptoms are usually treated with beta-blocker When medications are needed, Hydroxy- medications and the underlying condition will methylglutaryl (HMG) coenzyme (Co A) reductase resolve on its own over time. inhibitors, or statins, are often first used if the If these therapies fail, a THYROIDECTOMY,or triglyceride levels are lower than 500 mg/dl. These removal of the thyroid gland, may be performed. medications lead to an increase in LDL receptors However, it is usually chosen as the last resort. that further leads to a decrease in the cholesterol in hypocalcemia 125 the blood. If the patient’s triglyceride level is 500 patient may die. Fortunately, such severe hypocal- mg/dl or greater, there is an increased risk of devel- cemia is a very rare condition, and death from oping pancreatitis. Consequently, drugs known as hypocalcemia is highly unusual. Most people with fibric acid derivatives (fibrates) and nicotinic acid hypocalcemia experience some identifiable symp- may be added to or substituted for statins. In the toms that precede the development of tetany, such United States, the fibrates Lopid (gemfibrozil) and as severe muscle cramps, and thus the majority of Tricor (fenofibrate) may be administered. They will patients can be treated well before their condition decrease triglyceride levels by 40–60 percent and becomes dangerous. also increase HDL levels by 10–20 percent. These agents must be used carefully; in patients with renal Risk Factors impairment, they may also be associated with the development of gallstones. When taken with statin Infants born to mothers with DIABETES MELLITUS are medications, they can be associated with myositis at risk for hypocalcemia. Supplemental calcium and rhabdoymyolysis. and vitamin D can be administered to the newborn Niacin will lower triglyceride levels by 20–50 to resolve the problem, once diagnosed. Individuals percent and increase HDL by 15–40 percent. It can who have undergone thyroid or parathyroid sur- cause upset stomach, increased liver enzymes, gery within the past 48 hours have the highest risk increased uric acid (and may precipitate the onset for developing hypocalcemia. These individuals are of gout), increased glucose levels (typically only experiencing HYPOPARATHYROIDISM, or abnormally 5–15 mg/dl), and flushing and itching that can be low levels of the parathyroid hormone. Hypo- severe but that can usually be prevented by taking calcemia may also occur after a partial (sometimes a 325 mg aspirin prior to the niacin. called a subtotal) thyroidectomy. However, it is See also CHOLESTEROL. more commonly found after a total thyroidectomy or parathyroid surgery, when the entire gland is removed because of cancer or for other medical hypocalcemia A condition resulting from abnor- reasons. mally low levels of calcium in the blood, often due In most postsurgical cases of hypocalcemia, the to unusually low levels of parathyroid hormone. problem is temporary. Only about 3 percent of Normal total calcium levels are 8.5–10.5 mg/dl for people who have undergone thyroid surgery will individuals of all ages, and levels below 8.5 are have a permanent problem with hypocalcemia. abnormally low. Other individuals may also be at risk for devel- Patients with chronic problems with hypocal- oping hypocalcemia. They include those who: cemia should generally be treated by endocrinologists, who have particular expertise in both normal • Are deficient in magnesium (hypomagnesemia) and abnormal functions of the endocrine glands. • Have severe kidney disease, particularly kidney Errors of extremes, which means providing either failure inadequate or excessive therapy, could result in • Have liver disease severe medical consequences. When treating • Have pancreatitis patients with hypocalcemia, endocrinologists are unlikely to make such errors. • Are alcoholic Hypocalcemia can deteriorate. If left untreated, • Are in an intensive care unit with a severe ill- it can lead to heart arrhythmias and cataracts. It ness, especially malnutrition can also lead to a medical emergency known as TETANY, in which the person’s calcium levels drop so low that he or she begins experiencing severe Function of Calcium muscle cramps and spasms and may also have Calcium in the blood and bones is carefully regulat- seizures. If calcium and vitamin D are not adminis- ed by the parathyroid glands, which are endocrine tered intravenously to the convulsing person, the glands embedded in and around the thyroid gland. 126 hypocalcemia

The parathyroids control the transfer of calcium um and magnesium levels. If these levels are found among the blood, bone, and other tissues. Dietary to be below normal, the patient will require supple- calcium may also protect against hypertension, mental calcium and may also need high doses of colon cancer, and other medical problems. Vitamin prescribed vitamin D. The severely ill patient will D is also involved in the absorption of calcium. need to receive these supplements intravenously, but the patient whose levels are slightly low will Signs and Symptoms of Hypocalcemia usually improve after taking oral preparations. Some The most frequently occurring symptom of patients need to take vitamin D regularly. hypocalcemia is a feelings of pins and needles Calcium preparations in the form of calcium car- (paresthesia), usually experienced in the fingers, bonate or calcium citrate are available at virtually toes, and around the mouth. any pharmacy, supermarket, or health food store. Other indicators of chronic hypocalcemia Calcium carbonate is the most popular form of sup- include the following: plemental calcium used in the United States, followed in popularity by calcium citrate. Some • Coarse hair individuals take calcium lactate, which can be dif- • Very dry skin ficult to find, although it can be ordered from sites on the Internet. • Chronic yeast infections (candida) Treatment with calcium may cause minor side effects such as constipation. The addition of mag- Indicators of acute hypocalcemia (requiring nesium, in about half the dose of the calcium that emergency medical treatment, which is the intra- is taken, may help to rectify cases of constipation. venous administration of calcium), include: However, the individual’s physician should be consulted before a patient adds a magnesium supple- • Severe muscle cramps ment because the supplement could interact with • Numbness other medicines the patient may be taking. The • Irritability physician should also determine the dose of any • Low blood pressure (hypotension) supplemental magnesium. People who have been diagnosed with hypocal- • Mental confusion and psychiatric problems cemia will usually require periodic testing of their blood and urine. The frequency of such testing will Diagnosis and Treatment of Hypocalcemia be determined by the patient’s physician. In some Several classic physical examination tests may indi- cases, if the underlying problem is corrected, cate hypocalcemia. For example, if the nerve in the patients who have hypocalcemia may regain a nor- cheekbone is lightly tapped by the physician, the mal blood level of calcium, in which case they face of the person with hypocalcemia will often would no longer need to take supplemental doses react involuntarily with an uncontrollable, sneer- of calcium and vitamin D. In fact, continued sup- like contortion of the mouth. This particular facial plementation for such people could cause them to tic is known as CHVOSTEK’S SIGN, named after the develop HYPERCALCEMIA, a dangerously high level doctor who identified the phenomenon. of calcium in the blood. Another clinical test for hypocalcemia is to inflate If the hypocalcemia was caused by damage to or a blood pressure cuff on the patient’s arm. If the per- a malfunction of the parathyroid glands, the indi- son has hypocalcemia, within several minutes the vidual usually needs to take supplemental calcium person’s arm will usually spasm and/or cramp and vitamin D for life. The patient should be tested uncontrollably (this is called TROUSSEAU’S SIGN). periodically to verify that his or her blood calcium In addition to checking for clinical signs, such as levels remain in the appropriate range. With aging, Chvostek’s or Trousseau’s signs, the physician most individuals will also need to increase their should take a complete medical history and order intake of vitamin D and calcium supplements. laboratory tests to determine both the patient’s calci- See also HYPERPARATHYROIDISM. hypoglycemia 127

Headley, Carol M. “Hungry Bone Syndrome Following Treatment Parathyroidectomy.” ANNA Journal 25, no. 3 (June Hypoglycemia is usually treated by consuming 1998): 283–289. glucose-containing foods or drinks. However, if the Lepage, R., et al. “Hypocalcemia Induced During Major individual becomes unconscious, emergency med- and Minor Abdominal Surgery in Humans.” Journal of ical treatment is required to avoid coma and even Clinical Endocrinology & Metabolism 84, no. 8 (1999): death. The patient will usually be given glucose or 2,654–2,658. glucagon by emergency medical personnel. Once Marx, Stephen J., M.D. “Hyperparathyroid and the glucose levels are stabilized, the patient usually Hypoparathyroid Disorders.” New England Journal of normalizes as well. Medicine 343, no. 25 (2000): 1,863–1,875. Petit, William A. Jr., M.D., and Christine Adamec. The Encyclopedia of Diabetes. New York: Facts On File, Inc., Advance Preparation for 2002. Chronic Hypoglycemic Attacks People who suffer from chronic hypoglycemia or hypoglycemia Abnormally low levels of blood from conditions that can often lead to hypoglycemia sugar. Having extremely low levels of blood sugar is should not skip any meals, because failing to eat reg- known as insulin shock. Physicians determine the ular meals can exacerbate the condition. They presence of hypoglycemia based on the patient’s should also avoid drinking much or any alcohol. symptoms as well as the chemical analysis of the In addition, patients with chronic attacks of patient’s blood sugar, which is typically defined as a hypoglycemia should also wear medical bracelets fasting glucose level of less than 55 mg/dl. or necklaces that state their medical problem and that are easily seen on the person’s body. Medical Risk Factors cards are not sufficient because they are usually left Individuals with DIABETES MELLITUS and ADDISON’S in wallets, and emergency personnel may not have DISEASE are at risk for developing hypoglycemia. If access to wallets or have time to search them. the person with diabetes has a severe bout of hypo- People with frequent bouts of hypoglycemia glycemia, the condition may devolve into DIABETIC should also keep glucose-containing snacks in their KETOACIDOSIS, a dangerous condition requiring homes and their cars. Some patients may need a emergency hospitalization and treatment. glucagon kit for emergency use, which can be pre- Hypoglycemia can also occur among individuals scribed by their doctors. with insulin-secreting tumors of the pancreas as Patients who exhibit hypoglycemic symptoms well as among patients with liver disease or kidney while driving should pull off the road as soon as pos- disease. Some individuals develop hypoglycemia sible and should also consume an item with glucose after drinking alcohol. Sometimes the cause of in it. If they have blood-testing equipment available hypoglycemia cannot be determined. (as patients with diabetes should have), they should check their blood sugar level 15 minutes after eating Symptoms of Hypoglycemia the glucose snack. If it is above 70 mg/dl, the person Some key symptoms of hypoglycemia are as follows: should, in most cases, be able to drive. See also COMA. • Cold sweats For further information on hypoglycemia, con- • Fatigue tact the following organizations: • Confusion American Diabetes Association • Headache National Service Center 1710 North Beauregard Street • Shakiness Alexandria, VA 22311 • Hunger (800) 342-2383 (toll-free) • Rapid heartbeat http://www.diabetes.org 128 hypogonadism

Juvenile Diabetes Research Foundation because testosterone makes prostate cancer grow International faster. As a result, such men experience all the 120 Wall Street symptoms and signs of hypogonadism. When they Ninth Floor stop taking the hormones, their normal levels of New York, NY 10005 testosterone resume, and the signs and symptoms (800) 342-2383 (toll-free) of hypogonadism disappear. http://www.jdrf.org Causes of Hypogonadism Hypogonadism has many different causes. In hypogonadism Abnormally low levels of TESTOS- infants and toddlers, the cause may be an unde- TERONE in males. An estimated one in 500 males scended testicle, which can be corrected by surgery. are affected by this condition. Hypogonadism may KLINEFELTER SYNDROME, a chromosomal disorder, is be either primary or secondary. Primary hypogo- another cause. Males normally have one X and one nadism results from abnormalities in one or both Y chromosome, but with Klinefelter syndrome, the testicles. Secondary hypogonadism is usually individual has two or more X chromosomes as well caused by a problem with the pituitary gland, as the Y chromosome. which controls the production of testosterone. Other causes of primary hypogonadism include: Effects of Hypogonadism Depend on When It Occurs • Hemochromatosis (excessive levels of iron in the blood) Hypogonadism may occur as early as during fetal development. It may also occur during puberty or • Damage to the testicles after adulthood. The symptoms and signs of hypo- • Hernia surgery gonadism vary depending on at what stage in life the hypogonadism occurred. For example, if it occurred Causes of secondary hypogonadism include the before birth and the gonads did not produce enough following: male hormone, then the child may have genitals that are neither clearly male nor female. • Kallmann’s syndrome (impaired development If the condition occurs at or before puberty, the of the hypothalamus, which ultimately affects boy will not experience the normal adolescent the release of testosterone) changes of most adolescent males, such as a deep- • Disorders of the pituitary gland, such as tumors ened voice, increased body hair, and further • Sarcoidosis growth of the penis and testes. Instead, the boy will experience greater-than-normal growth in the • Mumps orchitis arms and legs, and he may also experience GYNECO- • Some medications, such as some psychiatric MASTIA (enlarged breast tissue). drugs or other medications If the fully developed male becomes hypogonadal, he will usually experience problems with ERECTILE DYSFUNCTION (impotence), INFERTILITY, Diagnosis and Treatment decreased muscle mass, increased fat, gynecomas- In addition to taking a complete medical history tia, and OSTEOPOROSIS. He may also experience the and performing a physical examination, particular- symptoms that are common among women in ly of the penis and testicles, the physician will usu- menopause, such as HOT FLASHES, mood swings, ally order a test of the male’s blood levels of diminished sexual drive, depression, and fatigue. testosterone. The physician may also order imaging Of interest is that in some cases, hypogonadism tests, such as an ultrasound or MAGNETIC RESONANCE is purposely induced. For example, men with IMAGING (MRI) scan. In adult males, the doctor may advanced prostate cancer are often treated with also order a semen analysis to determine whether hormone therapy to stop testosterone production, the sperm count is within the normal range. hyponatremia 129

If the hypogonadism did not occur during fetal pubic hair, underarm (axillary) hair, or facial hair development, the male with hypogonadism can in males. Some patients have an inability to smell often be treated with testosterone replacement (anosmia). therapy (TRT). Boys and men on TRT must be care- This condition is diagnosed by tests of hormone fully monitored, because levels that are too high blood levels as well as the gonadotropin-releasing can cause other health problems, such as prostate hormone (GnRH) stimulation test. This latter test disease and infertility. Testosterone can be given in measures hormone levels after they are stimulated the form of an injection every two weeks, and by injected hormones. patients can be trained to self-inject. Patients may Male patients with hypogonadotropism are also use a testosterone transdermal patch that is treated with intramuscular injections of testos- placed onto the scrotum or onto another part of the terone. Females are usually treated with female body. Testosterone is also available in the form of a hormones, such as estrogen and progesterone pills. skin gel. Males and females may also be treated with growth See also HERMAPHRODITISM,KALLMANN’S SYN- hormone. DROME. See also HYPOGONADISM.

Lange, Paul M., M.D., and Christine Adamec. Prostate Cancer for Dummies. New York: Wiley Publishing, 2003. hyponatremia A lower-than-normal concentra- Nachtigall, Lisa B., M.D., et al. “Adult-Onset Idiopathic tion of sodium in the bloodstream. It is invariably a Hypogonatatropic Hypogonadism—A Treatable Form problem of water. In other words, too much water of Male Infertility.” New England Journal of Medicine is in the system in relationship to the amount of 336, no. 6 (February 6, 1997): 410–415. sodium. This is contrary to a common misconcep- Petak, Steven M., M.D. “American Association of Clinical tion, which is that the hyponatremia results from Endocrinologists Medical Guidelines for Clinical inadequate sodium or salt intake. Hyponatremia is Practice for the Evaluation and Treatment of diagnosed when sodium levels are less than 135 Hypogonadism in Adult Male Patients—2002 Update.” millimoles per liter in an adult. The most common Endocrine Practice 8, no. 6 (November/December 2002): causes of hyponatremia are the use of thiazide 439–456. diuretic medications for hypertension or loop Sih, Rahmawati, et al. “Testosterone Replacement in diuretics that were given to remove excess salt and Older Hypogonadal Men: A 12-Month Randomized water from the body. Controlled Trial.” Journal of Clinical Endocrinology & HYPOTHYROIDISM can sometimes lead to hypona- Metabolism 82, no. 6 (1997): 1,661–1,667. tremia, as patients with hypothyroidism are unable Snyder, Peter J., et al. “Effects of Testosterone to excrete any excess water in the system. Primary Replacement in Hypogonadal Men.” Journal of Clinical ADRENAL INSUFFICIENCY will also lead to hypona- Endocrinology & Metabolism 85, no. 8 (2000): tremia due to the deficiency in mineralocorticoids. 2,670–2,677. In addition, an extreme intake of water can also dilute the serum sodium, causing hyponatremia. hypogonadotropism Decreased or absent gonadal The condition can also be seen in the syndrome of function (in the ovary or the testes) due to the inappropriate secretion of antidiuretic hormone absence of the gonadal-stimulating pituitary hor- (SIADH) and sometimes (very rarely) in abused mones, including FOLLICLE-STIMULATING HORMONE infants and children. Mentally ill individuals, such (FSH) and LUTEINIZING HORMONE (LH). This condi- as patients with schizophrenia, may also ingest tion is also known as gonadotropin deficiency, excessive amounts of water, causing hyponatremia. KALLMANN’S SYNDROME, or secondary hypogonadism. Symptoms of Hyponatremia Hypogonadotropism is characterized by the lack The common symptoms of hyponatremia are of pubertal development in adolescence and the malaise, nausea and vomiting, headache, lethargy, absence of secondary sexual indicators, such as muscle cramps, and decreased deep tendon reflex- 130 hypoparathyroidism es. If the hyponatremia is not resolved, patients opment of kidney stones (nephrolithiasis). Thus, may further worsen to the point of seizures, coma, ironically hypocalcemia can cause calcification. brain damage, and even death. Causes of Hypoparathyroidism Diagnosis and Treatment The most common cause of this condition is surgery Physicians will suspect that a patient may have on the thyroid or parathyroid glands or other neck hyponatremia based on the clinical symptoms and surgery that causes the removal of or damage to the medical history, especially with respect to medica- parathyroid glands. In some cases, hypoparathy- tions that were recently taken. Hyponatremia is roidism is caused by the autoimmune destruction of diagnosed by blood testing that reveals a lower- the parathyroid glands. Autoimmune hypoparathy- than-normal serum sodium concentration. roidism may exist on its own or as a part of a defi- To treat hyponatremia, the patient is typically ciency syndrome involving many organs. In rare given an intravenous sodium chloride containing cases, hypoparathyroidism results from radioactive solution with a concentration of sodium that is iodine treatment given to treat hyperparathy- greater than what exists in the individual’s blood- roidism (a condition of excessively high levels of stream, even to the point of using very small doses parathyroid hormone). of hypertonic saline (a 3 percent sodium chloride Rarely, severe deficiencies of magnesium, a con- solution). On occasion, a loop diuretic, such as dition seen in malnourished patients and alco- furosemide, may be used. Often free water must be holics, can lead to a state of hypoparathyroidism withheld from the patient as well; patients are not and hypocalcemia (abnormally low blood levels of allowed to drink as they wish, and water intake is calcium). limited to less than 1.0–1.5 or sometimes 0.5 liters per day. If the case is a mild one, patients can be Signs and Symptoms of Hypoparathyroidism observed only, while water is withheld. Patients with hypoparathyroidism may experience See also HYPERGLYCEMIA. some or all of the following signs and symptoms:

Adrogue Horacio, J., M.D., and Nicolaos E. Masias, M.D. • Muscle cramps “Hyponatremia.” New England Journal of Medicine 342, no. 21 (May 25, 2000): 1,581–1,589. • Abdominal pain • Tingling in the feet, hands, and face • Spasms in the hands or feet hypoparathyroidism A condition in which there is inadequate parathyroid hormone in the blood- In severe cases, patients may experience seizures stream as well as in the bone, the gut, the kidneys, or convulsions caused by TETANY, a dangerous con- and other organs. Parathyroid hormone is pro- dition of extremely low calcium blood levels. duced by the parathyroids, which are glands embedded in the neck behind the thyroid gland. Diagnosis and Treatment If hypoparathyroidism becomes severe, the Physicians diagnose hypoparathyroidism based on patient develops a condition called HYPOCALCEMIA the patient’s medical history, particularly any past and, in extreme cases, may have seizures. Without history of any form of neck surgery, as well as the treatment after seizures from hypocalcemia, the apparent presence of hypocalcemia. Patients with patient may die. This occurs for several reasons. hypocalcemia may respond with a characteristic One is that without adequate parathyroid activity facial twitch when the cheekbone is tapped in the bloodstream, the kidneys cannot hold onto (CHVOSTEK’S SIGN). Others may show TROUSSEAU’S needed calcium so excessive calcium is lost via the SIGN, an arm spasm and cramp that results from a urine. Some excess calcium may be deposited into test using a blood pressure cuff. the tissues of the kidneys and lead to calcification The doctor will also order laboratory tests of the of the kidneys (nephrocalcinosis) or to the devel- patient’s serum calcium levels. Low levels indicate hypopituitarism 131 hypocalcemia. The doctor may also check serum MONE (LH), PROLACTIN, and THYROID-STIMULATING parathyroid hormone levels (which are below nor- HORMONE (TSH). The production of the posterior mal in the presence of hypoparathyroidism), serum pituitary hormone desmopressin acetate (DDAVP) phosphorus levels (which are high with hypopara- can also be impeded, although this is certainly less thyroidism), and serum magnesium levels (which common unless there is significant destruction of are low with hypoparathyroidism). The physician the pituitary gland. Typically, the pituitary hor- may also order tests of ionized calcium in the blood mones decline in a specific order. In other words, and/or calcium excretion in the urine. some of the cells are more susceptible to damage To treat hypoparathyroidism, physicians order than others. The usual order of decline is LH, FSH, over-the-counter oral calcium. They also order GH, TSH, ACTH, and then prolactin. CALCITRIOL (prescribed vitamin D), often in very Hypopituitarism may result in ADRENAL INSUFFI- high doses. (Vitamin D supplements available in CIENCY, HYPOTHYROIDISM, HYPOGONADISM, and health food stores are not sufficient.) If the patient GROWTH HORMONE DEFICIENCY as well as deficiencies is very ill, he or she may need to be hospitalized to of antidiuretic hormone (ADH) and prolactin. receive calcium and vitamin D intravenously. Abnormal or unexpected pairings of laboratory test The ENDOCRINOLOGIST must be careful to recom- results may indicate hypopituitarism. For example, mend adequate yet not excessive amounts of calci- the patient’s levels TSH may be normal but the lev- um and vitamin D to alleviate the patient’s els of T3 and T4 are low, which should lead the symptoms while avoiding the patient from losing a physician to consider laboratory error, EUTHYROID severe amount of calcium via the urine. Often SICK SYNDROME, or pituitary or hypothalamic dys- patients do not need to attain normal calcium function. blood levels, however, which may be too high for Patients with hypopituitarism should wear med- these patients and could cause complications of the ical bracelets describing their condition in the event kidneys, or even kidney failure and death. that it should worsen and they require emergency See also CALCIUM ABSORPTION; CALCIUM BALANCE. treatment. Studies performed in the United Kingdom and Sweden indicate that hypopitu- Abugassa, Salem, et al. “Bone Mineral Density in Patients itarism increases the risk of death by double or with Chronic Hypoparathyroidism.” Journal of Clinical more compared with individuals of the same age Endocrinology & Metabolism 76, no. 6 (1993): and gender without the condition. Much of this 1,617–1,621. increased mortality is due to cardiovascular causes. Marx, Stephen J., M.D. “Hyperparathyroid and Hypoparathyroid Disorders.” New England Journal of Causes of Hypopituitarism Medicine 343, no. 25 (December 21, 2000): 1,863–1,875. Hypopituitarism has many different possible caus- Stock, John L., et al. “Autosomal Dominant Hypopara- es. It may be caused by a macroadenoma (a tumor thyroidism Associated with Short Stature and greater than one centimeter in diameter) of the Premature Osteoarthritis.” Journal of Clinical pituitary gland, which damages or destroys the Endocrinology & Metabolism 84, no. 9 (1999): remainder of the pituitary. Sometimes a cyst 3,036–3,040. (Rathke’s cleft cyst) or tumor (craniopharyngioma) in the hypothalamus may cause hypopituitarism. This medical problem may also be a complication of hypopituitarism Excessively low or insufficient irradiation of the pituitary in the course of the levels of pituitary hormone production. In the most patient receiving treatment for tumors of the pitu- extreme cases, complete PITUITARY FAILURE (panhy- itary or from radiation of nearby tissue in the nose, popituitarism) occurs, although this condition is rare. throat, or brain. Any one of the six anterior pituitary hormones Rarely, hypopituitarism is caused by pituitary may become deficient: adrenocorticotropic hor- apoplexy, which results from severe bleeding (hem- mone (ACTH), FOLLICLE-STIMULATING HORMONE orrhage) and subsequent enlargement of the pitu- (FSH), GROWTH HORMONE (GH), LUTEINIZING HOR- itary gland. POSTPARTUM PITUITARY NECROSIS 132 hypotension

(Sheehan’s syndrome), which is caused by severe most growth hormone-deficient adults are not bleeding after childbirth, may also result in hypopi- given growth hormone. Nonetheless, growing evi- tuitarism. In addition, some rare diseases may cause dence indicates that treating growth hormone defi- the condition. These diseases include hemochro- ciency leads to a better quality of life. matosis (an iron overload disease), sarcoidosis (one If hypopituitarism is not treated, patients may of several granulomatous conditions that may dam- experience a loss in bone density due to hypogo- age the pituitary), and genetic disorders such as nadism and a greater-than-normal risk of develop- KALLMANN’S SYNDROME. A direct injury to the pitu- ing osteoporosis. itary, such as an injury caused by a car crash, may See also PITUITARY GLAND. also result in hypopituitarism. Mulinda, James R., M.D. “Hypopituitarism (Panhypo- Diagnosis and Treatment pituitarism),” Available online. URL: http:// www.emedicine.com/med/topic1137.htm. The diagnosis of hypopituitarism may be difficult, Downloaded on January 15, 2004. because the patient’s symptoms may mimic Schmidt, Diane N., M.D., and Kathleen Wallace, M.D. hypothyroidism or other disorders, which must be “How to Diagnose Hypopituitarism.” Postgraduate ruled out. With hypopituitarism, patients have a Medicine 104, no. 7 (July 1998): 77–87. secondary form of hypothyroidism—growth hor- Vance, Mary Lee. “Hypopituitarism.” New England Journal mone deficiency—and thus often have a milder of Medicine 330, no. 23 (June 9, 1994): 1,651–1,662. form of symptoms. Because the etiology is secondary—that is, the patients’ bodies no longer make TSH but their thyroid gland is still intact—the thyroid still makes hypotension Abnormally low blood pressure some thyroid hormone. In contrast, in patients readings, which may be found among very ill or who have a primary thyroid problem in which the elderly individuals or among those with severe thyroid gland is completely destroyed, their bodies HYPERTHYROIDISM, PITUITARY FAILURE, or ADDISON’S make no thyroid hormones at all, and their symp- DISEASE. Some medications, such as drugs with toms are much worse. sedating qualities, some antidepressants, antianxi- If a patient’s hypopituitarism is caused by a ety medications, heart medicines, and other med- tumor that can be surgically removed, the condi- ications can cause low blood pressure. Some condition may reverse itself completely after surgery. If tions, such as DEHYDRATION (which can be caused the cause is not treatable, if tissue has been by HYPERGLYCEMIA, heart failure, shock, or cardiac destroyed by radiation or trauma, for example, arrythmias) can also cause hypotension to occur. then treatment involves partial or complete hor- Hypotension can be dangerous because it can mone replacement so that the results of the dys- impair people so much that they experience severe function can be managed. As a result, such patients falls and FRACTURES. Studies have shown that the who are exhibiting hypothyroid symptoms are type of hypotension that occurs after eating a meal treated with supplemental levothyroxine (T4). (postprandial hypotension) is also a high-risk indi- Patients with adrenal insufficiency are given cator for falls, especially among patients with DIA- glucocorticoids, such as hydrocortisone, pred- BETES MELLITUS or those who take three or more nisone, or cortisone acetate. Men with hypogo- medications. In general, chronic hypotension refers nadism (insufficient production of testosterone) are to patients who have blood pressure levels below treated with supplemental testosterone (transder- 90/60. mal or intramuscular). Women with an insufficient ORTHOSTATIC HYPOTENSION refers to a sudden production of estrogen are treated with hormone drop in blood pressure (about 20 mm Hg in the sys- replacement therapy (transdermal, oral, or intra- tolic blood pressure) that occurs when a person muscular). Growth hormone replacement in adults changes from a lying-down to a sitting-up position is a mildly controversial issue. As of this writing, or from a sitting-up to a standing position. hypothalamus 133

Emergency symptoms of hypotension that indi- main controller of that end organ’s functional sta- cate urgent medical treatment may be needed tus. All three exist in a homeostatic loop to main- include the following: tain hormone function at the appropriate levels.

Chrousos, George P., M.D. “The Hypothalamic-Pituitary- • Chest pain Adrenal Axis and Immune-Mediated Inflammation.” • Shortness of breath New England Journal of Medicine 332, no. 20 (1995): • A fever over 101 degrees Fahrenheit 1,351–1,362. • Severe headache • Severe pain in the upper back region hypothalamus The endocrine gland ultimately • Diarrhea and vomiting that lasts more than a day responsible for directing the release of the anterior • The presence of black or maroon-colored stools pituitary hormones: thyrotropin-releasing hor- • Urine that smells foul mone (TRH), growth hormone-releasing hormone (GHRH), gonadotropin-releasing hormone (GRH), • Fainting corticotropin releasing hormone (CRH), and dopamine. Each of these hormones triggers the Diagnosis and Treatment production of other key hormones needed by the body (see Table). When hypotension is diagnosed, the cause is The hypothalamus also helps to regulate blood sought through a medical history and physical pressure, appetite, satiety (a feeling of fullness after examination as well as tests such as a complete eating), libido, and body temperature. Malfunctions blood count (CBC), urinalysis, chest X-rays, and of the hypothalamus may range from minor med- tests for thyroid function. When the doctor has ical problems to life-threatening conditions. determined the probable cause, a treatment plan A cyst or tumor in the hypothalamus may cause can be developed to improve the hypotension. For HYPOPITUITARISM. Excessive release of GHRH, leading example, if the hypotension is caused by medica- to further release of GROWTH HORMONE, causes tions, the doctor may be able to change the med- ACROMEGALY. If the condition occurs before puberty, ication or reduce the dosage. If Addison’s disease is it is called GIGANTISM because it causes the individual the cause of hypotension, supplemental steroids to be much larger in height and size than the aver- and intravenous fluids will improve the condition. age person. The impaired development of the hypo- See also BLOOD PRESSURE/HYPERTENSION. thalamus in the fetus leads to KALLMANN’S SYNDROME. hypothalamic-pituitary-adrenal axis (HPA axis) Refers to the connections and interconnec- tions between the organs of the hypothalamus, PITUITARY HORMONES THAT CAUSE THE STIMULATION pituitary, and the adrenal glands. The HPA axis is OF OTHER KEY HORMONES also affected by input from both the cerebral cortex and the brain stem. Pituitary Hormone Effect The HPA axis is activated by stress. Part of the TRH Releases TSH stress response may lead to inflammation by caus- GHRH Releases GH GRH Releases LH and FSH ing the production of cytokines. These further lead CRH Releases ACTH to the creation of tumor necrosis factor, inter- Dopamine Inhibits prolactin leukin-1 and interleukin-6, and other mediators of TSH = thyroid-stimulating hormone inflammation used to protect the body. GH = growth hormone LH = luteinizing hormone All other anterior pituitary hormones have a FSH = follicle-stimulating hormone hypothalamic-pituitary–end organ axis that is the ACTH = adrenocorticotropic hormone 134 hypothyroidism

The hypothalamus releases antidiuretic hor- Medications, such as lithium (used for bipolar mone (ADH), also called vasopressin or desmo- illness) can induce hypothyroidism, impairing the pressin acetate (DDAVP). This hormone is released synthesis of thyroid hormone. Usually if the lithi- directly into the posterior pituitary via neurons and um is replaced by another drug, the patient’s nor- if insufficient amounts are released, will cause the mal thyroid functioning will return. Some drugs development of DIABETES INSIPIDUS. have excessively high levels of iodine and can See also HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. impair thyroid function, such as amiodarone, a cardiac drug. Interferon, commonly used to boost the immune system in patients with hepatitis C, can hypothyroidism The metabolic condition caused lead to hypothyroidism. In addition, antithyroid by abnormally low levels of thyroid hormone in drugs given to treat hyperthyroidism, such as the bloodstream, usually due to an undersecretion propylthiouracil and methimazole, may induce from the thyroid gland. Experts estimate that more hypothyroidism in some patients. than 10 million Americans are affected by this Very rarely, diet can induce hypothyroidism, medical problem. particularly a diet very high in bamboo shoots, cab- bage, cassava, and sweet potatoes. Sometimes the thyroid gland itself continues to Causes of Hypothyroidism function normally, but a malfunction in either the Hypothyroidism may be mild, moderate, or severe. pituitary or the hypothalamus causes the condition As with hyperthyroidism, hypothyroidism can be of secondary or central hypothyroidism (inade- subclassified as biochemical or subclinical (low lev- quate stimulation of the thyroid gland by thyroid- els of thyroid hormone activity without any signs stimulating hormone). In these cases, the free T4 or symptoms) or clinical (with typical signs and level may be low normal or low while the TSH symptoms). level is normal or low. Thus, if a TSH level is meas- Some infants are born with CONGENITAL ured first, the physician is more likely to suspect HYPOTHYROIDISM, which must be treated immedi- hyperthyroidism than hypothyroidism. ately to avoid long-term irreversible developmental delays in physical and intellectual functioning. An Hypothyroidism May Be estimated one in every 3,000 babies has congenital Misdiagnosed as Depression hypothyroidism. (Newborns are screened for low Sometimes hypothyroidism is misdiagnosed as thyroid levels.) Hypothyroidism is also caused by depression, particularly when the signs and symp- the surgical removal of the thyroid gland or by its toms are mild. As a result, all patients diagnosed destruction through external radiation or radioac- with possible depression should be screened for tive iodine treatments. hypothyroidism before receiving any antidepres- The most common cause of hypothyroidism is sant medications (unless the patient is severely HASHIMOTO’S THYROIDITIS, which is an autoimmune depressed and withholding medications until the disorder that damages the thyroid gland over the blood was tested for thyroid disease would be con- course of years. Early on in this syndrome, the thy- sidered dangerous). roid gland may be normal in size. As the disease Both hypothyroidism and depression may share progresses and thyroid-stimulating hormone (TSH) the common symptoms of constipation, decreased levels increase, the gland typically enlarges to a concentration, decreased libido, depressed mood, GOITER (an abnormally enlarged thyroid gland). diminished interest in activities that formerly Finally, after years of exposure to the destructive appealed to the patient, fatigue, sleep increase, and antibodies, the thyroid gland may become small or weight increase. People who are depressed, how- may atrophy. ever, may also have suicidal thoughts. People with Another cause of hypothyroidism, although hypothyroidism also have cold intolerance, delayed rarely seen in the United States, Canada, and other relaxation phase of the deep tendon reflexes, goi- developed countries, is iodine deficiency. ter, less and coarser hair, skin changes (thicker, hypothyroidism 135 drier, and doughier), and slow heart rate (brady- • Slowed movements cardia), features not commonly found among peo- • Thinning of the outer third of the eyebrows ple with depression alone. However, a person with (also known as Queen Ann’s eyebrow) hypothyroidism can also have depression, compli- • High cholesterol levels (about 56 percent of cating the diagnosis and treatment. Treating the patients experience this sign) hypothyroidism is critical because antidepressant medications do not work optimally in an untreated • Skin that is cool and dry to the touch hypothyroid patient. • Puffy face • Failure to ovulate (ANOVULATION) Signs and Symptoms of Hypothyroidism • Excessively heavy menses (menorrhagia) There are several common symptoms of hypothy- • Enlarged tongue (macroglossia) roidism. However, children age five and under who are hypothyroid may have no apparent symptoms If hypothyroidism is severe and continues (although they will often have decreased growth). untreated, the following signs and symptoms may Adolescents may have only a few signs and symp- occur: toms, such as facial puffiness and fatigue. Doctors should not prescribe thyroid hormone to a patient •HYPOGLYCEMIA (low blood sugar) without checking his or her blood to verify that the • Hypothermia (below-normal body temperature) thyroid levels are too low. The patient may have another medical problem altogether, and the • Hypoventilation (below-normal breathing rate) administration of unnecessary thyroid hormones •HYPONATREMIA (inadequate levels of sodium in could create other medical problems, such as iatro- the blood) genic HYPERTHYROIDISM. • Water retention The general symptoms and signs of hypothy- • Bradycardia (slow heartbeat) roidism include: • Depression • Fatigue • Shock • Cold intolerance (patients with hypothyroidism •MYXEDEMA COMA get cold faster and the cold bothers them more than others) • Chronic constipation Some studies have shown other indicators of • Decreased appetite hypothyroidism. In a 1997 issue of The Physician and Sportsmedicine, the authors reported on the case • Apparent (or actual) depression of a male athlete with knee and shoulder pain who • Muscle cramping and weakness, especially of had been diagnosed with tendonitis and fibromyal- the proximal muscles gia. Routine blood tests showed a highly elevated • Anemia TSH level. The patient was treated with levothy- • Reduced sexual libido roxine, and his problems resolved. Said the authors of this study, “Previous muscu- • Decreased perspiration loskeletal symptoms and fatigue did not recur. He • Paresthesias (pins and needles feelings) has since attained personal best race times and has • Carpal and tarsal tunnel syndromes had his best triathlon season.” They concluded that • Weight increase/difficulty with weight loss “the dramatic improvement and complete resolu- tion of the symptoms with thyroid replacement • Sleepiness therapy after failure with other medical treatments • Decreased memory/concentration suggest that normal tendon healing is impaired in • Hoarseness (thickened vocal cords) hypothyroidism.” 136 hypothyroidism

Risk Factors roidism is a common problem among people over Women face about 10 times the risk of developing age 65. However, doctors may assume that older hypothyroidism as men, and the risk is greatest for people are “supposed” to feel tired, lethargic, and women who are older than age 40. Nearly 10 per- constipated and thus may mistakenly attribute the cent of all women between the ages of 45 and 64 symptoms of hypothyroidism to “normal” aging. are hypothyroid. About 12 percent of women over age 60 have elevated levels of TSH, indicating Treatment hypothyroidism. About 7 percent of men between In most cases, patients quickly improve with the the ages of 65 and 74 have hypothyroidism. administration of LEVOTHYROXINE (l-thyroxine), Women who are menopausal are also at risk for usually in an oral form, such as Synthroid or hypothyroidism. Women who already take med- Levoxyl. In addition, the TSH should be measured ications for hypothyroidism may need to increase about six to eight weeks after any change in either their dosage of thyroid hormone based on the l-thyroxine brand or a change in the prescribed results of their blood levels. dosage of the medication. Thyroid disease (of all types) is often hereditary. Once patients are stabilized, they should be As many as 50 percent of patients with thyroid dis- monitored regularly and should receive at least ease inherited the gene for thyroid disorders. annual checks of their TSH blood levels. Patients diagnosed with hypothyroidism should also have Diagnosis of Hypothyroidism regular checks of their total cholesterol levels, Physicians assess thyroid status by performing a because studies have shown that hypothyroidism physical examination and ordering laboratory tests increases the risk of HYPERCHOLESTEROLEMIA (high that check TSH levels, levels of free T4, total T3, cholesterol levels in the blood). Once thyroid levels and antithyroid antibodies (usually antithyroid are within the normal range, however, cholesterol peroxidase antibody or anti-TPO). Physicians levels often drop as well. should also take a careful medical history, noting Sometimes patients have only slightly elevated the presence of any past thyroid disease or whether TSH levels or have some symptoms of hypothy- a patient has any first-degree relatives (parents or roidism but also have normal blood levels. Mild siblings) who have thyroid disease since thyroid thyroid failure may be caused by autoimmune thy- disease runs in families. roiditis, treatment for GRAVES’ DISEASE (a promi- In a physical examination, the doctor palpates nent form of hyperthyroidism), lithium carbonate the neck to check for any unusual enlargement of therapy for bipolar disorder (manic depression), the thyroid. The doctor will also measure for slow radiation to the neck, and iodine and iodine- pulse, look for enlarged tongue and a delayed containing medications. relaxation phase of the deep tendon reflex, and In such cases, physicians often treat patients check for edema (fluid retention), especially under with thyroxine supplements. The reason for such the eyes. Blood pressure is usually higher in treatments is to prevent a progression to overt patients with hypothyroidism and often decreases hypothyroidism, to prevent enlargement of the after the condition is treated. thyroid gland, to alleviate symptoms, to help with Based on the 2003 guidelines from the symptoms of depression, to normalize serum lipid American Academy of Clinical Endocrinologists levels, and also to normalize the cardiac function of (AACE), in most laboratories, treatment for patients. hypothyroidism should be considered if the TSH levels are above 3.04 mU/l. In the past, the cutoff for hypothyroidism was at a higher level, or 5.0 Hypothyroidism and Pregnancy mU/l, which did not include many patients with About 2.5 percent of all pregnant women are mild hypothyroidism. hypothyroid. Hypothyroidism is often associated Sometimes the diagnosis for hypothyroidism with an increased risk of obstetrical complications. may be missed altogether. For example, hypothy- In addition, pregnant women with positive thyroid hypothyroidism 137 antibodies face an increased risk of suffering from measured in each trimester during the pregnancy miscarriages. and should then be rechecked again within six to Hypothyroidism can be more difficult to diag- eight weeks after the birth of the child. nose during pregnancy because the symptoms of weight gain and fatigue are also commonly seen in Postpartum Thyroiditis nearly all pregnant women. In addition, about one- Some women do not become hypothyroid before third of pregnant women who are hypothyroid or during pregnancy, but instead, their hypothy- have no symptoms at all, and only one-third have roidism occurs postpartum. The prevalence of post- moderate symptoms. Also, the TSH levels in partum thyroiditis (including both hypothyroidism hypothyroid women are often unchanged and con- and hyperthyroidism) is about 8 percent. Of the tinue to lie within the normal range. Instead, the women who develop postpartum thyroiditis, about total T4 and total T3 are increased, and the thyroid 36 percent have hypothyroidism only, 38 percent hormone binding ratio (T3-resin uptake) is have hyperthyroidism only, and 26 percent have decreased. hyperthyroidism first, which is then followed by Risk factors for developing hypothyroidism hypothyroidism. among pregnant women are as follows: The usual course is first to develop hyperthyroidism that can last from one to four months, with • The presence of a goiter the levels returning to the normal range for the fol- • Previous therapy for hyperthyroidism lowing one to two months. After this time, thyroid levels may dip to hypothyroid levels for one to two • The presence of TYPE 1 DIABETES months before again returning to normal. It is not • A family history of thyroid disease uncommon for the postpartum hypothyroidism to • The presence of other autoimmune disorders be permanent. Thus, with the plethora of symp- •HYPERLIPIDEMIA toms that many postpartum women can have, as well as the ups and downs that their thyroid levels • Previous experience with high-dose external may go through after giving birth, the diagnosis of neck radiation hypothyroidism can be delayed and may some- • Previous postpartum thyroiditis times be completely missed by physicians. Women with the highest risk of developing Untreated hypothyroidism among pregnant postpartum thyroiditis include those who: women can have serious consequences in addition to miscarriage. Other possible consequences • Have Type 1 diabetes include: • Have a previous history of postpartum hypothyroidism • Gestational hypertension (hypertension that occurs only during pregnancy) • Have other autoimmune diseases, such as HASHIMOTO’S THYROIDITIS or Graves’ disease • Preterm delivery

• Anemia See also THYROID BLOOD TESTS; THYROIDITIS; • Fetal complications THYROID-STIMULATING HORMONE.

• Postpartum hemorrhage Arafah, Baha M., M.D. “Increased Need for Thyroxine in Women with Hypothyroidism During Estrogen When hypothyroidism is diagnosed among Therapy.” New England Journal of Medicine 344, no. 23 pregnant women, they are generally prescribed (June 7, 2001): 1,743–1,749. levothyroxine. About half of the women who take Baskin, H. Jack, M.D., et al. “American Association of levothyroxine before their pregnancy will need to Clinical Endocrinologists Medical Guidelines for take an increased dose of the drug during their Clinical Practice for the Evaluation and Treatment of pregnancies. Thus, their TSH blood levels should be Hyperthyroidism and Hypothyroidism.” Endocrine 138 hypothyroidism

Practice 8, no. 6 (November/December 2002): Knopp, William D., M.D., Matthew E. Bohm, M.D., and 457–469. James C. McCoy, M.D. “Hypothyroidism Presenting as Daniel K. Cherry, M.S., Catharine W. Burt, and David A. Tendinitis,” Available online. URL: http://www. Woodwell. “National Ambulatory Medical Care physsportsmed.com/issues/1997/01jan/knopp.htm. Survey: 2001 Summary.” Division of Health Care Downloaded on January 5, 2004. Statistics, Centers for Disease Control and Prevention, no. Marlash, Cary N., M.D., and Jack H. Oppenheimer, M.D. 337, August 11, 2003. “The Thyroid Gland,” in Endocrine Pathophysiology. Guha, Bhuvana, M.D., Guha Krishnaswamy, M.D., and Madison, Conn.: Fence Creek Publishing, 1998, Alan Peiris, M.D. “The Diagnosis and Management of 37–59. Hypothyroidism.” Southern Medical Journal 95, no. 5 Toft, Andrew D., M.D. “Subclinical Hypothyroidism.” (2002): 475–480. New England Journal of Medicine 345, no. 7 (August 16, Kamel, Hosam K., M.D. “Hypothyroidism in the Elderly,” 2001): 512–516. Available online. URL: http://www.mmhc.com/cg/ articles/CG9911/kamel.html. Downloaded on November 10, 2003. I impaired glucose tolerance (IGT) A condition in one endocrine disease for which newborns are which an individual’s blood glucose levels are high- screened. This disease must be diagnosed and treat- er than normal but are not high enough that the ed as soon as possible to avoid the long-term, serious person could be diagnosed as having diabetes. consequences of major developmental delays in the Former names of IGT, no longer in use (because physical and intellectual functioning of the child. they are inaccurate), are borderline diabetes, subclini- Infants may also suffer from other endocrine cal diabetes, chemical diabetes, and latent diabetes. diseases and disorders, such as TYPE 1 DIABETES. This More recently, the condition has become known as is why newborns are carefully screened by pedia- PREDIABETES. tricians when born and also followed up shortly Patients may go on to develop Type 2 diabetes. afterward. Sometimes illnesses are not immediate- However, some studies have demonstrated that ly apparent and may be found during a routine lifestyle changes such as weight loss, increased checkup of the child by a pediatrician. exercise, and decreased sugar consumption can prevent or delay the onset of diabetes. In one study, published in The New England Journal of Medicine, infertility The inability to create a pregnancy due one group of individuals with impaired glucose tol- to a medical problem. Infertility can be found in erance made lifestyle changes and subsequently men and in women. Primary infertility is defined as experienced an 11 percent incidence of diabetes. the failure to conceive a pregnancy within one year Members of the control group, who made no of attempting to do so, which is a problem for lifestyle changes, showed a significantly higher 10–20 percent of couples who are actively seeking incidence of diabetes, 23 percent. to have a child. Secondary infertility refers to infer- See also HYPERGLYCEMIA. tility that occurs to couples who have borne one or more children but are now unable to achieve a Davies, M. J., N. T. Raymond, J. L. Day, et al. “Impaired pregnancy. Glucose Tolerance and Fasting Hyperglycemia Have Many different medical reasons cause both Different Characteristics.” Diabetes Medicine 17, no. 6 males and females to be unable to reproduce. The (2000): 433–440. key reason is age, because fertility nearly always Tuomilehto, Jaakko, M.D., et al. “Prevention of Type 2 declines with aging, particularly for women. Even Diabetes Mellitus by Changes in Lifestyle among women who are as young as 35 years have a sig- Subjects with Impaired Glucose Tolerance.” New nificantly reduced ability to attain a pregnancy England Journal of Medicine 344, no. 18 (2001): when compared with younger women. Each pass- 1,343–1,350. ing year increases a woman’s risk of having a fertility problem. Male fertility, in contrast, may continue until infants Newborn babies and children up to about the male is elderly, although the odds of fathering age two. Even newborns can suffer from endocrine a child generally decrease in aging men due to diseases and disorders (although, fortunately, such problems such as ERECTILE DYSFUNCTION, TYPE 2 DIA- situations are rare). CONGENITAL HYPOTHYROIDISM is BETES, hypertension, and other illnesses.

139 140 infertility

In a study among women who had sought the Some genetic abnormalities that may cause infer- services of fertility clinics in 1999, published in tility are KALLMANN’S SYNDROME, hypergonadotropic 2001 by the Centers for Disease Control and HYPOGONADISM, CONGENITAL ADRENAL HYPERPLASIA, Prevention (CDC) in the United States, researchers and MCCUNE-ALBRIGHT SYNDROME. Some women found that only 15.9 percent of women ages 41–42 may also be resistant to FOLLICLE-STIMULATING HOR- years achieved a pregnancy, compared with 24.4 MONE (FSH), LUTEINIZING HORMONE (LH), or gonada- percent of women ages 38–40 years, and 31.6 per- tropin-releasing hormone (GnRH). cent of women ages 35–37 years. The highest suc- Some women may require surgery to open cess rate (37.3 percent) occurred among women blocked tubes or to correct other structural defects younger than age 35. that are preventing a pregnancy from occurring. These statistics are a matter of concern because In many cases, infertile women are given fertili- many people in the United States, Canada, and ty drugs to cause the ovaries to release one or more other developed countries purposely delay child- eggs. These eggs are then harvested, and a preg- bearing as they concentrate on their careers. Many nancy is created in an in vitro fertilization (IVF) women and men mistakenly believe that women procedure. Several states (Illinois, Massachusetts, can easily become pregnant in their late 30s or in and Rhode Island) have mandated that health their 40s and are shocked to learn that they are, insurance companies must cover the entire cost of instead, at risk for infertility. IVF treatment. Five states (Arkansas, Hawaii, Maryland, Ohio, and West Virginia) require at least Causes and Treatments for partial coverage. Infertility Among Women In the other states, patients must pay for the costs Age is not the only factor affecting fertility. Other of IVF treatments out of their own pockets. In an potential problems include endometriosis, blocked interesting study of insurance coverage and IVF out- fallopian tubes, past infections that have scarred comes, published in a 2002 issue of the New England the woman’s fallopian tubes, and other causes, Journal of Medicine, the pregnancy rate was found to such as hormonal imbalances: For example, undi- be higher in states that did not require insurance agnosed and untreated HYPOTHYROIDISM may impair coverage. The reasons for this are unclear but should a woman’s fertility. A history of amenorrhea (lack be considered by legislators making public policy. of menstrual periods) or oligomenorrhea (infre- Because IVF is costly for most people (at least quent periods) indicate a potential underlying $11,000 per cycle in 2003), experts are attempting medical problem that physicians should investi- to find ways to bring down costs. According to a gate. The past use of intrauterine devices may also 2003 article in the Wall Street Journal, some fertility have affected a woman’s fertility. clinics are retrieving immature eggs even before In some women, the problem lies with failed ovulation occurs and then inducing growth in the interactions in the hypothalamic-pituitary-ovarian laboratory before attempting fertilization with axis, which basically means that biochemical sperm. With this procedure, fertility drugs are not changes that should occur do not occur. According needed as part of treatment and the cost to con- to Dr. Eli Adashi and Dr. Jon Hennebold in their sumers is lower than with traditional IVF. 1999 article for the New England Journal of Medicine, As an aside, one problem with in vitro fertiliza- “The operational characteristics of the reproductive tion as well as with intracytoplasmic sperm injec- axis leave little room for error, which may explain tion is that the infants conceived in this manner the relatively high incidence of cycling disorders in have twice the risk of suffering from major birth women. Most of these are thought to be acquired defects, according to a 2002 issue of the New disorders of suprapituitary origin, but some women England Journal of Medicine. may be genetically predisposed to them. “Most genetically determined cycling disorders Causes of Infertility Among Men are of suboptimal [below normal] origin, with the There are many causes of infertility among men. ovary being the most common site of origin.” One cause is the absence of sperm (azoospermia), a infertility 141 problem experienced by an estimated 8 percent of blocked fallopian tubes. If both infertility problems infertile males, according to Dr. Victor Brugh and are successfully corrected, then the odds of achiev- his colleagues in their article in a 2003 issue of ing a pregnancy are usually increased, although Endocrinology and Metabolism Clinics of North America. creating a pregnancy is never a certainty, even with Insufficient sperm or sperm that have poor motility a healthy man and woman who have no detectable (movement) are other common causes of infertility. medical problems. Some men may also have scarring from sexually transmitted diseases, which impedes their fertility. Unknown Reasons for Infertility According to Dr. Brugh and his colleagues, many In many cases, doctors can find no cause for the infertile men (as many as 20 percent) have an infertility in either the man or the woman, which is underlying endocrine disorder. Tests of serum testos- an extremely frustrating situation for both individ- terone and FSH can identify many abnormalities. uals and may be very hard for them to accept. Some Physicians may also test levels of LH, PROLACTIN, and individuals continue to seek answers for their infer- estradiol. When medical problems are identified, tility from other physicians, who also cannot find a they can often be treated. Some males have specific cause for the infertility. Infertile couples decreased testosterone-to-estradiol ratios, which can may blame themselves or may blame each other. sometimes be remedied with oral aromatase The situation can become extremely stressful, inhibitor medications and thereby improve fertility. straining their relationship. In such cases, a skilled Another common problem is varicocele, which and sympathetic counselor may be effective at is a dilated spermatic vein that impedes fertility. pointing out the flaws in their thinking and helping Varicocele can often be repaired by physicians. them to accept their situation. Sometimes medications such as nitrofurantoin or spironolactone can cause infertility in men by affecting their sperm count. Heavy marijuana use If Pregnancy Is Not Possible also impairs fertility. Although some couples who are infertile choose to Procedures such as intracytoplasmic sperm injec- remain childless, other couples decide to adopt a tion (ICSI) have enabled some men to overcome baby or older child and later say they wonder what the problem of a low sperm count as long as they took them so long to make this decision. They may produce at least a few sperm. In this procedure, one adopt a child from the United States or from anoth- sole sperm is injected directly into the female egg in er country. (Interestingly, studies have shown that an in vitro (outside the body) procedure. The fertil- only about 15 percent of couples who adopt chil- ized egg is later implanted into the woman’s uterus. dren later have a biological child, contrary to pop- Some men may also suffer from chromosomal ular rumors that adopting a child somehow makes abnormalities or immunological problems that pre- infertile couples fertile.) vent them from achieving a pregnancy with their Still other couples or individuals hire a surrogate partner. Some men may need minor or more seri- to carry a child. The pregnancy may be created ous surgery to correct structural problems although from a husband’s sperm or donor sperm and the chromosomal problems cannot be corrected. surrogate’s ovum. Sometimes the embryo is In some cases, the cause for infertility cannot be derived from both the sperm of a husband and the detected or, if detected, cannot be treated with cur- ovum of a wife. In other cases, neither partner has rent therapies. a genetic relationship to the baby that the surrogate is carrying. Laws on surrogacy vary drastically from Joint Reasons for Infertility state to state, and some states do not address the Sometimes both the man and women have infertil- issue. Infertile individuals considering surrogacy ity problems, and both problems must be resolved should be very familiar with their state laws before (if possible) before the couple can have a child. For choosing this option. example, the man may have a low sperm count See also FEMALE REPRODUCTION; FERTILITY; MALE and the woman may also have endometriosis or REPRODUCTION; REPRODUCTIVE ENDOCRINOLOGY. 142 insulin

For further information on resolving infertility, Rates: National Summary and Fertility Clinic Reports. contact the following organizations: December 2001. American Fertility Association 666 Fifth Avenue insulin A protein hormone normally produced by Suite 278 the beta cells, specifically in the islets of Langerhans New York, NY 10103 in the pancreas. All individuals with TYPE 1 DIABETES (888) 917-3777 (toll-free) (and some individuals with long-term Type 2 dia- http://www.theafa.org betes as well) must inject insulin in order to live. American Society for Reproductive Medicine Insulin is secreted into the bloodstream in response 1209 Montgomery Highway to changes in ambient blood glucose levels as well Birmingham, AL 35216 as in response to ingested nutrients, specifically car- (205) 978-5000 bohydrates and proteins. In an individual with nor- http://www.asrm.org mal pancreatic physiology, insulin is cosecreted with amylin, while at the same time glucagons and RESOLVE: The National Infertility Association other hormone levels decrease. 7910 Woodmont Avenue The insulin first travels to the liver via the por- Suite 1350 tal vein, where it decreases the amount of glucose Bethesda, MD 20814 that the liver is secreting into the bloodstream. (301) 652-8585 Insulin helps the amino acids that are extracted http://www.resolve.org from dietary proteins assimilate into new proteins. Adashi, Eli Y., M.D., and Jon D. Ahennebold. “Single- It also helps store the breakdown of ingested fats Gene Mutations Resulting in Reproductive into triglycerides. Inadequate insulin will lead to Dysfunction in Women.” New England Journal of increases in blood glucose levels (HYPERGLYCEMIA), Medicine 340, no. 9 (1999): 709–718. and excess insulin will lead to low blood glucose Brugh, Victor M., III, M.D., H. Merrill Matschke, M.D., levels (HYPOGLYCEMIA). On very rare occasions, the and Larry I. Lipshultz, M.D. “Male Factor Infertility.” pancreas can form tumors, called INSULINOMAS, that Endocrinology and Metabolism Clinics of North America 32, secrete excess insulin. no. 3 (2003): 689–707. Insulin was discovered in 1921 by Dr. Frederick Guzick, David S., M.D. “Sperm Morphology, Motility, and Banting and Mr. Charles Best (a medical student at Concentration in Fertile and Infertile Men.” New the time) in Canada. Their breakthrough finding England Journal of Medicine 345, no. 19 (November 8, enabled many patients with Type 1 diabetes to lead 2001): 1,388–1,393. normal lives rather than dying young, as was the Hansen, Michele, et al. “The Risk of Major Birth Defects inevitable outcome for patients before then. After Intracytoplasmic Sperm Injection and In Vitro Today many different types of insulin prepara- Fertilization.” New England Journal of Medicine 346, no. tions are available, including rapid-acting, short- 10 (March 7, 2002): 725–730. acting, intermediate-acting, long-acting, and very Jain, Tarun, M.D., Bernard L. Harlow, and Mark D. long-acting. In addition, some forms may be com- Hornstein, M.D. “Insurance Coverage and Outcomes bined into one injection. As of this writing, all of of In Vitro Fertilization.” New England Journal of the available insulins are recombinant human Medicine 347, no. 9 (August 29, 2002): 661–666. insulins that are made synthetically. Compared Marcus, Amy Dockser. “Finding a Cheaper Way to Make with the previously available beef and pork a Baby.” Wall Street Journal (March 6, 2004): D1. insulins, they are more pure and begin to work United States Department of Health and Human Services, more quickly, but they also do not last quite as long Atlanta, Georgia, Division of Reproductive Health, as the previous types. National Center for Chronic Disease Prevention and Although these synthetic forms of insulin are Health Promotion. Centers for Disease Control and very similar to the endogenous insulin made by the Prevention. 1999 Assisted Reproductive Technology Success pancreas itself, all patients who have been taking insulinoma 143 insulin for a significant length of time will develop PLASIA, Type 1 (MEN 1) have an increased risk for some antibodies to the insulin, which may decrease developing insulinomas. its efficacy slightly. Usually these antibodies do not Some key indicators of the presence of an insuli- cause clinically significant problems. noma are the following symptoms: As of this writing, insulin is either injected sub- • Rapid heart rate cutaneously by the patient, using a syringe or pen device, or administered via a catheter attached to • Sweating an insulin pump. In addition, a variety of inhaled • Headache insulin preparations are being studied. These • Confusion inhalers are similar to but more sophisticated than • Dizziness those currently used to deliver asthma drugs into the lungs. • Loss of consciousness See also BASAL-BOLUS THERAPY. • Anxiety

Most of these indicators are the signs and symptoms of hypoglycemia. Patients with postprandial insulinoma A tumor, usually benign, of the (after-eating) hypoglycemia, anxiety, depression, insulin-secreting cells that lie within the pancreas. HYPERTHYROIDISM, cardiac irregularities, and other About 5–10 percent of all insulinomas are malig- conditions, may show the same symptoms. The key nant tumors. Insulinomas cause an excessive pro- difference is that when these indicators occur only or duction of insulin, which can lead to HYPO- mainly in the morning prior to eating, hypoglycemia GLYCEMIA. The hypoglycemia may range from mild and possibly insulinoma should be suspected. to severe. Insulinomas are also called islet cells ade- Because these symptoms may occur with many nomas. They occur in only about one in 250,000 other conditions, physicians must further investi- individuals. People with MULTIPLE ENDOCRINE NEO- gate with tests. A low blood glucose level and a

INSULIN FORMS AND SPEED AND LENGTH OF ACTION

When Insulin Begins to Work PEAK Effect Typical Length of Effect Rapid Lispro* (Humalog) 15 minutes 1 hour 3–5 hours Aspart (Novolog) 15 minutes 1 hour 3–5 hours

Short Regular* (Humulin and Novolin) 45 minutes 2–3 hours 5–8 hours

Intermediate NPH* (Humulin and Novolin) 2–4 hours 4–10 hours 10–16 hours Lente* (Novolin and Humolin) 3–4 hours 4–12 hours 12–18 hours

Long Ultralente (Humulin) 6–8 hours 10–18 hours 16–24 hours Glargine† (Lantus) 2–4 hours No peak 20–26 hours * Also available in pen devices. † Glargine is an acidic insulin that cannot be combined with other insulins.

Premixed Forms of Insulin 70/30 Insulin* (Humulin and Novolin) 70% NPH/30% Regular 75/25 Insulin* (Humulin) 75% Neutral protamine lispro/25% lispro 50/50 Insulin (Humulin) 50% NPH/50% Regular * Available in pen devices. Note: Onset, peak, and length of effects are significantly affected by injection site, activity, smoking, kidney function, and a variety of other factors. 144 insulin resistance high blood insulin level, as well as a high C-peptide Both women and men experience insulin resist- level, can all indicate the possible presence of an ance. Women with insulin resistance have a greater insulinoma. If the ratio of insulin to glucose is inap- risk for developing POLYCYSTIC OVARY SYNDROME propriate and an insulinoma is suspected, imaging (PCOS). It is also important to note that birth control studies may then be undertaken. pills may increase insulin resistance. This is especial- Typically, COMPUTERIZED TOMOGRAPHY (CT) or a ly true for progesterone-only contraceptives. MAGNETIC RESONANCE IMAGING (MRI) is used to If a person has a genetic predisposition to devel- localize the tumor. In some cases, such as when a oping Type 2 diabetes (that is, if an individual has a CT scan or MRI do not show any tumor but the parent or sibling who has diabetes) and if he or she physician is still concerned that one may be pres- already has insulin resistance, some medications ent, pancreatic arteriography may also be per- may cause diabetes. Some examples of medications formed. In this procedure, a small catheter is that may induce diabetes include: threaded into the arteries supplying the pancreas, and intravenous contrast is given to image the pan- • Glucocorticoids creas carefully, section by section. In some cases, • Nicotinic acid/niacin (generally has a small effect) the tumor cannot be localized preoperatively and • Alpha-adrenergic agonists the surgeon will palpate the pancreas at surgery to locate the tumor. • Thiazides that cause low potassium levels If a patient is diagnosed with an insulinoma, the • Dilantin (this rarely induces diabetes) treatment is usually surgery. Patients who have mul- • Pentamidine tiple tumors may need a partial pancreatectomy. • Interferon alpha therapy Doctors try to leave at least 15 percent of the pancreas intact so that it can continue to create the pan- • Diazoxide creatic enzymes needed to digest food. If no tumor is found or if surgery would be dangerous for an indi- Diagnosis and Treatment vidual patient, the physician may order medication such as diazoxide (Acetazolamide) to decrease If a patient has PREDIABETES, which means that oral insulin secretion and, in turn, to reverse hypo- glucose tolerance tests and other tests show levels glycemia. In some cases, another medication known that are not high enough to indicate diabetes but as octreotide is given to decrease insulin production. are above normal, most physicians will urge the patient to exercise and to lose weight if obesity is a problem. Some physicians will prescribe low doses of medications in an effort to avert the develop- insulin resistance A condition in which the pan- ment of diabetes, although studies have not shown creas produces sufficient insulin but the patient’s this to be efficacious. body is unable to use it. If insulin resistance levels See also OBESITY. should worsen, the condition will be diagnosed as Type 2 diabetes. Insulin resistance may be a prob- Facchini, Francesco S., et al. “Insulin Resistance as a lem for years before the insulin resistance and/or Predictor of Age-Related Diseases.” Journal of Clinical diabetes is actually diagnosed. Insulin resistance Endocrinology & Metabolism 86, no. 8 (August 2001): does not always proceed to diabetes, although it 3,574–3,578. increases the risk of developing diabetes in future Matthaei, Stephan, et al. “Pathophysiology and years. The problem of insulin resistance is wors- Pharmacological Treatment of Insulin Resistance.” ened in large part by both obesity and the lack of Endocrine Reviews 21, no. 6 (2000): 585–618. sufficient physical activity. Some researchers have Petit, William A. Jr., and Christine Adamec. The also found that prediabetic insulin resistance tends Encyclopedia of Diabetes. New York: Facts On File, Inc., to be much higher among smokers. 2002. iodine-induced thyrotoxocosis 145 insulin resistance syndrome The metabolic syn- proper medical nutrition and exercise, leading to drome that may exist when a person is resistant to weight loss to decrease their risk of complications. the hormonal effects of insulin. The characteristic As of this writing, no single drug is approved to components of this syndrome—insulin resistance, treat all of the components of insulin resistance diabetes, hypertension, and dyslipidemia—are also syndrome. Yet there are plenty of data to suggest known as the deadly quartet. Insulin resistance syn- that the medication metformin (Glucophage, drome is also called metabolic syndrome, metabolic- Glucophage-XR) will indirectly help decrease the cardiovascular syndrome, and syndrome X. (A insulin resistance. The medication’s specific cellular variant form of angina pectoris is also known as and biochemical actions cause changes that lead to syndrome X.) decreased insulin resistance. In addition, two thia- Insulin resistance syndrome is always modulat- zolidinedione drugs, rosiglitazone (Avandia) and ed by OBESITY. The more obese the person is, the pioglitazone (Actos), will decrease insulin resistance worse the insulin resistance. This is most true of directly. These medications directly cause biochem- abdominal obesity, specifically visceral abdominal ical and cellular changes that decrease the resist- obesity (fat that is within the abdominal cavity as ance to insulin. Several studies have shown that opposed to being purely subcutaneous). An these drugs will also decrease the risk of developing extreme example of such a case would be a person overt diabetes mellitus. Many pharmaceutical com- who is at a normal body weight but has increased panies are actively working to develop newer ver- abdominal fat and insulin resistance. People with sions of these drugs that will treat/prevent diabetes this syndrome are also at high risk for developing and also slow or prevent atherosclerosis. abnormal clotting in blood vessels that may con- Insulin resistance syndrome is to be distin- tribute to atherosclerosis, heart attacks, or stroke. guished from the clinical issue of resistance to The national Cholesterol Education Program’s insulin. About 80–95 percent of all patients with Adult Treatment Panel III suggests that any person Type 2 diabetes have at least some insulin resist- with three of five risk factors can be clinically diag- ance and as it increases, they require more therapy nosed with insulin resistance syndrome. These fac- in the form of large doses of oral medications or tors include: increased dosages of insulin. The medication’s specific cellular and biochemi- • Waist circumference of greater than 40 inches cal actions cause changes that lead to decreased in men and greater than 35 inches in women insulin resistance. In addition, there is an extreme- • Triglyceride levels greater than or equal to 150 ly rare syndrome where patients develop antibod- mg/dl ies to insulin and/or to the insulin receptor and require tremendously high doses of insulin (such as • High-density lipoprotein (HDL) levels less than thousands of units of insulin per day). 40 mg/dl in men and less than or equal to 50 in Interestingly, they do not die, and sometimes their women condition improves. There are so few of such • Blood pressure that is greater than or equal to patients that little is known about their natural his- 130/85 mm Hg tory. • Glucose levels greater than 100 mg/dl See also CHOLESTEROL; HYPERLIPIDEMIA; INSULIN RESISTANCE; PREDIABETES. When applying these criteria to a survey of nearly 9,000 adults, the prevalence of insulin resistance syndrome was found to be 22 percent in all adults iodine-induced thyrotoxocosis Extreme output and as high as 43.5 percent in those ages 60–69 years. of thyroid hormone caused by an individual ingest- Doctors strongly recommend that patients with ing high levels of iodine. This is a rare condition. insulin resistance syndrome begin a program of See also THYROTOXICOSIS.

Joslin Diabetes Center A prestigious, nonprofit 14 Clara Drive diabetes treatment, research, and educational insti- Suite 4 tution affiliated with Harvard Medical School. The Mystic, CT 06355 Joslin Diabetes Center specializes in treating (860) 245-0565 patients with diabetes and performing leading-edge Lawrence & Memorial Hospital research on both diabetes treatment and preven- 50 Faire Harbor Place tion. It is the largest single organization in the Suite 2E United States devoting its energies and efforts sole- New London, CT 06320 ly to diabetes research and care. The Joslin Diabetes (877) JOSLIN-1 Center provides comprehensive clinic services for patients with diabetes, including endocrinology, New Britain General Hospital ophthalmology, nephrology, pediatric endocrinolo- 100 Grand Street gy, obstetrics, mental health, nutrition, and exer- New Britain, CT 06050 cise physiology. (888) 4-JOSLIN (toll-free) The Joslin Center was originally formed in 1898 by Elliott P. Joslin, M.D., a noted Boston physician Florida and author dedicated to treating diabetes. Today Morton Plant Hospital the Joslin Diabetes Center has affiliates throughout 455 Pinellas Street the United States. Clearwater, FL 33756 For more information, contact the Joslin (727) 461-8300 Diabetes Center: One Joslin Place Indiana Boston, MA 02215 Floyd Memorial Hospital & Health Services (617) 732-2415 1850 State Street http://www.joslin.harvard.edu New Albany, IN 47150 Affiliates to Joslin Diabetes Center are as follows: (812) 949-5700 St. Mary’s Medical Center California 3700 Washington Avenue Evansville, IN 47750 University of California–Irvine (812) 485-1814 Gohschalk Medical Plaza Irvine, CA 92697 Maryland (949) 824-8656 North Arundel Hospital 301 Hospital Drive Connecticut Glen Burnie, MD 21042 Lawrence & Memorial Hospital (410) 787-4940

147 148 juvenile diabetes

University of Maryland Medical System Western Pennsylvania Hospital 22 South Greene Street 5140 Liberty Avenue N6W100 Pittsburgh, PA 15224 Baltimore, MD 21201 (412) 578-1724 (410) 328-6584 South Carolina Massachusetts Prevecare Anna Jaques Hospital 234 Seven Farms Drive 25 Highland Avenue Daniels Island Newburyport, MA 01950 Charleston, SC 29492 (978) 463-1344 (843) 576-3700

New York Washington Arnot Health Swedish Medical Center HCGW 910 Boylston Avenue 600 Fitch Street Seattle, WA 98104 Suites 202-203 (206) 215-2440 Elmira, NY 14905 (607) 737-8107 West Virginia SUNY Upstate Medical University St. Mary’s Medical Center 90 Presidential Plaza 2900 First Avenue Syracuse, NY 13202 Huntington, WV 25702 (315) 464-5726 (304) 526-8363

Pennsylvania juvenile diabetes A term once used to describe Forbes Regional Hospital what is now called TYPE 1 DIABETES. The name was Forbes LifeStyle Center changed to avoid confusion, because juvenile dia- Professional Office Building 2 betes is also found in many adults. The disease may 2580 Haymaker Road be diagnosed in childhood or adolescence, or it Suite 403 may not be diagnosed until early adulthood and Monroeville, PA 15146 sometimes later. It continues on throughout the (412) 858-4474 individual’s life, requiring lifelong treatment. K

Kallmann’s syndrome (KS) A condition that high-pitched voice and lack facial hair. Underarm results from a deficiency of gonadatropin-releasing (axillary) hair may be scanty. Pubic hair may begin hormone (GnRH) from the hypothalamus and that to develop due to the presence of adrenal andro- is associated with anosmia (loss of the sense of gens. Usually the testicles are very small, one to smell). Without the anosmia, the condition is called two cubic centimeters. On occasion, they may be as idiopathic hypogonadatropic hypogonadism. large as 12–15 cubic centimeters if any pubertal The GnRH deficiency stems from a congenital development occurred. Patients with Kallmann’s defect in neurons in the hypothalamus that lead to syndrome who have normal testes and spermato- a deficiency of GnRH. As a result, the pituitary zoa are referred to as fertile eunuchs. Typically gland secretes decreased amounts of LUTEINIZING there is no GYNECOMASTIA (breast swelling) due to HORMONE (LH) and FOLLICLE-STIMULATING HORMONE the low levels of estrogen in men. (FSH), leading to testosterone deficiency, INFERTILI- Females with Kallmann’s syndrome may be TY, and ERECTILE DYSFUNCTION. About one-third of deficient in estrogen, causing primary amenorrhea the cases of KS are inherited, while the remaining in girls. If untreated, this estrogen deficiency may cases appear to be caused by genetic mutations. An in the clinical course of the condition cause HOT estimated one in 10,000 males and one in 50,000 FLASHES, OSTEOPOROSIS, and painful intercourse females are affected. (dyspareunia) due to insufficient vaginal lubrica- Kallmann’s syndrome is the most common tion. The vagina may be a darker red than is found cause of secondary HYPOGONADISM. The syndrome in women without KS. was named after F. J. Kallmann. In 1944, Kallmann Other abnormalities associated with Kallmann’s and his colleagues reported in the American Journal syndrome are cleft lip or cleft palate and hearing of Mental Deficiency about families in which many loss. In children who have Kallmann’s syndrome, members had delayed or absent puberty the kidneys may fail to develop (renal agenesis), (eunuchoidism), anosmia, and color blindness. and some patients may become obese. In severe Kallmann noted that some of the individuals with cases, patients have skeletal abnormalities. Patients the syndrome were also developmentally delayed may also have congenital heart disease. Most (in the past known as mentally retarded). patients with KS are infertile, although fertility may be regained with medical treatment. Signs and Symptoms Some patients with KS have unusually long DELAYED PUBERTY is a common feature of this syn- arms that are five centimeters or greater than nor- drome. Males with Kallmann’s syndrome may mal (eunuchoidal). This is due to the delayed clo- have an extremely small penis (MICROPENIS) as well sure of their growth plates (epiphyses) during as undescended testicles (cryptorchism). On occa- puberty. Their height is usually normal for their age sion, patients will begin puberty but fail to mature despite the lack of pubertal development. completely. Boys will also have decreased muscle strength Diagnosis and Treatment and will not be as aggressive as the average male Patients with Kallmann’s syndrome are diagnosed with normal testosterone levels. Males may have a based on their signs and symptoms, but obviously,

149 150 Klinefelter syndrome diagnosing the condition is easier if there is any Dr. Harry Klinefelter first identified the condition family history of KS. Blood tests of testosterone in 1942. levels (serum testosterone) will reveal extremely low testosterone levels in males, while serum estra- Signs and Symptoms diol will be extremely low in females with KS. A The key feature for virtually all patients with MAGNETIC RESONANCE IMAGING (MRI) scan of the Klinefelter syndrome is small and firm testes. skull will reveal the presence of abnormal olfacto- Patients may also have GYNECOMASTIA (enlarged ry systems, a very common condition among as breasts), which is present in 50–75 percent of many as 75 percent of patients with KS. patients; decreased pubic hair (40–60 percent of Other tests that may be performed include a patients); and decreased facial hair (60–80 per- dual-energy X-ray absorptiometry (DEXA) scan to cent). A small penis (MICROPENIS) is present in determine if the patient has osteoporosis and an about 10–25 percent of these patients. Patients echocardiogram to identify the presence of congen- with Klinefelter syndrome do not undergo the nor- ital heart disease. mal changes of male puberty. Nearly 100 percent Patients with KS are usually treated with hor- are infertile. They also have decreased muscle mass mone replacement therapy to restore normal sec- in comparison with their peers. Some males with ondary sexual characteristics and fertility and to Klinefelter syndrome are taller than average. normalize bone and muscle mass. Males are treated with testosterone replacement and females with Associated Illnesses estradiol replacement. In women, estrogen is given Patients with Klinefelter syndrome have a high risk alone initially, to maximize breast development, of developing tumors. Some experts believe that and progestational agents are added later. When the disease itself may be caused by a tumor. fertility is desired, GnRH can be used in men and Although breast cancer is rare among men, patients women, although in men, often human chorionic with Klinefelter syndrome have a 20 times greater gonadatropin (HCG) is used, followed by FSH. risk of developing breast cancer than do other men. If other conditions are present (such as osteo- However, experts say that screening mammogra- porosis, heart disease, and so forth), those medical phy for men with Klinefelter syndrome is not usu- problems are treated. ally recommended since the occurrence of breast See also KLINEFELTER SYNDROME. cancer is still extremely rare. Men with Klinefelter syndrome have an Tritos, Nicholas A., M.D. “Kallmann Syndrome and increased risk for developing autoimmune disor- Idiopathic Hypogonadotropic Hypogonadism,” ders, such as rheumatoid arthritis, systemic lupus Available online. URL: http://www.emedicine.com/ erythematous, and Sjögren’s syndrome. Androgens med/topic1216.htm Downloaded on December 15, may be protective against autoimmune disorders. 2003. Since men with Klinefelter syndrome have low Wynbrandt, James, and Mark D. Ludman. The levels of testosterone, this may be the reason for Encyclopedia of Genetic Disorders and Birth Defects, 2d ed. their greater incidence of autoimmune diseases. New York: Facts On File, Inc., 2000. Another possible cause may be lymphocyte abnormalities found in these patients. Patients with Klinefelter syndrome have an Klinefelter syndrome An extra X chromosome increased risk of learning disabilities such as that occurs in about one in 1,000 baby boys. There dyslexia and attention deficit disorder. They may can be multiple X chromosomes. The greater the also exhibit psychiatric problems such as anxiety number of X chromosomes present, the more the disorder, depression, and even psychotic disorders. physical abnormalities. Patients with Klinefelter Boys with Klinefelter syndrome have difficulty syndrome usually develop HYPOGONADISM and with peer groups and are less interested in girls INFERTILITY due to the absence of sperm in the than other boys. Said authors Cynthia Smyth and semen (azoospermia) and other health problems. William Bremner in their 1998 article on Klinefelter syndrome 151

Klinefelter syndrome in Archives of Internal Medicine, Diagnosis and Treatment “The combination of feminine physical features, Patients with Klinefelter syndrome are diagnosed poor motor coordination, and difficulties in speech based upon their medical history as well as on their and memory probably impairs the attainment of signs and symptoms. Laboratory tests will also adequate self-esteem, increases anxiety, and pro- reveal elevated gonadotropin levels and decreased motes insecurity.” Testosterone treatment may lead testosterone levels in most patients. to improvement of the patient’s self-esteem. The treatment is usually testosterone replace- Because of their androgen deficiency, patients ment therapy. This will not make the man fertile, with Klinefelter syndrome are also at an increased but it will improve many problems. It will increase risk for developing OSTEOPOROSIS. Testosterone the facial and body hair, redistribute body fat, replacement decreases the risk for osteoporosis, improve sexual desire and ability, improve bone especially when it occurs before the male is age 20. mineral density, and reduce the risk for psychiatric Klinefelter syndrome also increases the risk for problems. These virilizing changes will usually also endocrine disorders such as DIABETES MELLITUS, improve self-esteem. In general, testosterone although it is usually a mild form of TYPE 2 DIA- replacement therapy is started early in puberty or BETES. HYPOTHYROIDISM may be present in some around age 12 and must continue for the patient’s patients. life. Most patients receive testosterone injections, Varicose veins are common in patients with although testosterone creams are also available, as Klinefelter syndrome. In one study, 20 percent of are transdermal skin patches. 104 patients had varicose veins. Patients also expe- See also DELAYED PUBERTY; HERMAPHRODITISM; rience 10–20 times the risk of venous ulcers and a KALLMAN’S SYNDROME. higher-than-normal risk for pulmonary embolism and deep venous thrombosis. Kurzrock, Eric A., et al. “Klinefelter Syndrome and An estimated 40 percent of patients with Precocious Puberty: A Harbinger for Tumor.” Urology Klinefelter syndrome have dental abnormalities, 60, no. 3 (2002): 515xiv–515xv. which can be identified with dental X-rays and Smyth, Cynthia M., M.D., and William J. Bremner, M.D. treated. “Klinefelter Syndrome.” Archives of Internal Medicine 158, no. 12 (June 22, 1998): 1,309–1,314.

L levothyroxine A synthetic formulation of thyroid lowed with patients who have THYROID CANCER. hormone, albeit structurally the same as the mole- Levothyroxine is given to the individuals to sup- cule made by the thyroid gland, and used primari- press the secretion of TSH completely with the ly to treat individuals with HYPOTHYROIDISM due to hopes that if any thyroid cancer cells have been left all causes (autoimmune hypothyroidism, surgical behind, the lack of TSH will keep them from grow- hypothyroidism, destructive and medication- ing any further. induced hypothyroidism). Levothyroxine is also called T4 because of the four iodine molecules attached to the tyrosine rings, in contrast to tri- Lugol’s solution A 5 percent iodine and 10 per- iodothyronine or T3, in which only three iodine cent potassium iodide solution that is used in three molecules are present. situations, as follows: The usual replacement dosage for a person with no thyroid function is about 2 mcg/kg/day, or 1. To block iodine uptake into the thyroid gland about 150 mcg per day in a person weighing 150 transiently in a patient with HYPOTHYROIDISM. pounds (70 kg). The dosage is typically titrated to a 2. To help decrease the blood flow in a thyroid thyroid-stimulating hormone (TSH) level of gland just prior to thyroid surgery. between 0.5 and 2.0 microunits per ml. 3. To block the thyroid gland during a radiation The three market leaders of levothyroxine med- emergency, blocking radioactive iodine from ications in the United States in 2003 were entering the thyroid gland. Synthroid, Levoxyl, and generic levothyroxine. These medications had combined sales of over a bil- Lugol’s solution is also used (in unlabeled uses, lion dollars in 2003, and the largest seller was that is, not specifically approved for the purpose by Synthroid, at over $500 million. According to the the Food and Drug Administration, although doctors Centers for Disease Control and Prevention, may order it) as an expectorant and as a dermato- Synthroid was the seventh most popular of all drugs logic treatment to treat Sweet’s disease (acute neu- prescribed to patients during office visits in 2001. trophic dermatosis). It is also sometimes used to treat Some patients also take desiccated thyroid hor- lymphocutaneous sporotrichosis, a fungal disease. mone extract, which is obtained from pig thyroid glands. Until the late 20th century, this extract was the dominant form of medication for people with luteinizing hormone (LH) An important hor- hypothyroidism. mone for both men and women, produced by the Levothyroxine is also used to attempt to sup- anterior pituitary. Luteinizing hormone affects the press thyroid nodules and goiters. The exogenous synthesis and release of hormones of the ovaries thyroid hormone that is given increases the levels and the testes, such as estrogen, progesterone, and of hormone in the bloodstream and then decreases testosterone. It also affects the synthesis and the secretion of thyrotropin-releasing hormone release of eggs or sperm that are released to create (TRH) from the hypothalamus and the secretion of a pregnancy. Luteinizing hormone is also called TSH from the pituitary gland. A similar plan is fol- interstitial cell-stimulating hormone (ICSH).

153 154 luteinizing hormone

LH is secreted in a pulsatile fashion. In spite of cuss with her own gynecologist whether or not to this, the normal levels in men fall within a fairly take HRT. narrow range. As with all pituitary hormones, the Deficiencies of LH in women of childbearing age LH level must be interpreted in the context of the or in men may cause INFERTILITY. If estradiol or associated testosterone level or semen analysis. In testosterone levels are low and a concomitant women, marked variations in LH secretion occur measure of LH is also low, this indicates a possible throughout the menstrual cycle. Physicians must hypothalamic or pituitary problem. If so, individu- therefore interpret a woman’s LH levels within the als who wish to have children may be treated with context of the specific time of her cycle as well as hormones, such as luteinizing hormone-releasing consider her concomitant estradiol levels. hormone (LHRH). Sometimes LH is very low or Luteinizing hormone is involved in a complex altogether absent, as in conditions such as hypogo- FEEDBACK LOOP between the gonad (ovary or testi- nadotropic HYPOGONADISM,KALLMANN’S SYNDROME, cle), the pituitary gland, and the hypothalamus. or other forms of secondary hypogonadism. For example, during a woman’s menstrual cycle, Tumors that secrete excessive amounts of LH are blood LH levels increase, and this, in turn, causes rare. However, inappropriate levels of LH in the the ovary to produce estradiol. When estradiol lev- blood are seen in a condition called POLYCYSTIC els reach a certain point within the body, the estra- OVARY SYNDROME. diol and the gonadotropin-releasing hormone Medical science has enabled doctors to manipu- (GnRH) cause a sharp increase in LH production late LH production to the ends of patients. For (the preovulatory surge). This increase causes ovu- example, ORAL CONTRACEPTIVES block the LH surge lation to occur. The LH levels reach a certain point, that precedes the release of an egg and thus pre- and then they decline. vent pregnancy. When women go through menopause, they See also FOLLICLE-STIMULATING HORMONE. may experience periodic HOT FLASHES, which are Griffin, James E., and Ojeda, Sergio R. Textbook of surges of luteinizing hormone in the bloodstream. Endocrine Physiology, 4th ed. New York: Oxford HORMONE REPLACEMENT THERAPY (HRT) may resolve University Press, 2000. this symptom, although each woman should dis- M macrocephaly An unusually large head of a lent, and a patient’s health insurance may not pro- newborn infant. The macrocephaly may be due to vide coverage for the open MRI. an increased brain volume (megencephaly), See also COMPUTERIZED TOMOGRAPHY. increased cerebrospinal fluid (hydrocephalus), or bony/vascular enlargement. Large heads are also characteristic of some endocrine disorders. For male reproduction The ability of a male, with a example, dwarfing syndromes may cause large female, to create a pregnancy and a child. Male heads that are disproportionate to the size of the reproduction is complex and involves many differ- individual’s body. ent factors, such as testosterone production, the Other causes of macrocephaly include HYPO- durability and presence of sufficient sperm, as well PARATHYROIDISM, ADRENAL INSUFFICIENCY, hyper- as the health of the sperm. A couple that is unable phosphatasia, osteopetrosis (an extremely rare to create a pregnancy after a year of unprotected condition inherited by infants that causes dense intercourse is generally diagnosed with infertility. bones that break easily because of micro-architec- Initially, whether the cause lies with the female or tural abnormalities), RICKETS, or OSTEOGENESIS male or if factors within each person are impairing IMPERFECTA. Steroid therapy in the mother may fertility is usually unknown. also cause macrocephaly in the child that she bears. Physicians who are experts in fertility, including See also MICROCEPHALY. obstetricians, urologists, and endocrinologists, can often assist couples in creating a pregnancy, although no doctor can issue a guarantee to any magnetic resonance imaging (MRI) A diagnostic patient. Even healthy individuals with no medical scanning device that uses a magnetic field to form problems sometimes cannot bear children and doc- an image of the interior organs being studied. tors are unable to determine any underlying cause. Many physicians use this tool to help with diag- This is called unexplained infertility. However, the nosing a broad array of diseases, ranging from can- cause may be a relatively minor problem that is cer to fractures. It is the imaging test of choice for readily resolved. In addition, infertility may also the PITUITARY GLAND and the HYPOTHALAMUS. indicate a serious health problem that is present in The MRI test is usually painless. On occasion, a the male or female, and thus, physicians should nonradioactive element called gadolinium is inject- investigate it. ed intravenously. Aging decreases male fertility, although it does Most scanners are closed, and thus the patient is not end fertility, as it does with females who have enclosed in a small chamber that to some patients undergone menopause. In at least half of all the feels like a tomb. Patients who are claustrophobic cases of a couple who are unable to conceive a have difficulty with undergoing an MRI scan. child together, there is some element of male infer- However, the administration of a drug like tility. In an estimated 30 percent of cases, the infer- diazepam (Valium) about an hour or so beforehand tility is solely caused by a problem with the male. usually calms such fears. Some scanners are open, At age 20, there is about a 6 percent rate of male but these are generally more costly and less preva- infertility among couples who are unable to con-

155 156 malnutrition ceive, which increases to 64 percent by the ages of Some men have disorders of ejaculation, such as 40–44 years. retrograde ejaculation, in which the semen goes In a study of 708 infertile couples in England, 28 the wrong way. This disorder may be treated med- percent had idiopathic infertility and 24 percent of ically or surgically, depending on the patient. the cases were caused by male factors. According to For couples considering intracytoplasmic sperm Dr. Victor Brugh and his colleagues in their 2003 injection, genetic studies are performed to check article on male infertility for Endocrinology and for Y chromosome abnormalities. Metabolism Clinics of North America, at least 20 percent See also FEMALE REPRODUCTION; HYPOGONADISM; of infertile men have an underlying endocrine disor- INFERTILITY. der. Laboratory tests of TESTOSTERONE and FOLLICLE- Brugh, Victor M., III, M.D., H. Merrill Matschke, M.D., STIMULATING HORMONE (FSH) levels can identify the and Larry I. Lipshultz, M.D. “Male Factor Infertility.” disorder in nearly all men. Endocrinology and Metabolism Clinics of North America 32, The first analysis, which is nearly always done in no. 3 (2003): 689–707. a man suspected of infertility, is the semen analy- Hull, M. G., et al. “Population Study of Causes, sis. After refraining from sexual activities for two to Treatment, and Outcome of Infertility.” British Medical three days, the man masturbates and produces a Journal 291, no. 6510 (1985): 1,693–1,697. semen sample. Doctors will then check the semen for the absence of sperm (azoospermia), a problem that about 8 percent of infertile males experience. malnutrition Very serious condition in which an A sperm count greater than 48 million per milliliter individual’s daily caloric intake is so low that if it is with greater than 63 percent motility is considered not increased soon, he or she will die. The condition a fertile count. For men with low sperm counts, may be caused by a disease, such as hepatitis, cir- intrauterine insemination of the woman will rhosis of the liver, or CANCER. It may also be caused increase the chance of conceiving. by poverty and/or famine. Malnutrition may some- The physical examination and other tests may times be caused by the inability of an individual (a reveal other underlying problems. For example, child or an elderly person) to feed himself when some men (from 19–41 percent of infertile males) others fail to provide food or purposely withhold it. have developed varicocele, which is dilated veins In some cases, people with eating disorders such as that impede fertility, although experts disagree on ANOREXIA NERVOSA develop malnutrition and may exactly how they prevent fertility. Repair of the actually starve themselves to death. varicocele may improve fertility as well as the quality of the semen. Marfan’s syndrome A genetic disorder that Some men have disorders producing or secreting affects the cardiovascular, ocular, and skeletal sys- hormones, such as gonadatropin-releasing hormone tems. Marfan’s syndrome was named after its dis- (GRH), luteinizing hormone, or follicle-stimulating coverer, French pediatrician Bernard-Jean Antonin hormone. Others have genetic disorders, such as Marfan, who first identified the syndrome in 1896. KALLMANN’S SYNDROME, that can be treated with This medical condition is very rare. Individuals with hormonal injections. Marfan’s syndrome should avoid competitive sports Disorders of the pituitary can lead to infertility, because the strain on their hearts from such vigor- such as a tumor in the pituitary gland. Surgery or ous activity could be life-threatening. Marfan’s syn- radiation of the tumor may lead to improved fertility. drome may cause an early death from aneurysm or Many medications can impair fertility in men, heart disease. In some cases, HOMOCYSTINURIA may such as calcium channel blockers, beta-blockers, tri- be mistaken for Marfan’s syndrome. cyclic antidepressants, tetracycline, nitrofurantoin, Characteristic traits of individuals with Marfan’s and other drugs. In addition, illegal drugs such as syndrome may include the following: cocaine and marijuana are known to decrease sperm production. Alcohol can also impede suffi- • Very long arms, legs, and fingers that are spider- cient sperm production. like and disproportionate to the patient’s height McCune-Albright syndrome 157

• Joints that are hypermobile (can bend beyond slender African-American adolescents. At least five the span of most people) different genetic subtypes of MODY have been • Spinal curvature (scoliosis) identified as of this writing. MODY accounts for approximately 2–5 percent of all Type 2 diabetes • Protruding or indented breastbone (pectus cari- cases. MODY is different from the Type 2 diabetes natum and excavatum) that is being diagnosed in increasing numbers of • Presence of mitral valve prolapse, a serious children and adolescents due to their obesity and heart condition that can cause heart arrhyth- sedentary lifestyles. mias, infections of the heart valve, and even MODY is typically inherited as an autosomal death (this condition is treatable if identified) dominant condition. The known genetic defects responsible for MODY include abnormalities of glu- Treatment cokinase, the hepatocyte nuclear factor-4 alpha, Studies have indicated that replacement of the aor- hepatocyte nuclear factor-1 alpha, insulin promoter tic root in the heart can successfully decrease the factor 1, and the sulfonylurea 1 receptor subunit. risk of heart disease in patients with Marfan’s syn- See also ADOLESCENTS; DIABETES MELLITUS. drome. Because of the high risk of heart disease in patients with Marfan’s, patients with this syndrome should probably have the surgery even before they McCune-Albright syndrome (MAS) A medical show any signs of either heart disease or aneurysm. condition, also known as osteitis fibrosa dissemi- In a 1999 issue of the New England Journal of nate, that is rare among females and even more Medicine, researchers studied the outcomes for 675 rare among males. McCune-Albright syndrome patients who had aortic root replacement at 10 was named after the two physicians (Doctors surgical centers in the United States and Europe. Donovan James McCune and Fuller Albright) who Most patients (70 percent) were male, and their separately described it in journal articles written in average age was 34 years. Of the patients, 455 had 1936 and 1937. MAS is not inherited, but it is undergone elective surgery and the others were caused by a genetic mutation in the GNAS1 gene. treated with urgent surgery. The death rate for the The cause for this mutation is unknown. patients who had elective surgery was 1.5 percent The syndrome is characterized by EARLY PUBERTY versus the markedly higher rate of 11.7 mortality and by endocrine diseases such as HYPERTHY- for patients who had emergency surgery. ROIDISM, short stature, CUSHING’S SYNDROME, PRO- According to the researchers, patients and their LACTINOMAS, or ACROMEGALY as well as by skin families “should understand that cardiovascular changes with increased pigment. Most patients complications of Marfan’s syndrome can be man- with McCune-Albright syndrome also have bone aged effectively in most cases by moderate restric- diseases and thus are at an increased risk for devel- β tion of physical activity, -adrenergic blockade, oping FRACTURES and deformities of the arms, legs, routine imaging of the aorta, and prophylactic and skull. As of this writing, MAS cannot be detect- [elective] replacement of the aortic root before the ed or treated before birth. diameter exceeds 5.5 to 6.0 cm.” Precocious Puberty Gott, Vincent L., M.D., et al. “Replacement of the Aortic Root in Patients with Marfan’s Syndrome.” New The key feature among female patients with England Journal of Medicine 340, no. 17 (April 29, McCune-Albright syndrome is precocious puberty 1999): 1,307–1,313. (early puberty). Small children and even infants Wynbrandt, James, and Mark D. Ludman. The have been identified with this medical problem. Encyclopedia of Genetic Disorders and Birth Defects, 2d ed. According to Dr. Boston in his article on MAS, New York: Facts On File, Inc., 2000. female infants as young as four months have experienced breast development or vaginal bleeding (first menstruation). maturity onset diabetes of youth (MODY) A rare Researchers believe that the early puberty char- genetic form of Type 2 diabetes, generally found in acteristic of McCune-Albright syndrome is often 158 McCune-Albright syndrome caused by estrogens generated by OVARIAN CYSTS. Other Endocrine Disorders This is difficult to treat because when these cysts Girls and women with McCune-Albright syndrome are removed, new cysts often develop. In addition, may have an excessive production of cortisol if one cystic ovary is removed, then the other ovary (hypercortisolism), which is also known as often starts to develop cysts. Cushing’s syndrome. Females with this medical Unfortunately, the synthetic drugs used to treat problem are obese and also have very sensitive early puberty in other girls and that suppress skin. Treatment may involve the removal of the luteinizing hormone and follicle-stimulating hor- adrenal gland that is causing the problem (ADRENA- mone will generally not be effective in girls with LECTOMY) or administering drugs that block the McCune-Albright syndrome. Some doctors are try- synthesis of cortisol. Hypercortisolism in infants ing oral drugs to block the synthesizing of estrogen, can cause a lack of appetite and failure to thrive. including such medications as tesolactone and Some children with McCune-Albright syndrome fadrozole. These medications appear to be effective have extremely low levels of blood phosphorus, in some patients with McCune-Albright syndrome, which is due to a loss of phosphorus that is excreted although further studies are needed. in their urine. This loss of phosphorus may cause bone changes similar to those found in children with Thyroid Abnormalities RICKETS, a severe pediatric bone disorder. Children According to the National Institute of Child Health with this problem can usually be treated with oral and Human Development in the United States, an phosphates as well as vitamin D supplements. estimated half of all girls who have McCune- Some females with McCune-Albright syndrome Albright syndrome have some form of thyroid dis- have severe bone diseases, while others do not. ease. Many of these patients have GOITERS, THYROID When bone disease occurs, it is characterized by NODULES, or thyroid cysts, although sometimes these fibroblast cells that replace normal bone cells. This abnormalities are not obvious and can be detected can cause fractures if the bone displacement occurs only with an ultrasound. THYROID-STIMULATING in weight-bearing areas such as the upper leg bone HORMONE (TSH) blood levels among patients with (femur). Fibrous dysplasia may also occur in the MAS are often low, indicating hyperthyroidism. skull and upper jaw of patients, causing facial Drugs to suppress thyroid synthesis, such as propy- deformity. Abnormal bone growth that occurs in lthiouracil or methimazone, may be given to treat the skull may cause blindness or deafness. It is very the hyperthyroidism. difficult for physicians to correct these bone defor- When hyperthyroidism occurs in infants, it may mities, which may require complex surgery. cause a severe FAILURE TO THRIVE and tachycardia. Liver abnormalities may also occur. Some This may result in a heart attack and even death. infants with McCune-Albright syndrome have severe neonatal jaundice. Growth Hormone Abnormalities Some patients with McCune-Albright syndrome Skin Changes have excessive levels of growth hormone secretion. Many children and adults with MAS have charac- This problem is usually identified when they are teristic café au lait spots, which are easiest to spot young adults and is caused by a pituitary tumor. in fair-skinned children. These spots are most like- Such young women have the characteristic fea- ly to be seen on the individual’s back and cause no tures of acromegaly, which include coarse facial medical problems. Adolescents or adults who are features, large hands and feet, and arthritis. Other troubled by them can usually cover them up com- patients may present with GIGANTISM if the pitu- pletely with makeup. itary tumor develops before puberty. Patients may have surgery on the part of the pituitary that Diagnosis and Treatment secretes growth hormone. The administration of McCune-Albright syndrome is diagnosed based on somatostatin, a growth hormone suppressant, is signs and symptoms. Laboratory tests will provide another treatment for acromegaly. further information. Patients are usually tested with melatonin 159 a multichemistry panel for liver function, thyroid interact directly or indirectly to impair the ability of function, and serum adrenocorticotropic hormone one or both drugs to provide the appropriate effect. (ACTH) levels. A 24-hour urine collection may be One medication may boost or weaken the action of ordered to check for urinary free cortisol. Growth another drug or change its action in some other hormone tests may be ordered as well. Imaging tests way. Some herbal supplements, such as ginkgo bilo- are also important, such as a pelvic ultrasonography ba, can cause thinning of the blood and should not to identify ovarian cysts in females and a bone scan be taken by patients taking warfarin (Coumadin) or to locate areas of fibrous dysplasia. other drugs with similar actions. For this reason, Females with MAS are usually treated with testo- individuals should always report all medications lactone or tamoxifen, while boys are treated with that they take, including any over-the-counter ketoconazole or testolactone and spironolactone. drugs, herbs, or supplements, to their physicians. A The other manifestations of McCune-Albright syn- medication interaction may cause mild symptoms drome, such as hyperthyroidism, bone diseases, and or may be severe, causing coma and even death. so forth, are treated as well. Surgery may be needed, People who take many medications (including such as an adrenalectomy for adrenal tumors. prescribed drugs, over-the-counter drugs, and See also SKIN. herbal supplements and vitamins) have a greater For further information, contact the following risk of experiencing a medication interaction than organizations: others. In addition, because they often take three or more medications to manage chronic diseases and McCune-Albright Syndrome/Fibrous Dysplasia may also have slower metabolisms than younger Division people, elderly people have an increased risk for MAGIC Foundation experiencing a medication interaction. It is critically 6645 West North Avenue important that such individuals attempt to fill all Oak Park, IL 60302 prescriptions at a single pharmacy or, if that is not (708) 383-0808 possible, to report all the medications and supple- http://www.magicfoundation.org ments that they take whenever they do fill a pre- National Arthritis and Musculoskeletal and Skin scription. This will allow the pharmacist to use one Diseases Information Clearinghouse of the many computer programs available to assess 1 AMS Circle the possibility of an interaction or adverse effect. Bethesda, MD 20892 See also ALTERNATIVE MEDICINE; MEDICATIONS. (301) 495-4484 http://www.niams.nih.gov medications Drugs that are used to treat medical National Institute of Child Health and Human problems, including prescribed drugs, over-the- Development counter drugs, and herbal remedies and supple- P.O. Box 3006 ments. Many endocrine diseases and disorders Rockville, MD 20847 require medications that are hormones. Sometimes (301) 496-5133 supplemental hormones are needed, such as http://www.nichd.nih.gov LEVOTHYROXINE for patients with HYPOTHYROIDISM, Boston, Bruce, M.D. “McCune-Albright Syndrome,” INSULIN for patients with TYPE 1 DIABETES (and some- Available online. URL: http://www.emedicine.com/ times for patients with long-term TYPE 2 DIABETES), PED/topic1386.htm. Downloaded on November 30, or TESTOSTERONE for males with HYPOGONADISM. 2003.

melatonin A hormone produced by the pineal medication interactions The condition that exists gland that plays an important role in the sleep cycles when two or more medications, or a medication of humans. The chemical name for natural mela- and a nutrient, or a medication and a supplement tonin is N-acetyl-5-methoxytryptamine. Melatonin 160 melatonin is metabolized in the liver and excreted in the urine. tonin in concert with radiation therapy or Its precise role in the sleep/wake circadian cycle chemotherapy. Some studies have shown improve- remains poorly understood, despite studies. ments in patients with breast cancer and other can- Melatonin secretion in most people starts soon cers who took melatonin in addition to the more after darkness falls and usually peaks between the standard therapies. Further and larger studies are hours of 2 and 4 A.M. Melatonin secretion varies by needed to determine the cancer-fighting capabili- age. Infants who are younger than age three ties of this hormone. months have very low levels of melatonin secretion. Secretion rises thereafter and generally peaks Supplements of Melatonin between the ages of one and three years, dropping Some people who have difficulty sleeping will take gradually after that age. supplements of melatonin to improve their sleep Many older people have difficulty with sleep quality, although the long-term effect of taking such disorders. Some may have pineal insufficiency, drugs is unknown. Other individuals have taken causing the decreased production of melatonin. In melatonin because they must travel long distances a study reported in a 1995 issue of Lancet, and are attempting to stabilize their body rhythms to researchers found that the elderly subjects had those of the area where they are traveling and thus below-normal nocturnal secretions of melatonin. avoid jet lag. For example, they may take melatonin Patients who were given controlled-release mela- to cause themselves to fall asleep at an earlier time tonin experienced significantly improved sleep than usual but at a time that would be at about right over those patients given placebo. The patients in the area to which they are traveling. given the melatonin did not sleep more hours, but Melatonin supplements at dosages of one to five they slept more soundly. milligrams have been found to induce melatonin Other Potential Effects of Melatonin rates in the blood up to 100 times greater than those normally found in patients. Patients should In addition to its effect on sleep cycles, some not take any supplements without first checking experts believe that the pineal gland affects puber- with their physicians to ensure that the drug is ty through the secretion of melatonin. In medical likely to be safe and will not interact with other anecdotal reports, some children whose pineal medications they already take. Problems with puri- glands were destroyed by tumors experienced an ty and quality control have been found in some EARLY PUBERTY. In addition, experts have found that supplements. So consumers should purchase prod- some children with precocious puberty have ucts manufactured by large companies within their unusually low levels of melatonin in their blood. own countries. Further research is needed to determine if the See also ELDERLY; PINEAL GLAND. pineal gland and/or melatonin secretion play a significant role in early puberty. Brzezinski, Amnon, M.D. “Melatonin in Humans.” New Some evidence indicates that the release of mela- England Journal of Medicine 336, no. 3 (January 16, tonin by the pineal gland may play a protective role 1997): 186–195. against the development of cancer or in already- Garfinkel, D., et al. “Improvement of Sleep Quality in existing cancer, although further studies are need- Elderly People by Controlled-Release Melatonin.” ed. Sometimes melatonin is used to supplement the Lancet 346, no. 8974 (1995): 541–544. effects of chemotherapy in individuals with cancer. Kunz, D., et al. “Melatonin in Patients with Reduced Individuals who have undergone a pinealectomy REM Sleep Duration: Two Randomized Controlled have shown an increased risk for the growth of Trials.” Journal of Clinical Endocrinology & Metabolism 89, tumors, while the administration of melatonin no. 1 (2004): 128–134. improves the condition or even reverses it. Panzer, A., and M. Vijoen. “The Validity of Melatonin as In some patients with advanced cancer, physi- an Oncostatic Agent.” Journal of Pineal Research 22, no. cians have treated them with large doses of mela- 4 (1997): 184–202. menstruation, painful 161 menopause The stage of life in which women no Arafah, B. M. “Increased Need for Thyroxine in Women longer menstruate nor do they release a monthly with Hypothyroidism During Estrogen Therapy.” New egg that could be combined with a sperm to pro- England Journal of Medicine 344, no. 23 (2001): duce an embryo. Menopause usually occurs to 1,743–1,749. women in their late 40s or early 50s, although menopause may occur earlier or later. Some experts have defined perimenopause as a stage that pre- menstruation, painful Difficult menstrual cycle, cedes menopause for several years, during which often accompanied by severe cramping, copious time estrogen production is diminished and women bleeding (menorrhagia)—which is probably the are unlikely to become pregnant. Women who have most severe problem, as well as overall achiness, both of their ovaries removed before the normal headaches (including migraines), and a general onset of menopause, because of OVARIAN CANCER,an feeling of being out of sorts. Some women have a OVARIAN CYST, or another medical problem, experi- painful menstruation every month. In such cases, ence an early, surgically induced menopause. they should consult with a gynecologist to deter- Women who take LEVOTHYROXINE for hypothy- mine if there is a correctable medical cause for the roidism may need higher doses if they also take problem. The physician will usually order a blood ESTROGEN REPLACEMENT THERAPY (ERT) to counter- test for the woman’s hormone levels and may act the effects of menopause such as HOT FLASHES, order an ultrasound to determine if an ovarian cyst vaginal dryness, and mood swings, according to or another condition is present. Some endocrine some studies. disorders, such as HASHIMOTO’S THYROITIDIS (a form Not all women experience signs and symptoms of hypothyroidism), are associated with painful of menopause. For those who do, the signs or and heavy menstrual periods. symptoms may be short-lived and mild. For other Some physicians place women with very painful women, the symptoms are very difficult to manage. menstrual cycles on birth control pills (ORAL CON- TRACEPTIVES) in an attempt to stabilize the cycles. In some cases, women need to see an ENDOCRINOLO- Diagnosis and Treatment GIST to determine if an endocrine disease or disor- Physicians may diagnose women with menopause der rather than a gynecological disorder may be based on their age and their symptoms. However, it causing their problems. is best to order a blood test of estrogen levels to In the past, some women with severely painful confirm that menopause has occurred. If the menstrual periods and/or menorrhagia were given hysterectomies despite the lack of cancer or other woman is menopausal, she may wish to take HOR- disease. The removal of the uterus effectively ends MONE REPLACEMENT THERAPY (HRT), which is a combination of estrogen and progesterone. Some all menstruation, permanently. If the ovaries are also women take estrogen replacement therapy (ERT) removed at the same time, the woman will undergo alone, particularly if they no longer have an intact a sudden onset of MENOPAUSE. More recently, some uterus (due to a hysterectomy) and thus do not physicians have turned to less extreme measures, have to worry about developing uterine cancer. such as endometrial ablation which can be used as For further information, contact the following an alternative to the hysterectomy. organization: In one study, reported in a 1996 issue of the New England Journal of Medicine, physicians performed American Menopause Foundation an endometrial resection on 95 percent of 525 350 Fifth Avenue women with menorrhagia. Of these women, 6 per- Suite 2822 cent experienced surgical complications. Physician New York, NY 10118 follow-ups with questionnaires over the course of (212) 714-2398 five years determined that the majority of the www.americanmenopause.org women experienced significant relief. The majority, 162 metabolism

80 percent, of the patients did not need further sur- people do not have thyroid disease or other gery for menstrual problems, and only 9 percent endocrine disorders, while at the same time, indi- later required a hysterectomy. viduals who appear slow moving to others do not necessarily have a metabolic disorder. In addition, O’Connor, Hugh, and Adam Magos, M.D. “Endometrial some individuals who may appear normal to oth- Resection for the Treatment of Menorrhagia.” New ers do have a metabolic disorder. England Journal of Medicine 335, no. 3 (July 18, 1996): In the case of many hormones, although some 151–156. of the hormone must be present for the person’s metabolism to function at a normal level, changes in the levels may not have a dramatic effect on the metabolism The use of energy to perform the metabolism. This is referred to as being permissive overall processing of the body’s functions, includ- for normal metabolism. Examples of such hor- ing digestion, breathing, blood circulation, and so mones are cortisol and growth hormone. forth. The formal terms for metabolism are basal metabolic rate or resting energy expenditure. Metabolism increases relative to weight from birth metaiodobenzylguanide scan (MIBG scan) A test until the age of two years old and then gradually for an endocrine tumor. MIBG is similar in struc- declines until puberty. It then increases again until ture to norepinephrines and acts as a precursor for adolescence is complete. Thereafter, metabolism the synthesis of catecholamines. This molecule can very slowly declines with age, although many vari- be labeled with radioactive iodine (either I-131 or ables will affect it. I-123) and used to attempt to locate small Basal metabolic rate correlates best with fat-free pheochromocytomas (adrenal tumors) that have mass (FFM), and fat-free mass correlates with mus- not been found by computed tomography (CT) cle mass. Thus, the more muscle mass a person has, scans, magnetic resonance imaging (MRI) scans, or the higher the basal metabolic rate. Basal metabol- other localizing radiological procedures. ic rate can be measured with a technique called The standard rule of thumb for all endocrine calorimetry; unfortunately, this technique is not tumors is that the physician must first substantiate readily available because it requires expensive that the patient has a clinical syndrome consistent complex equipment that is tricky to use accurately. with the disorder and also that the appropriate bio- It is often used with patients in intensive care units chemical markers are elevated in the patient’s on ventilators. In addition, there is a significant blood or urine. Rarely, if ever, is it appropriate for variation from measurement to measurement with a physician to attempt to identify a tumor via a current techniques, leading to a fairly wide normal scan without first having some biochemical evi- range. Usually, formulas are used to calculate basal dence of the presence of a tumor, because there is metabolic rate and thus determine the appropriate a high risk of a false-positive result. The presence of intake of nutrition. a nodule or mass, which is often normal and The rate of metabolism in an individual is affect- benign, can cause a false positive. ed by many variables. Hormones are key variables, Before having the MIBG scan, patients need to particularly thyroid hormones. Thyroid disease can be taken off any drugs that could affect their cate- speed up or slow down a person’s metabolism. cholamine metabolism, such as beta-blocker med- HYPOTHYROIDISM tends to decrease an individ- ications and tricyclic antidepressants. Patients are ual’s metabolism, causing that person to be more given some iodine prior to the test to protect their sluggish and slow moving. In contrast, HYPERTHY- thyroid glands from damage that could be caused ROIDISM generally increases metabolism and causes by the radioactive iodine. The scan is usually done individuals to have an increased heart rate, more as an outpatient test. It can help detect very small rapid digestion, and so on. However, of importance tumors and/or the 10 percent of pheochromocy- is that people have varying metabolisms that lie tomas that are not adrenal tumors as well as the within the normal range. Some highly energetic rare patient who has multiple tumors. milk-alkali syndrome 163 microcephaly Unusually small head size, usually treatment must occur before puberty, as the in a newborn infant. Microcephaly may be an indi- response after puberty is usually poor. cation of a developmental delay and always implies Studies of the sexual function of men with an abnormally small brain (microencephaly). micropenis indicate they can have normal sex lives. Severe placental insufficiency due to poorly con- According to Woodhouse, regarding a study of 20 trolled DIABETES MELLITUS may lead to micro- adult males with micropenis, “The most surprising cephaly. Organic acidurias such as HOMOCYSTINURIA feature of these patients was the firmness with may also lead to microcephaly. which they were established in the male role and Standard head circumferences have been devel- the success that they had in sexual relationships. In oped for children between the ages of birth and 18 the adult group, all were heterosexual, all had years old. Special head curve charts are available erections and orgasms, and 11 of 12 ejaculated.” for children with NEUROFIBROMATOSIS TYPE 1, One patient had both a wife and a mistress, and achondroplasia, and Williams syndrome. one patient had fathered a child. See also MACROCEPHALY. See also TESTES/TESTICLES. Woodhouse, C. R. J. “Sexual Function in Boys Born with Exstrophy, Myelomeningocele, and Micropenis.” micropenis An unusually small-sized penis, Urology 52, no. 1 (1998): 3–11. often caused by a genetic disorder. The male infant with a micropenis has a penis that is less than 2.5 centimeters in length and 0.9 cm in diameter. It can be caused by decreased exposure to TESTOSTERONE milk-alkali syndrome The triad of very high in the second or third trimesters of pregnancy, blood calcium levels, excess alkali, and kidney insensitivity to androgens, or deficient GROWTH insufficiency caused by a combination of an exces- HORMONE or LUTEINIZING HORMONE. sive amount of milk and/or alkaline antacids, par- Some infants are candidates for gender reassign- ticularly baking soda (bicarbonate of soda). Patients ment, which means that they are raised as girls. who are taking vitamin D further aggravate the However, this is a highly controversial practice. problem. Milk-alkali syndrome was a common Many males with Klinefelter syndrome, although cause of HYPERCALCEMIA prior to the advent of the not all, have very small penises. newer therapies for peptic ulcer disease, especially According to Dr. C. R. J. Woodhouse in his 1998 the use of histamine-2 receptor blockers such as article in Urology, some boys with micropenis have cimetidine (Tagamet) and ranitidine (Zantac). this problem due to an isolated growth hormone However, the incidence of milk-alkali syndrome deficiency, which can be treated with human has been increasing as greater numbers of patients recombinant growth hormone (HRH). Although use large amounts of calcium carbonate (Tums) this may cause the penis to increase in size, it will supplements to help prevent or treat OSTEOPOROSIS still be below the average length in size for males. and to decrease blood phosphorus levels among Another form of treatment in infants and young those with severe chronic renal disease. boys is to administer testosterone or human chori- Interestingly, some patients have developed onic gonadatropin (HCG). This treatment may HYPOCALCEMIA when the excess calcium was enable the penis to grow to a normal size. removed from their diets. Some physicians have treated boys with Historically, milk-alkali syndrome first began in micropenis with dihydrotestosterone (DHT) cream 1915 with the introduction of a regimen, by that is applied to the penis. This hormone causes Dr. Sippy, that treated peptic ulcer disease with both the penis and the prostate gland to increase in magnesium carbonate, sodium carbonate, and size. In one study of 22 children, all of them expe- bismuth subcarbonate. The chronic form of rienced increased penile growth with DHT treat- this condition was also called Burnett’s syndrome, ment, including four boys who had not responded and the subacute form was known as Cope’s to treatment with other forms of testosterone. The syndrome. 164 mineralocorticoids

Milk-alkali syndrome can cause calcium of calcium in the bloodstream (HYPERCALCEMIA), deposits in the kidneys, which are seen in COMPUT- which can then cause kidney stones and renal ERIZED TOMOGRAPHY (CT) scans, MAGNETIC RESO- (kidney) damage. Hyperparathyroidism may also NANCE IMAGING (MRI) scans, X-rays, or ultrasounds cause constipation, bone pain, muscle pain, fatigue, of the kidneys. The modern patient who has milk- indigestion, and weakness. alkali syndrome typically has no signs or symptoms Patients with MEN 1 may also have abdominal of this medical problem. However, physicians may pain, nausea and vomiting, vision problems, loss of suspect the problem based on the patient’s history coordination, lack of appetite, weight loss, and of calcium intake and then the measurement of hypotension (low blood pressure). Women may serum calcium levels as well as other ancillary experience infertility and amenorrhea and may blood findings. Patients who are heavy users of also fail to lactate, making it impossible to breast- antacids are at risk for milk-alkali syndrome. feed their babies. Men may have decreased libido If symptoms do occur, they may include and a loss of facial or body hair. headache, nausea, and weakness. The patient may If MEN 1 is suspected by the physician, tests are also have pain in the back or the loins and may performed on the endocrine glands to evaluate their experience excessive urination. function. A magnetic resonance imaging (MRI) scan Most cases of milk-alkali syndrome are may show a pancreatic tumor. A fasting blood sugar reversible when the patient stops drinking high test may be low, while serum glucagon may be high. levels of milk and/or consuming many antacids. In In evaluating the parathyroid glands, the serum severe cases (which are rare), the kidney is dam- parathyroid hormone and serum calcium levels are aged and the patient may experience kidney failure elevated if MEN 1 is present. A scan of the head may and may require dialysis or a kidney transplant. show that a pituitary tumor is present. Physicians See also CALCIUM BALANCE; VITAMIN D. may also check for hormone levels of cortisol, adrenocorticotropic hormone (ACTH), luteinizing hormone, and follicle-stimulating hormone. mineralocorticoids See ALDOSTERONE. If hyperparathyroidism is diagnosed, the usual treatment is to remove three of the four parathyroid glands and part of the fourth gland. (A portion of the multiple endocrine neoplasia (MEN) A rare and fourth parathyroid gland is left in place so that it can serious hereditary disorder of cancer of the continue to generate some parathyroid hormone.) endocrine glands. MEN is further subdivided into MEN 1 and MEN 2. MEN 2 With MEN 2, patients develop thyroid cancer MEN 1 (medullary carcinoma of the thyroid) as well as MEN 1 involves multiple tumors that may occur in cancer of the adrenal glands (pheochromocytoma). one or more endocrine glands. This medical prob- MEN 2 is caused by a mutation in the RET gene. lem is a hereditary disorder that occurs in an esti- The incidence is unknown. The cancers do not mated three to 20 people of every 100,000 always appear at the same time. MEN 2 is also individuals. It can present at any age and affects known as Sipple’s syndrome. males and females in equal numbers. MEN 1 is also The following symptoms are common with known as multiple endocrine adenomatosis or MEN 2: Wermer’s syndrome. Researchers report that often MEN 1 affects the • Chest pain parathyroid glands in the neck first, causing all four • Abdominal pain parathyroid glands to become overactive and to secrete excessive levels of parathyroid hormone. • Weight loss This HYPERPARATHYROIDISM then causes high levels • Coughing blood myxedema coma 165

• Increased thirst such as pneumonia, influenza, myocardial infarc- • Severe headache tion, urinary tract infection, significant cold exposure, or exposure to narcotics. • Back pain These patients are often seen in a hospital emer- • Increased urination gency department with mental status changes (severe cases are referred to as myxedema mad- Since these symptoms are common to other dis- ness), low body temperature, slow heart rate orders, the physician must perform diagnostic test- (bradycardia), low blood sodium level (HYPONA- ing. For example, an adrenal biopsy may reveal a TREMIA), hypoventilation, and low blood sugar pheochromocytoma, while an MRI of the abdomen (HYPOGLYCEMIA). may show a mass in the adrenal glands. Thyroid If the diagnosis of myxedema coma is suspected, scans may show nodules, as may an ultrasound of the emergency room physicians will begin therapy the thyroid gland. Laboratory tests will show ele- before confirmatory laboratory results have been vations of urine catecholamines and urine returned. Therapy includes gentle warming, appro- metanephrine. Patients with MEN 2 also have ele- priate intravenous fluids (with attention to sodium, vated levels of calcitonin and serum calcium but glucose, and fluid volume), artificial ventilation if decreased levels of serum phosphorus. needed, and intravenous levothyroxine and/or tri- Patients with MEN 2 need surgery to remove iodothyronine. In addition, if an underlying or pre- the existing tumors and should be carefully fol- cipitating medical illness has not been identified, lowed up by their doctors. Thyroid tumors are the physician must still search for one and begin removed with a total excision of the thyroid gland, appropriate therapy. and patients must take thyroid replacement hor- The most common form of underlying hypothy- mone for the rest of their lives. The thyroid tumors roidism is primary hypothyroidism; the thyroid- found in MEN 2 are unusually aggressive, which is stimulating hormone (TSH) is elevated and the free why the entire gland must be removed to attempt T4 is low. If the TSH is normal or low, the physician to prevent any spreading of the cancer. must suspect secondary or tertiary hypothyroidism Brandi, Maria Luisa, et al. “Guidelines for Diagnosis and due to pituitary or hypothalamic disease. In these Therapy of MEN Type 1 and Type 2.” Journal of Clinical cases, patients must also be tested for CORTISOL defi- Endocrinology and Metabolism 86, no. 12 (2001): ciency (ADDISON’S DISEASE) and begun on therapy 5,658–5,671. with intravenous glucocorticoids until the testing determines that this hormone is not required. The term myxedema megacolon refers to the severe myxedema coma The metabolic syndrome of dilation that can occur in the colon, especially in the very severe HYPOTHYROIDISM with associated cecum, and that can mimic a mechanical bowel hypothermia (low body temperature) and other obstruction. It usually resolves slowly with the use associated organ system dysfunction or failure. It is of thyroid hormones, intravenous fluids and nutri- a rare syndrome with a significant mortality rate ents, and bowel rest (avoidance of solid and liquid (one out of three people die), although this rate has food). If the dilation in the cecum exceeds 15 cen- been declining over time due to better diagnosis timeters, surgery may be needed, although in many and supportive care. cases, the colon can be decompressed via a tube Patients typically have long-standing hypothy- placed under radiologic guidance. roidism and have stopped taking their thyroid hor- The term pretibial myxedema refers to a mone. Some patients have never been diagnosed brawny, nonpitting swelling of the ankles and with hypothyroidism and thus were never treated lower shins. It is nontender, brownish orange in for it. Myxedema coma is most common in elderly color, and may be plaque-like. It is only seen in women and has been seen in all types of hypothy- patients with GRAVES’ DISEASE. The name refers to roidism. The crisis can be precipitated by an illness the appearance of the skin under the microscope, 166 myxedema coma which is similar to what is seen in the skin of See also COMA; ELDERLY;HASHIMOTO’S THYROIDITIS. patients with severe hypothyroidism. N

National Institutes of Health (NIH) A large fed- Signs and Symptoms eral organization in the United States that oversees NF-1 patients have neurofibromas and café au lait such organizations as the National Center for spots (CALS). According to the National Institutes Health Statistics, the Centers for Disease Control of Health (NIH), in order to make the diagnosis of and Prevention (CDC), the National Institute of NF-1, the patient must have at least two of the fol- Diabetes and Digestive and Kidney Diseases lowing signs and symptoms: (NIDDK), the National Institute of Mental Health, and others. • Six or more CALS (greater than five millimeters For further information, contact the NIH at: in prepubertal individuals and greater than 14 millimeters in postpubertal individuals) National Institutes of Health • Two or more neurofibromas of any type or a 9000 Rockville Pike plexiform neurofibroma Bethesda, MD 20892 (301) 496-4357 • Axillary (underarm) or inguinal (pelvic) freckling • An optic glioma • Two or more hamartomas of the iris (Lisch nodules) neurofibromatosis type 1 (NF-1) A serious genetic disorder that is linked to chromosome 17 • A distinctive body lesion, such as sphenoid dys- and affects an estimated one in 3,000 individuals. plasia with or without pseudoarthrosis NF-1 is also known as von Recklinghausen’s NF, • A first-degree relative (parent or sibling) with and it accounts for 85 percent of all NF cases. It is NF-1 inherited in an autosomal dominant pattern. Those who inherit NF-1 are at risk for all possible compli- The café au lait spots present in NF-1 are hyper- cations of the disorder, but variable degrees of dis- pigmented skin lesions that usually appear after the ease are seen. patient is age one and that increase in size and NF-1 patients have about a 6 percent increased number during childhood. Some people without risk for developing optic gliomas and outer central NF-1 may also develop CALS, and one of every nervous system tumors. They are also at an four people without NF-1 will have one to three increased risk of noncentral nervous system CALS. These CALS fade as a person ages, making tumors, such as neurofibrosarcoma and PHEOCHRO- the diagnosis more difficult to make later in life. MOCYTOMA (a tumor of the adrenal gland). Patients with NF-1 also have an increased risk of A Multisystem Disease cognitive dysfunction, learning disabilities, Neurofibromatosis is a multisystem disease that seizures, MACROCEPHALY (a large head), and abnor- affects the endocrine glands, the skin, the central mal results on MAGNETIC RESONANCE IMAGING (MRI) nervous system, and the skeleton. Adults with scans of the brain. neurofibromatosis have an increased risk of devel-

167 168 neurofibromatosis type 1 oping tumors, and some experts have estimated For further information on neurofibromatosis, that about 10 percent of adults with this illness will contact the following organizations: develop pheochromocytomas. The presence of National Neurofibromatosis Foundation multiple café au lait spots along the anterior axil- 95 Pine Street lary line, located at the edge of the armpit, is asso- 16th Floor ciated with a greater risk of pheochromocytoma, New York, NY 10005 which means that these individuals should be (212) 344-6633 or (800) 323-7938 (toll-free) screened for the presence of pheochromocytomas. http://www.nf.org Most children and adults with neurofibromatosis do not require medical attention except for fol- Neurofibromatosis, Inc. low-ups for the development of abnormalities that 9320 Annaplis Road usually occur and for treatment of those medical Suite 300 problems. Lanham, MD 20706 (301) 918-4600 or (800) 942-6825 (toll-free) Children and NF-1 http://www.nfinc.org Children with NF-1 have an increased risk of short Carmi, Doron, M.D., et al. “Growth, Puberty, and stature. In one study of 569 children with NF-1, Endocrine Functions in Patients with Sporadic or 213 children were greater than two standard devi- Familial Neurofibromatosis Type 1: A Longitudinal ations shorter than normal, which means that they Study.” Pediatrics 103, no. 6 (June 1999): 1,257–1,262. were statistically far below the normal height for Crossen, Margon H., M.D., et al. “Endocrinologic their age. Scoliosis (a curved spine) occurs in about Disorders and Optic Pathway Gliomas in Children 15 percent of patients with NF-1. In one large study with Neurofibromatosis Type 1.” Pediatrics 100, no. 4 of children and young adults with neurofibromato- (October 1997): 667–670. sis type 1, about half (48 percent) of the 10-year- DeBella, Kimberly, Jacek Szudek, and Jan Marshall old patients had neurofibromas while 84 percent of Friedman, M.D. “Use of the National Institutes of the 20 year old adults had neurofibromas. Health Criteria for Diagnosis of Neurofibromatosis 1 in Children with EARLY PUBERTY (precocious puber- Children.” Pediatrics 105, no. 3 (March 2000): ty) are at risk for developing neurofibromatosis, 608–614. although some patients with neurofibromatosis Short, M. Priscilla, M.D. “Neurofibromatosis Type I,” in may have a DELAYED PUBERTY. NORD Guide to Rare Disorders: The National Organization Neurofibromatosis Type 2 for Rare Disorders. Philadelphia, Pa.: Lippincott Williams & Wilkins, 2003. There is also a neurofibromatosis type 2. It is charac- ———.“Neurofibromatosis Type 2,” in NORD Guide to terized by problems with hearing loss and balance— Rare Disorders: The National Organization for Rare and it may lead to tumors and palsies. The most Disorders. Philadelphia, Pa.: Lippincott Williams & common symptom of neurofibromatosis type 2 is Wilkins, 2003. hearing loss, which may be gradual or sudden. Szudek, J., P. Birch, and J. M. Friedman. “Growth in North Patients may also experience weakness in the arms American White Children with Neurofibromatosis I and legs caused by tumors in the brain stem or spinal (NF 1).” Journal of Medical Genetics 37, no. 12 (2000): cord. An estimated one in 37,000 individuals have 933–938. neurofibromatosis type 2. The treatment involves routine hearing tests to evaluate the patient as well as surgery for any tumors that are present. O obesity Excessive body weight. Obesity is usually late with a significantly increased risk of the devel- measured by body mass index (BMI), which is a opment of TYPE 2 DIABETES, high blood pressure, person’s weight in kilograms divided by his or her and coronary artery disease. height in meters squared, or the weight in pounds divided by height in inches multiplied by 703. Most Statistical Data on Obese Individuals people prefer to simply look up their BMI status in According to statistics provided by the National tables that incorporate these calculations, and indi- Center for Health Statistics in 2003, nearly 31 per- viduals need know only their height and weight to cent of all Americans are obese, including 34 per- find their BMI on the table. An optimal weight is a cent of women and 27.7 percent of men. African BMI between 21 and 24.9. A BMI of 25–29.9 con- Americans have the highest risk of becoming stitutes overweight, while obesity is defined as 30 obese, and 40.4 percent of all African Americans or greater. are obese, including 28.9 percent of the men and High BMIs correlate with a greater risk for ill- 50.4 percent of the women. Mexican-American nesses, such as diabetes, heart disease, and hyper- women also have a high percentage of obesity. tension. In addition, some studies have shown that In considering a state-by-state look at individu- obese individuals have a greater risk of dying from als who are obese, as reported in a 2003 issue of cancer, particularly colon cancer, esophageal can- Morbidity and Mortality Weekly Report (MMWR), cer, liver cancer, PANCREATIC CANCER, and kidney researchers have found that the largest percentage cancer. Some researchers maintain that obesity is of obese individuals in 2001 were in the following the second-leading cause of deaths that could have states or territories: Mississippi (27.1 percent), been avoided, after smoking. Michigan (25.8 percent), and the Virgin Islands Individuals who are at risk for INSULIN RESIST- (25.5 percent) (see Table 1). ANCE have the most urgency for resolving their Increasing numbers of individuals are also obesity in order to avoid the consequences of dia- severely obese, with a BMI of 40 or greater. Most betes, hypertension, and other serious illnesses. severely obese individuals weigh at least 100 Diet and exercise are both recommended. As of this pounds above the normal weight for their height. writing, a combination of pharmacotherapy and Obesity also has a high economic cost. counseling appears to be most efficacious for sus- According to a study published in a 2004 issue of tained weight loss, although many people struggle Obesity Research, the annual medical expenses with a lifelong tendency toward obesity. incurred as a result of obesity in the United States BMI is a better marker of obesity than are waist were $75 billion in 2003, and about half of these measurements or waist-to-hip ratio measurements. costs were borne by Medicare and Medicaid gov- Yet some organizations continue to rely upon obe- ernment programs. Furthermore, an estimated sity measurements other than BMI. The National 3–7 percent of all health costs are attributable to Cholesterol Education Program uses a waist meas- high weight and obesity, as described by Dr. urement of 40 inches or greater in men or 35 inch- George Bray in his 2003 article in Endocrinology and es or greater in women as a marker for metabolic Metabolism Clinics of North America. The direct costs syndrome. These waist measurements also corre- of obesity were calculated at about $52 billion in

169 170 obesity

1995, a figure that is probably greatly elevated in chromosome 18p11, a connection described in a 2004, as of this writing. 2001 issue of Diabetes. The number of severely obese adults has Scientists have begun studying genetic risks for increased dramatically in the United States. For the development of obesity in great depth. example, in a study reported in the Archives of According to authors Coleen Damcott, Paul Sack, Internal Medicine, researchers found that the num- and Alan Shuldiner in their 2003 article on the bers of people who were severely obese, with a genetics of obesity in Endocrinology and Metabolism BMI of 40 or greater, had quadrupled from 1986, Clinics of North America, “There is compelling evi- when about one in 200 adults in the United States dence from family, twin, and adoption studies sup- were severely obese, to one in 50 by the year 2000. porting an important genetic component to obesity. These and other studies estimated that genetics Abdominal Obesity Is Dangerous influences 40% to 75% of variation in BMI; how- A significant number of individuals who are obese ever, the genetics of obesity are not simple and carry much of their weight in the abdominal area. rarely follow Mendelian patterns.” Instead, say the Simply put, they are apple-shaped, with most of authors, mutations in several different genes may their weight apparent around their waist. In con- lead to obesity. For example, mutations in the trast, pear-shaped individuals carry their fat prima- genes coding for leptin and other substances have rily around their hips. Studies have shown that been demonstrated to cause obesity in humans. abdominal obesity raises the risk of the develop- Studies have linked markers, on a wide variety of chromosomes, to obese individuals as well as to ment of diseases such as DIABETES MELLITUS, hypertension, and coronary artery disease. mice. Future research may hold the key to determining which individuals are most genetically susceptible to obesity and may also lead to a method Causes of Obesity to manipulate these genes. Individuals become obese when the total calories Some of the obesity-related gene mutations that (energy) that they take in as food are significantly have been identified to date, according to the more, over an extended time, than the total calo- Centers for Disease Control and Prevention (CDC), ries they expend. Rarely, illnesses may increase the include the following: risk for obesity, such as PRADER-WILLI SYNDROME, which causes patients to have an uncontrollably • LEP (leptin) ravenous appetite. Contrary to popular belief, most • LEPR (leptin receptor) endocrine disorders, such as HYPOTHYROIDISM,do not cause obesity, although when such diseases are • POMC1 (pro-opiomelanocortin) resolved, the individual may lose a few pounds. • SIM1 (human homologue of drosophila single- Complex hormonal factors may be at work caus- minded 1) ing obesity, but they are yet to be discovered. As a • PC1 (prohormone convertase 1) result, the only way for most obese people to lose • MC4R (melanocortin-4 receptor) weight is to eat less and exercise more, as unsatis- fying as that solution may sound. Unfortunately, The presence of a genetic predisposition to obe- many people actively seek the one diet that sity does not mean that such individuals are some- “works,” as evidenced by the continued presence of how doomed to be fat. Genetic predispositions only diet books on best-selling book lists. indicate greater likelihood of an event occurring, and some individuals with obese parents will be of Genetic Causes of Obesity average weight themselves or even slender. In Evidence indicates that some individuals may have addition, it is currently nearly impossible for most a genetic predisposition to being overweight or even people to know if they carry a genetic mutation for to being obese. Researchers have found a genetic obesity since such tests are very expensive and link between both Type 2 diabetes and obesity on complex. obesity 171

People who are obese, with or without the pres- obesity causes depression or depression causes obe- ence of a genetic propensity, need to work with sity is not clear. However, resolving the obesity their doctor on a program of weight loss to reduce often does help alleviate depression. their weight as well as their health risks and thus In a study reported in a 2003 issue of the extend their lives. Archives of Internal Medicine, 487 subjects were observed. The researchers found that depression, as Medications measured by the Beck Depression Inventory (BDI), In some cases, medications for illnesses other than was more commonly found among patients who obesity may cause temporary or chronic increases were young, were female, and had a poor body in weight, although such increases do not usually image. The scores on the BDI improved significant- result in obesity. Some examples of medications ly with weight loss, particularly among women that may cause a significant weight gain include who were severely obese. This may mean that GLUCOCORTICOIDS, antidepressants, antipsychotic bariatric surgery, also known as gastric bypass sur- drugs, and lithium. Sometimes physicians can gery, may be indicated in some individuals who are change or reduce the dosage of the medications to severely obese, although physicians must take each reduce the weight gain. Other times patients need patient’s individual health risks into account. to exercise more frequently and pay close attention to limiting the number of calories they consume. Children and Obesity Many adolescents and younger children also have Television Watching a weight problem, and some are obese or even Some behaviors have been found to be linked with severely obese. The problem of overweight among obesity. For example, a study reported in a 2003 children has increased dramatically since issue of the Journal of the American Medical 1971–1974, when only about 4 percent of chil- Association found that prolonged television watch- dren ages 6–11 years old were obese. By ing was significantly linked to both a greater risk of 1999–2000, the percentage had increased to 15.3 obesity and the presence of Type 2 diabetes. The percent of the children in that age group (see study considered about 50,000 women in the Table 2). Part of the problem may be that children Nurses’ Health Study from 1992–98 who were not and adolescents take part in fewer physically obese when the study began. The study also con- demanding activities and spend more time watch- sidered about 68,000 women over the same period ing television than in past years. who did not have diabetes when the study began. Sometimes obesity in young adulthood can be The researchers also looked at other sedentary predicted based on parental obesity when children activities, such as reading, playing board games, were growing up. In a study reported in a 1997 sewing, driving a car, and so forth. They still found issue of the New England Journal of Medicine, that prolonged television watching resulted in a researchers observed 854 young adults, including lower metabolic rate and a higher risk of obesity 135 who were obese. The researchers studied the and diabetes than the other activities. The subjects’ childhood obesity and the obesity of their researchers said that their study suggested that 30 parents when the subjects were children, based on percent of the cases of patients with obesity and 43 medical records. Their findings state, “Parental obe- percent of the cases of patients with Type 2 dia- sity more than doubles the risk of adult obesity betes could be prevented if patients watched less among both obese and non-obese children under than 10 hours a week of television and walked 10 years of age.” Clearly, obese parents should have briskly for 30 minutes or more per day. two motivations for weight loss: their own health and the future health of their children. Depression and Obesity Severe obesity is often linked to depression, and Resolving Obesity researchers have found that a significant weight Researchers fervently disagree about what diets are loss can improve the depression problem. Whether the safest and best for most people as well as what 172 obesity

TABLE 1: PREVALENCE OF OBESITY* IN ADULTS ≥ AGED 20 YEARS, 1991, 2000, AND 2001 AND BY SEX, 2001— UNITED STATES, BEHAVIORAL RISK FACTOR SURVEILLANCE SYSTEM

Both sexes Men Women (%) 2001 2000 1991Difference 2001 2001

State or Territory % 95% CI* (±) % 95% CI (±) % 95% CI (±)1991–2001 % 95% CI (±) % 95% CI (±) Alabama 24.9 2.0 24.5 2.2 14.4 1.9 72.8 24.9 2. 24.9 2.4 Alaska 22.9 2.2 21.5 2.5 13.6 2.6 68.3 20.0 3. 26.3 3.3 Arizona 19.3 2.0 20.1 3.1 11.8 1.9 63.7 20.5 3. 18.0 2.5 Arkansas 23.0 1.8 23.7 1.8 13.5 2.2 70.1 23.5 2. 22.6 2.2 California 22.6 1.6 20.5 1.6 10.8 1.3 109.1 21.5 2. 23.7 2.4 Colorado 15.5 1.8 14.4 1.8 8.9 1.5 75.1 15.8 2. 15.1 2.4 Connecticut 18.2 1.2 17.9 1.4 11.4 1.7 59.8 19.1 1. 17.3 1.4 Delaware 21.4 1.8 17.2 1.8 15.7 2.2 36.4 21.6 2. 21.1 2.4 District of Columbia 20.2 2.4 21.9 2.4 16.2 2.4 24.9 16.3 3. 23.8 3.1 Florida 19.2 1.4 18.9 1.4 10.6 1.5 80.6 19.3 2. 19.2 1.8 Georgia 23.1 1.6 21.9 1.6 9.8 1.5 136.0 22.4 2. 23.8 2.0 Hawaii 18.3 1.8 16.0 1.4 10.5 1.6 74.1 19.9 2. 16.7 2.2 Idaho 21.0 1.4 19.5 1.4 12.3 1.7 71.1 21.9 2. 20.2 1.8 Illinois 21.7 1.6 22.2 1.6 13.6 1.7 59.9 20.8 2. 22.6 2.0 Indiana 25.1 1.6 22.2 1.8 15.7 1.7 59.6 25.5 2. 24.8 2.0 Iowa 23.4 1.6 22.0 1.6 15.0 2.1 55.7 24.7 2. 22.0 2.2 Kansas 22.2 1.4 21.3 1.4 — — — 23.9 2. 20.5 1.8 Kentucky 24.8 1.6 23.5 1.6 13.7 1.8 81.0 26.1 2. 23.6 1.8 Louisiana 25.0 1.4 24.2 1.4 16.5 2.4 51.9 25.6 2. 24.4 1.8 Maine 20.0 1.8 20.7 2.0 12.8 2.3 56.5 20.7 2. 19.3 2.4 Maryland 20.4 1.6 20.8 1.6 11.9 1.9 71.6 19.8 2. 21.0 2.2 Massachusetts 17.1 1.0 16.9 1.0 9.3 1.7 83.9 18.1 1. 16.1 1.2 Michigan 25.8 1.6 23.0 2.0 16.3 1.7 58.2 26.2 2. 25.5 2.0 Minnesota 20.4 1.4 17.8 1.6 11.3 1.2 80.1 21.0 2. 19.7 2.0 Mississippi 27.1 2.0 25.3 2.2 16.2 2.2 67.1 26.1 2. 28.0 2.4 Missouri 23.8 1.8 22.5 1.8 12.6 1.8 88.6 25.8 2. 21.8 2.2 Montana 19.2 1.8 16.4 1.8 10.1 1.9 89.7 20.3 2. 18.2 2.4 Nebraska 21.2 1.6 21.4 1.8 13.8 2.1 53.5 22.8 2. 19.6 2.0 Nevada 19.9 2.7 18.3 2.5 — — — 22.7 4. 16.8 3.1 New Hampshire 19.9 1.4 18.5 2.2 10.9 1.8 83.2 21.9 2. 17.9 1.8 New Jersey 20.0 1.4 19.0 1.6 10.4 1.8 91.9 19.7 2. 20.3 2.0 New Mexico 20.3 1.6 19.6 1.6 8.5 1.9 140.2 21.5 2. 19.1 2.0 New York 20.8 1.6 17.9 1.6 13.8 1.8 51.2 21.2 2. 20.5 2.2 North Carolina 23.1 1.8 22.0 1.8 13.9 1.9 66.1 22.8 2. 23.3 2.2 North Dakota 20.6 1.8 20.9 2.2 13.7 1.8 50.5 22.0 2. 19.2 2.4 Ohio 22.8 1.8 22.1 2.2 16.2 2.4 40.7 23.2 2. 22.4 2.2 Oklahoma 23.2 1.6 19.9 1.6 12.5 1.8 86.3 25.2 2. 21.1 2.0 Oregon 21.6 1.8 22.0 1.6 12.0 1.2 80.8 20.1 2. 23.0 2.5 Pennsylvania 22.6 1.6 21.7 1.6 15.1 1.6 49.8 22.2 2. 23.0 2.2 Rhode Island 18.1 1.6 17.5 1.4 10.2 1.6 78.1 18.2 2. 18.0 2.0 South Carolina 23.0 1.8 22.7 1.8 14.5 1.9 58.7 23.4 2. 22.7 2.4 South Dakota 21.6 1.4 20.3 1.4 13.1 1.8 64.4 24.1 2. 19.0 1.6 Tennessee 24.2 2.0 23.1 1.8 13.2 1.5 83.9 25.2 3. 23.3 2.2 Texas 25.2 1.4 23.5 1.4 13.0 2.0 93.3 25.5 2. 24.9 1.8 Utah 19.9 1.8 19.7 2.0 10.5 1.6 88.8 20.7 2. 19.0 2.4 Vermont 18.1 1.4 18.4 1.4 10.7 1.7 69.3 19.2 2. 17.0 1.6 Virginia 21.4 1.8 18.7 2.0 10.7 1.7 100.6 22.2 2. 20.6 2.4 Washington 19.9 1.4 19.1 1.6 11.0 1.5 81.6 21.4 2. 18.4 1.8 West Virginia 25.3 1.8 23.7 2.0 15.6 1.7 61.8 25.6 2. 25.0 2.4 Wisconsin 22.7 1.8 20.3 1.8 13.1 2.0 73.9 22.9 2. 22.5 2.2 Wyoming 19.9 1.6 18.4 1.8 — — — 20.6 2. 19.3 2.2 Guam 21.9 3.3 — — — — — 21.2 4. 22.8 4.5 Puerto Rico 22.9 1.8 22.8 1.8 — — — 23.9 2. 22.0 2.2 Virgin Islands 25.5 2.4 — — — — — 20.7 3. 29.5 3.1 obesity 173

Summary

Both sexes Men Women

2001 2000 1991 2001 2001 No. of states/territories 54 52 48 54 54 Median 21.6 20.8 12.9 21.9 21.1 Range 15.5–27.1 14.4–25.3 8.5–16.5 15.8–26.2 15. 1–29.5 Mean 21.7 20.5 12.7 22.1 21.3 * Obesity is defined as having a body mass index > 30.0 and < 99.8 kg/m2. Source: “State-Specific Prevalence of Selected Chronic Disease-Related Characteristics—Behavioral Risk Factor Surveillance System, 2001.” Morbidity and Mortality Weekly Report 2, no. SS-8 (August 22, 2003), 19.

TABLE 2: OVERWEIGHT AND OBESITY BY AGE, UNITED STATES: 1960–2000

Children, 6–11 Years Adolescents, 12–19 Years Adults, 20–74 Years

Overweight Overweight Obese

Year Percent Percent Percent Percent 1960–62 —* — 44.8 13.3 1963–65 4.2 — — — 1966–70 — 4.6 — — 1971–74 4.0 6.1 47.7 14.6 1976–80 6.5 5.0 47.4 15.1 1988–94 11.3 10.5 56.0 23.3 1999–2000 15.3 15.5 64.5 30.9 * — Data not available. Source: V. M. Fried, et al. Chartbook on Trends in the Health of Americans. Health, United States, 2003. Hyattsville, Md.: National Center for Health Statistics, 2003. physical activities are best. As of this writing, the Behavioral therapy can be helpful and may lead public is currently enamored of the concept that to about a 8–10 percent weight loss in one year. changes in the ratios of fats, carbohydrates, and When added to low calorie diets or medications, it proteins in the diet will lead to more rapid, effec- will enhance weight loss. Unfortunately, most of tive, or permanent weight loss. Unfortunately, these losses are maintained for only six to 12 there is no data to demonstrate that this is true. months. To date, few people have been able to Two studies have shown that over six months, a show good maintenance of weight loss over a diet high in fat was slightly more effective than a three- to five-year period. balanced diet. However, after 12 months, there was Some physicians prescribe diet pills (anorectic no difference in weight loss. The group on the agents, or drugs to increase satiety or the feeling of high-fat diet also had a 40 percent dropout rate, fullness) to obese individuals. Pharmaceutical com- which is to say, 40 percent of the subjects were panies are actively testing many formulations in unable to adhere to the diet over a long term. the hopes of developing a safe and effective Most researchers agree, however, that people who antiobesity drug. As of this writing, the most com- wish to lose weight should eat less and exercise monly used drugs are phentermine (Adipex-P, more, particularly walking more frequently. Despite Ionamin) and sibutramine (Meridia). These drugs following such advice, many obese people find losing are adjunctive to proper nutrition and exercise. weight to be extremely difficult, which may be due to Phentermine will increase noradrenaline in the a combination of a genetic predisposition to obesity hypothalamus and decrease appetite. It can increase as well as hormones, such as GHRELIN, that actively blood pressure slightly, disrupt sleep, and increase work to keep an individual at a given weight. nervousness and tremulousness. Sibutramine 174 oral contraceptives increases the concentrations of noradrenaline, Hu, Frank B., M.D. “Television Watching and Other serotonin, and dopamine in the hypothalamus, Sedentary Behaviors in Relation to Risk of Obesity where there are nerves that increase satiety. This and Type 2 Diabetes Mellitus in Women.” Journal of drug can raise blood pressure slightly and cause the American Medical Association 289, no. 14 (April 9, palpitations, dry mouth, and headache. 2003): 1,785–1,791. The antiseizure drug topiramate (Topamax) has Mokdad, Ali H., et al. “Prevalence of Obesity, Diabetes, been shown to be effective at helping some indi- and Obesity-Related Health Risk Factors, 2001.” viduals lose weight. One trial, using 96–256 mil- Journal of the American Medical Association 289, no. 1 ligrams of topiramate in 1,289 patients, including (January 1, 2003): 76–79. 290 patients with BMIs greater than 35, led to Reaven, Gerald M., M.D. “Importance of Identifying the weight losses of 8–13 percent of total body weight. Overweight Patient Who Will Benefit the Most by In a second study, doses of 96–192 milligrams per Losing Weight.” Annals of Internal Medicine 138, no. 5 day led to a 5–6 kilogram weight loss as well as (2003): 420–423. lower systolic and diastolic blood pressure and Samaha, Frederick F., M.D., et al. “A Low-Carbohydrate improvement in fat distribution. Common adverse as Compared with a Low-Fat Diet in Severe Obesity.” effects include paresthesias (pins and needles), dry New England Journal of Medicine 348, no. 21 (May 22, mouth, fatigue, and impaired concentration. 2003): 2,074–2,081. Sturm, Roland. “Increases in Clinically Severe Obesity in Surgery the United States, 1986–2000.” Archives in Internal Medicine 163, no. 18 (October 13, 2003): 2,146–2,148. In extreme cases of obesity, physicians may recom- Thearle, Marie, M.D., and Aronne, Louis J., M.D. mend gastric bypass surgery. “Obesity and Pharmacologic Therapy.” Endocrinology See also BLOOD PRESSURE/HYPERTENSION; EATING and Metabolism Clinics of North America 32, no. 4 (2003): DISORDERS; GASTRIC SURGERY FOR WEIGHT LOSS. 1,005–1,024. Bray, George, A., M.D. “Risks of Obesity.” Endocrinology Whitaker, Robert C., M.D., et al. “Predicting Obesity in and Metabolism Clinics of North America 32, no. 4 (2003): Young Adulthood from Childhood and Parental 787–804. Obesity.” New England Journal of Medicine 337, no. 13 Calle, Eugenia E., et al. “Overweight, Obesity and (September 25, 1997): 869–873. Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults.” New England Journal of Medicine 348, no. 17 (April 24, 2003): 1,625–1,638. oral contraceptives Prescribed pills with female Damcott, Coleen M., Paul Sack, M.D., and Alan R. hormones that are taken by women on a regular Shuldiner, M.D. “The Genetics of Obesity.” basis in order to prevent a pregnancy from occur- Endocrinology and Metabolism Clinics of North America 32, ring. Also known as birth control pills or “the Pill.” no. 4 (2003): 761–786. The first clinical trials of birth control pills occurred Dixon, John B., Maureen E. Dixon, and Paul E. O’Brien, in the 1950s. Oral contraceptives contain estrogen M.D. “Depression in Association with Severe Obesity.” and progestin, with the exception of the minipill, Archives of Internal Medicine 163, no. 17 (September 22, which is a low dose of estrogen only. There are also 2003): 2,058–2,065. subdermal forms of contraceptives that physicians Faroq, I. Sadaf, M.D., et al. “Clinical Spectrum of Obesity can surgically insert under the patient’s skin, usual- and Mutations in the Melanocortin 4 Receptor Gene.” ly in the arm, for continuous action for about five New England Journal of Medicine 348, no. 12 (March 20, years. Currently, progestin levonorgestrel (Norplant) 2003): 1,085–1,095. is the subdermal contraceptive used in the United Finkelstein, Eric A., Ian C. Fiebelkorn, and Guijing Wang. States. “State-Level Estimates of Annual Medical Sometimes oral contraceptives are prescribed for Expenditures Attributable to Obesity.” Obesity Research other purposes as well, such as to control HIRSUTISM 12 (2004): 18–24. (extreme hairiness in women). Some women also oral glucose tolerance test 175 take the drugs to improve difficult menstrual peri- on the rights of minors to have contraceptives with- ods or to control the symptoms of POLYCYSTIC OVARY out their parents’ permission or awareness. SYNDROME. In one study, reported in a 2002 issue of The antiprogestin mifepristone, also known as Contraception, researchers reported that about 25 RU486 or the morning after pill, is not technically percent of women of all reproductive ages in the an oral contraceptive because it does not prevent a United States rely upon birth control bills to pre- pregnancy. Instead, it terminates a pregnancy that vent pregnancy. has already occurred, although the woman taking Most types of birth control pills fool the the drug would not know whether she was actual- woman’s body into thinking that she is already ly pregnant because it would be too soon for a pregnant by blocking the luteinizing hormone pregnancy test to be valid. surge that comes before ovulation. Thus an egg Davidson, Nancy E., M.D., and Kathy J. Helzlsouer, M.D. that could create a pregnancy is not released. (The “Good News About Oral Contraceptives.” New England minipill, an exception, does not work this way.) Journal of Medicine 346, no. 26 (June 27, 2002): Oral contraceptives are highly effective when 2,078–2,079. used properly. However, some drugs, such as Lidegaard O., B. Edstrom, and S. Kreiner. “Oral some antibiotics, can counteract the birth control Contraceptives and Venous Thromboembolism: A effect. Thus women taking antibiotics should use Five-Year National Case-Control Study.” Contraception alternative methods of birth control to avoid a 65, no. 3 (March 2002): 187–196. pregnancy. Marks, Lara V. Sexual Chemistry: A History of the Adverse Events Associated with Birth Control Pills Contraceptive Pill. New Haven, Conn.: Yale University Press, 2001. Before birth control pills are prescribed, doctors take a complete medical history to ensure that they are likely to be safe for the patient. Women who are at risk for stroke or heart attack should use oral glucose tolerance test (OGTT) A diagnostic alternative means of contraception. Women with test for DIABETES MELLITUS, either TYPE 1 DIABETES or well-controlled diabetes can usually take oral con- TYPE 2 DIABETES. traceptives if they are otherwise healthy. Female After fasting for eight to 14 hours, the patient’s smokers should avoid birth control pills because of blood is drawn and plasma glucose levels are the increased risk for heart attack. measured. Blood levels are taken again about one Past studies have indicated that women who and two hours later after the individual has ingest- take oral contraceptives may have an increased risk ed 75 g of glucose that is provided. Normal fasting for developing breast cancer. However, the results plasma glucose is defined as less than 100 mg/dl, from the Women’s Contraception and Reproductive and 100–125 mg/dl is categorized as impaired fast- Experiences (CARE) study, released in 2002, found ing glucose, while greater than or equal to 126 no association between the past or current use of mg/dl is indicative of diabetes. A one-hour level oral contraceptives and breast cancer among the that is less than 140 mg/dl is normal, and higher 4,575 female subjects who had developed breast levels are consistent with impaired glucose toler- cancer and the 4,682 controls. The women were ance or diabetes. Two-hour glucose levels less than ages 35–64 years, a group at a high risk of develop- 140 mg/dl are normal. Levels of 140–199 mg/dl ing breast cancer. are consistent with impaired glucose tolerance, and greater than 200 mg/dl is consistent with the Controversial Issues diagnosis of diabetes. Controversies surround birth control pills, such as An alternative test to the OGTT is the fasting whether they should be give to minor children and, plasma glucose (FPG) test. The AMERICAN DIABETES if so, under what conditions, such as without their ASSOCIATION recommends the FPG test over the parents’ knowledge and consent. State laws differ OGTT because it is easier, faster, and also less 176 orthostatic hypotension expensive than the OGTT. However, most other orthostatic hypotension An abnormal decrease institutions tend to disagree. More frequently, the in blood pressure that occurs when a person moves OGTT is used to determine whether a patient has from the lying to the seated or standing position. euglycemia (normal glucose levels), impaired glucose Typically, orthostatic hypotension is defined as a tolerance (PREDIABETES), or overt diabetes mellitus. drop in blood pressure by greater than 20/10 mm The percentage of patients with impaired glu- Hg. Any cause of hypotension in general can cause cose tolerance increases with age and obesity. One orthostatic hypotension. Endocrine causes of large study in the United States, the National orthostatic hypotension include autonomic neu- Health and Nutrition Examination Survey II ropathy due to DIABETES MELLITUS, pituitary failure, (NHANES II), estimated that 11 percent of patients HYPOTHYROIDISM, and ADDISON’S DISEASE. aged 20–74 years have impaired glucose tolerance If the cause is autonomic neuropathy, the treat- and 6 percent have Type 2 diabetes. ment is multifaceted. Usually the patient is allowed Results of the OGTT may be helpful in large pop- to ingest large amounts of salt, while medications ulations to predict cardiovascular risk. In a study of that may exacerbate the condition are adjusted or 25,000 patients followed for seven years, discontinued. Compressive stockings are prescribed researchers demonstrated that the value of the to patients to help push more blood from the legs two-hour glucose correlated with cardiovascular back into the abdomen and chest cavity. If this fails, mortality risk, while the fasting glucose level did medications are added. not provide this predictive information. This was As of this writing, the only drug formally also demonstrated in two large epidemiological approved by the Food and Drug Administration studies: and the Framingham study Diabetes (FDA) for orthostatic hypotension is midodrine Epidemiology: Collaborative Analysis of Diagnostic (Proamatine), which is an alpha receptor agonist. It Criteria in Europe (DECODE). is usually administered three times per day in The OGTT is also used for the diagnosis of gesta- divided doses. The major worrisome side effect is tional diabetes (diabetes that occurs due to preg- supine hypertension, which is blood pressure that nancy). First, a 50 g one-hour test is used as a is excessively high when the patient is lying down. screen. If the one-hour level is greater than or equal Sometimes the endocrinologist must accept to 140 mg/dl, the two-hour test is then done to con- some supine hypertension in order to allow the firm the initial results. The diagnosis of gestational standing blood pressure to be enough for the diabetes is made if a pregnant woman’s glucose patient to stand without being light-headed or level exceeds any two of the following three levels: fainting. Often the mineralocorticoid drug fludrocortisone (Florinef) is given. Initially, it helps the • Fasting glucose greater than 95 mg/dl patient to retain some salt and water. Chronically, • One-hour glucose level greater than 180 mg/dl though, it causes vasoconstriction, which is contraction of the smooth muscles in the blood vessels • Two-hour level greater than 155 mg/dl in the lower extremities, and forces more blood toward the chest cavity, raising blood pressure. In the past, a three-hour test was used. See also BLOOD PRESSURE/HYPERTENSION; Although they use different criteria for diagnosis, HYPOTENSION. both the American Diabetes Association and the World Health Organization now employ the two- hour test. osteoblasts Cells within the body that are respon- See also INSULIN RESISTANCE SYNDROME. sible for the creation of new bone. Osteoblasts work The DECODE Study Group on behalf of the European in concert with OSTEOCLASTS (which break down Diabetes Epidemiology Group, “Glucose Tolerance bone), and this mutual work leads to bone remodel- and Mortality: Comparison of WHO and American ing. Some buildup and teardown of bone is normal Diabetes Association Diagnostic Criteria.” Lancet 354, and healthy. When the processes go awry and there no. 9,179 (August 21, 1999): 617–621. is either too much bone (as with osteopetrosis) or not osteogenesis imperfecta 177 enough bone (such as with OSTEOPENIA/OSTEOPORO- an empty stomach because it is very poorly SIS), patients experience medical problems. absorbed when taken with any food or liquid Osteoblasts appear to derive from so-called mes- except water). enchymal stem cells, which may also develop into 3. Whether the medication is working adequately muscle, fat, and cartilage cells, depending on how to decrease the activity of osteoclasts in the they are stimulated. patient’s skeleton. This decrease in osteoclastic Osteoblasts help to synthesize new collagen and activity decreases bone loss and is coupled to other proteins that can later be calcified. Some of osteoblastic activity that leads to bone remod- the osteoblasts remain behind in the new bone and eling and the formation of new bones. are called osteocytes. They may be needed by the body in the future for further bone remodeling. Although osteoporosis causes increased osteo- These cells can be affected by many hormones clastic activity, this increased activity also can be and other cells, including parathyroid hormone, detected in cases of HYPERPARATHYROIDISM and vitamin D (calcitriol), thyroid hormones, growth PAGET’S DISEASE. In contrast, osteoclast activity is hormone, insulin-like growth factor, TESTOSTERONE, unusually low in a rare condition called osteopet- and estrogen. TERIPARATIDE (Forteo), a recombinant rosis. parathyroid drug, is the only medication approved Osteoclasts actually come from blood cells called by the Food and Drug Administration (FDA), as of monocytes and can be synthesized in the bone this writing, that will directly stimulate osteoblastic marrow and the spleen before traveling to the bone activity and subsequently lead to the formation of itself. They can also be affected by parathyroid hor- new bone. Osteoblastic activity can also be moni- mone, prostaglandins, vitamin D (calcitriol), and tored by measurements of a simple blood test called steroids. the bone specific alkaline phosphatase (BSAP). Osteoclasts live only about three to four weeks See also ESTROGEN; VITAMIN D. before they undergo apoptosis, which is genetically preprogrammed cell death. Estrogens may exert some of their beneficial effects on bone by inducing osteoclasts Cells in the bone that are responsible this apoptosis earlier in the life of these cells, thus giv- for bone breakdown. In concert with OSTEOBLASTS ing them a shorter time to cause bone breakdown. (which build up bone), osteoclasts control bone See also ESTROGEN. turnover and remodeling. BISPHOSPHONATES, such as alendronate and risedronate directly affect osteoclasts, decreasing their activity. Thus, these osteogenesis imperfecta (OI) A group of four drugs are used by physicians to counter the hereditary diseases (type I through type IV), pri- destruction of bone caused by diseases such as marily found in infants and small children (and OSTEOPOROSIS or osteopenia. occasionally, in adolescents and adults), which Physicians can monitor the activity of osteoclasts causes patients to have very fragile bones that are using simple urinary tests. These tests measure the prone to developing deformities and fractures. Type amounts of protein fragments in the urine called II is the most severe form of the disorder. Most N-telopeptides (NTX) and deoxypyridinolinium patients with this form will die while still in infan- cross-links (DpD). Endocrinologists will often cy. Type I, the most common form of OI, is also the measure the activity of osteoclasts for three to six mildest. Osteogenesis imperfecta is also known as months after starting a patient on bisphosphonates brittle bone disease or osteopsathyrosis. to determine three things: An estimated one in 10,000 people in the world and one in 20,000 children born in the United 1. Whether the patient is actually taking the States have osteogenesis imperfecta. According to medication. the National Institutes of Health Osteoporosis and 2. Whether the patient is taking the medicine Related Bone Diseases National Resource Center, properly (the medication should be taken on about 20,000–50,000 people in the United States 178 osteogenesis imperfecta have OI. As a result, it qualifies as an orphan dis- Women especially may see a rapid progression of the ease, or a disease with less than 200,000 cases, and, condition after pregnancy and breast-feeding. The thus, one that is less likely for pharmaceutical and hypermobility of the hands, wrists, and feet may other research resources to be expended upon the require orthopedic surgical intervention. disease, because so few individuals suffer from the problem in comparison to other diseases. Diagnosis and Treatment Some parents of children with osteogenesis Physicians may suspect OI based on frequent frac- imperfecta have been unfairly charged with child tures. If parents know or suspect that a child has abuse and neglect due to the seemingly abnormal OI, they should advise the child’s doctor. This way, frequency of broken bones that can occur in affect- the child can be tested and evaluated, and the doc- ed children. Furthering this problem is the fact that tor will not mistakenly report the family for possi- abused children and children with OI actually ble child abuse. share some common traits, such as fractures of the Physicians may also test for OI if other family ribs, fractures at various stages of healing, and frac- members have been diagnosed with the condition. tures that cannot be explained. There is no cure for OI. Fractures should be treated In most cases (about 75 percent), osteogenesis quickly, and patients may need mobility aids, such imperfecta is caused by a mutation in the COL1A1 as braces, wheelchairs, and other devices, particu- or COL1A2 genes, which are genes that create pro- larly when OI is severe. Many physicians recom- teins needed to create collagen. However, over 200 mend swimming as a good source of exercise for different gene mutations have been associated with patients with OI. If patients can walk, walking is OI and OI-like syndromes. Collagen is an impor- another good exercise. Physical therapy may also tant substance in the connective tissues, especially help some patients. in the bones. It is first synthesized as osteoid, before Some clinical studies are examining the use of it calcifies to make mature, healthy bone. pamidronate for individuals with OI. Bone marrow transplants are being investigated for use in chil- Signs and Symptoms dren who have severe osteogenesis imperfecta. In a study reported in a 2000 issue of the Journal Individuals with all forms of osteogenesis imperfec- of Clinical Endocrinology & Metabolism, researchers in ta experience, at a minimum, osteopenia, which is Canada investigated the effects of pamidronate a lesser form of bone loss than osteoporosis. As a treatment on severely ill children younger than age result, they also often suffer from numerous bone three. The study size was very small (nine subjects) fractures due to their fragile bones. They may also because few children have severe OI. According to experience easy bruising. Many have a short the researchers, “Pamidronate treatment in severe- stature. Some patients have brittle opalescent teeth ly affected OI patients under 3 yrs. of age is safe, that wear very quickly (dentinogenesis imperfec- increases BMD [bone mineral density], and ta), hearing loss (which may require a cochlear decreases fracture rate.” implant), curvature of the spine (scoliosis), loose See also BONE DISEASES; FRACTURES; OSTEOMALA- joints, and a bluish or grayish tint to the part of the CIA; OSTEOPENIA; OSTEOPOROSIS. eye that is normally white (the sclera). For further information, contact the following Adults with type I OI have premature osteo- organizations: porosis or accelerated osteoporosis after the loss of estrogen secretion at menopause. Some children National Institutes of Health will require wheelchairs and may develop hearing Osteoporosis and Related Bone Diseases—National loss due to defects in the middle ear bones that Resource Center conduct sound waves. 2 AMS Circle Children with short stature may be treated with Bethesda, MD 20892 recombinant growth hormone. Adults with type I OI (202) 223-0344 or (800) 624-BONE (toll-free) present at an earlier age than those with other types. http://www.osteo.org osteomalacia 179

Osteogenesis Imperfecta Foundation usually a bisphosphonate such as alendronate 804 West Diamond Avenue (Fosamax) or risedronate (Actonel). Suite 210 Rarely, osteomalacia is caused by a tumor (onco- Gaithersburg, MD 20878 genic osteomalacia), which is often benign. Removal (301) 947-0083 of the tumor usually resolves the problem. Serum http://www.oif.org phosphorus levels will return to normal, sometimes within hours or days after the surgery is performed. Clark, Robin E., and Judith Freeman Clark with Christine Some experts believe that these tumors secrete an Adamec. The Encyclopedia of Child Abuse, 2d ed. New as-yet undiscovered hormone that causes the loss of York: Facts On File, Inc., 2001. excessive phosphorus in the urine. However, the Plotkin, Horacio, et al. “Pamidronate Treatment of Severe skeletal changes may take months to improve. Osteogenesis Imperfecta in Children Under 3 Years of The tumors that cause oncogenic osteomalacia Age.” Journal of Clinical Endocrinology & Metabolism 85, may be small and hard for physicians to identify. no. 5 (2000): 1,846–1,850. Thus, these patients may live for years with weakness, bone pain, and/or fractures. Blood tests typi- osteomalacia The bone disorder usually charac- cally show low phosphorus levels. When a tumor terized by inadequate mineralization of newly cannot be found, some of these patients improve formed bone (the osteoid). In children in whom with phosphorus and vitamin D supplementation. the growth plates at the ends of the bones (epiphy- In general, the tumors are more likely to occur in ses) have not sealed, it is called rickets. On bone the head and neck and can be sought through X-rays, the radiologist cannot differentiate between COMPUTERIZED TOMOGRAPHY (CT) or MAGNETIC RESO- OSTEOPOROSIS and osteomalacia since both appear NANCE IMAGING (MRI) scans. as decreased mineralization of bone. Hypophosphatasia is a rare form of osteomalacia that can present in childhood or in a milder form in Types and Causes of Osteomalacia adults. Adults may have recurrent stress fractures, Osteomalacia may be due to an inherited defect hip pain, or pseudofractures (abnormalities seen on (X-linked hypophosphatemic rickets or vitamin X-ray that appear to be fractures). These patients D-resistant rickets). It may also be acquired, typi- also have low alkaline phosphatase levels, with cally due to a vitamin or mineral deficiency. normal or high levels of phosphorus and calcium. The most common form of osteomalacia is There is no known medical therapy for hypophos- caused by calcium and/or vitamin D deficiency. phatasia as of this writing. This can be due to malnutrition, failure to absorb nutrients (as in chronic pancreatitis, inflammatory Signs and Symptoms bowel disease), or to medications (GLUCOCORTI- Patients with osteomalacia have an increased COIDS, BISPHOSPHONATES, anticonvulsants, alu- risk for experiencing bone fractures. In addition to minum-containing antacids, and cholestyramine showing an increased risk for fracture, patients (Questran)). with osteomalacia often have proximal muscle In institutionalized adults, significant vitamin D weakness (shoulder and hip muscles). This weak- deficiency may occur in as many as 50 percent of ness makes walking up stairs or lifting objects over those tested. These patients, as well as the home- the head more difficult. It also causes muscle aches dwelling elderly and any patients with chronic ill- and pains, tender shins and wrists, and at times, nesses, may not obtain adequate sunlight, thus neuropathy (problems with the nervous system). leading to the deficiency. Osteomalacia can also be induced by medica- Diagnosis and Treatment tion given to treat PAGET’S DISEASE when it is When osteomalacia is suspected, an appropriate administered for excessively long periods of time evaluation would include measurement of blood or in excessive doses. The medication prescribed is calcium, phosphorus, alkaline phosphorus, and 180 osteopenia kidney and liver tests. In addition, parathyroid hor- osteoporosis Severe degenerative bone loss. mone is often measured, as patients with osteoma- Osteoporosis is a common problem among older lacia often have secondary hyperparathyroidism, individuals, particularly females, although some with low-normal or frankly low blood calcium lev- older men are also at risk for this medical problem. els and elevated parathyroid hormone levels. This At least 20 million women and men in the United increased parathyroid hormone acts at the bone to States have osteoporosis. In addition, the National remove calcium, exacerbating the loss of bone Osteoporosis Foundation estimates that 44 million strength, but also to maintain the blood calcium people (including 30 million women) are estimat- level as close to normal as possible. ed to have low bone mass. A 24-hour urine measurement for calcium (the When osteoporosis occurs due to aging, it is called best biological marker for calcium absorption) will primary osteoporosis. However, when medical condi- confirm the diagnosis if it is low. The normal range tions are contributing to osteoporosis, it is called sec- is two to four mg of calcium/kg body weight. ondary osteoporosis. Some of the secondary causes See also FRACTURES; OSTEOGENESESIS IMPERFECTA; include endocrine disorders such as HYPERPARATHY- OSTEOPENIA; VITAMIN D RESISTANCE. ROIDISM,CUSHING’S SYNDROME, DIABETES MELLITUS, VITAMIN D DEFICIENCY, and HYPERTHYROIDISM. Some Carpenter, Thomas O., M.D. “Oncogenic Osteomalacia— genetic disorders, like MARFAN’S SYNDROME, TURNER A Complex Dance of Factors.” New England Journal of SYNDROME and KLINEFELTER SYNDROME, can also lead Medicine 348, no. 17 (April 24, 2003): 1,705–1,708. to the development of osteoporosis. Certain digestive Dwivedi, Rohit, M.D., and Michael J. Econs, M.D. “X- diseases, such as inflammatory bowel disease, celiac Linked Hypophosphatemic Rickets,” in NORD Guide to diseases, and primary biliary cirrhosis, can also cause Rare Disorders: The National Organization for Rare osteoporosis due to decreased absorption of calcium Disorders. Philadelphia, Pa.: Lippincott Williams & and vitamin D. Wilkins, 2003. Other secondary causes of osteoporosis include the use of a variety of drugs, including glucocorticoids, antiseizure medications such as diphenylhy- osteopenia The term that defines bone mass that dantoin (Dilantin) and medications such as is less than normal but not low enough to meet the cyclosporine (Neoral, Sandimmune), and excessive definition for OSTEOPOROSIS. Technically, osteopenia doses of levothyroxine (Synthroid, Levoxyl). In is defined as a T-score of 1.0 to 2.49 standard devi- addition, significant liver and kidney disease as ations below the peak bone mass that is seen in 25- well as a variety of malignancies can also lead to to 30-year-old patients. Osteopenia is also the cor- osteoporosis. rect term for physicians to apply when looking at traditional X-rays: if the bones look thin, they are Risk Factors termed osteopenic. The bone density on the X-ray Small-boned and elderly (age 65 and older) could be low enough to be consistent with osteo- Caucasian women whose ancestors came from porosis, but the appearance of thin bones could western Europe have the greatest risk of develop- also be due to OSTEOMALACIA or even a problem ing osteoporosis, although any woman (or any with the X-ray technique. man) may develop osteoporosis. In general, Any suspicion of osteopenia, osteoporosis, or Caucasians and Hispanics have the highest risk of osteomalacia should be confirmed by a dual energy developing osteoporosis in their senior years: 10 X-ray absorptiometry scan (DEXA SCAN) or by a percent each, compared with a risk of 7 percent for quantitative COMPUTERIZED TOMOGRAPHY (CT) scan. African Americans of the same age. See also BONE DISEASES; BONE MASS MEASURE- Other risk factors for developing osteoporosis MENT; OSTEOGENESIS IMPERFECTA. include: osteoporosis 181

• A family history of osteoporosis energy X-ray absorptiometry (DEXA) scan. This • Eating disorders such as ANOREXIA NERVOSA or test is used to measure bone density. bulimia All patients diagnosed with osteoporosis should be taking sufficient amounts of calcium and vitamin • Diets low in calcium D, 1,000–1,500 mg/day of calcium and 400–800 IU • Cigarette smoking of vitamin D, in divided doses. They should also • Heavy alcohol consumption exercise regularly, a minimum of three hours per • Presence of inflammatory bowel disease week. The best form of exercise is walking. Other drugs that are prescribed for osteoporosis • Inactive lifestyle include: • Thyroid disease • Medications such as antiseizure drugs, blood • Alendronate (Fosamax) thinners, and corticosteroids • Risedronate (Actonel) • Raloxifene (Evista) A study of 14,824 men and women in the Norfolk branch of the European Prospective • Calcitonin (Miacalcin) Investigation into Cancer (EPIC-Norfolk) trial • Recombinant parathyroid hormone or TERI- showed a linear relationship between the quantita- PARATIDE (Forteo) tive calculation of heel density by ultrasound and the risk of hip and other fractures. Alendronate decreases clinical vertebral fractures by 45–55 percent and hip fractures by up to Signs and Symptoms of Osteoporosis 50 percent. Risedronate has decreased vertebral fractures by 40–70 percent and hip fractures by 30 Osteoporosis often causes no symptoms in the percent. These studies cannot be compared with early stages, when it is more readily treatable. At each other as they included different groups of later stages, patients with osteoporosis are at risk women treated for different lengths of time. Both for developing fractures. Often the first indicator of the daily and weekly preparations of these medica- osteoporosis is, sadly, a bone fracture. However, if tions appear to be equally effective. Only rise- physicians know that there is a family history of dronate is approved by the Food and Drug osteoporosis, they may screen a women younger Administration (FDA) for the prevention and treat- than age 65 in an attempt to treat this medical ment of glucocorticoid-induced osteoporosis as of problem before it becomes severe and before frac- this writing. tures occur. Raloxifene has been demonstrated to decrease A loss in height of an inch or greater is another vertebral fractures by 30–50 percent. Calcitonin possible indicator of osteoporosis. has shown a 33 percent decrease. In the Women’s Health Initiative study, in which Diagnosis and Treatment the study subjects used hormone replacement ther- If the physician suspects osteoporosis, he or she apy, clinical fractures were reduced by 34 percent will first obtain a medical history and physical (vertebral and hip) and 24 percent (all fractures). examination to elicit information on the aforemen- However, the increased risk, albeit quite small, of tioned risk factors as well as look for the signs and breast cancer, heart attack, and stroke make hor- symptoms of secondary causes. If there is suspicion mone replacement therapy less favored, given the of a secondary cause of osteoporosis, appropriate other available medication options. blood and urine tests will be ordered as well as X- Teriparatide in a 20 mcg dose has been shown to rays. The doctor will then usually order a dual- decrease vertebral fractures by 65 percent and non- 182 ovarian androgen overproduction vertebral fractures by 53 percent. It is the only FDA- National Osteoporosis Foundation approved agent that will directly increase bone den- 1232 22nd Street NW sity by up to 15 percent in the spine and by 3–5 Washington, DC 20037 percent in the hip in 18 months, the largest increas- (202) 223-2226 es that are seen with any agent. Teriparatide can http://www.nof.org cause mild headaches and nausea as well as mild Eastell, Richard, M.D. “Treatment of Postmenopausal HYPERCALCEMIA, typically not clinically significant. Osteoporosis.” New England Journal of Medicine 338, Other treatments under investigation to treat no. 1 (March 12, 1998): 736–746. osteoporosis are vitamin D metabolites and sodium Gallagher, J. C., et al. “Combination Treatment with fluoride. Some patients may also improve with Estrogen and Calcitriol in the Prevention of Age- supplemental magnesium, which should be taken Related Bone Loss.” Journal of Clinical Endocrinology & only under the direction of a physician because Metabolism 86, no. 8 (2001): 3,618–3,628. high levels of magnesium can be toxic to the body. Khaw, Kay-Tee, et al. “Prediction of Total and Hip Researchers in some studies have used growth Fracture Risk in Men and Women by Quantitative hormone and insulin-like growth factor 1 (IGF-1) to Ultrasound of the Calcaneus: EPIC-Norfolk enhance and maintain bone mass. Although study Prospective Population Study.” Lancet 363, no. 9,404 results with growth hormone have not been signifi- (January 17, 2004): 197–200. cant, IGF-1 appears to be a more promising agent to Meunier, Pierre, J., M.D., et al. “The Effects of Strontium combat osteoporosis. Other future potential agents Ranelate on the Risk of Vertebral Fracture in Women to treat osteoporosis are strontium ranelate, which with Postmenopausal Osteoporosis.” New England has been effective in clinical studies, and also med- Journal of Medicine 350, no. 5 (January 29, 2004): ications in the statin drug series, such as lovastatin. 459–468. Patients whose osteoporosis causes them pain Ringe, J. D., H. Faber, and A. Dorst. “Alendronate may obtain some relief with anti-inflammatory med- Treatment of Established Primary Osteoporosis in ications and other painkilling drugs. Calcitonin Men: Results of a 2-Year Prospective Study.” Journal of appears to have some analgesic effects. Both the sub- Clinical Endocrinology & Metabolism 86, no. 11 (2001): cutaneous and nasal forms have been used for two to 5,252–5,255. 12 weeks after an acute fracture to decrease pain. Rubin, Mishaela R., M.D., and John P. Bilezikian, M.D. In 2004, researchers reported on their findings “New Anabolic Therapies in Osteoporosis.” of treating postmenopausal osteoporosis with Endocrinology and Metabolism Clinics of North America 32, strontium ranelate. Both study groups received cal- no. 1 (2003): 285–307. cium and vitamin D, and one group received two g Stein, Emily, M.D., and Elizabeth Shane, M.D. “Secondary of strontium per day. The group that received the Osteoporosis.” Endocrinology and Metabolism Clinics of strontium had “significant and sustained reduc- North America 32 (2003): 115–134. tions in the risk of vertebral fractures,” according to the researchers, who reported on their findings on the New England Journal of Medicine. ovarian androgen overproduction Excessive See also BISPHOSPHONATES; DEXA SCAN; OSTEOPENIA. production of male hormones (androgens) by the For more information on osteoporosis, contact: ovary, particularly TESTOSTERONE. The condition is National Institutes of Health also known as ovarian hyperandrogenism. This Osteoporosis and Related Bone Diseases—National medical problem may be caused by an ovarian Resource Center tumor or a metabolic disorder that leads to 1232 22nd Street NW increased production of androgens in normal tis- Suite 500 sues. It may also be caused by other disorders, Washington, DC 20037-1292 such as POLYCYSTIC OVARY SYNDROME (PCOS), (202) 223-0344 or (800) 624-BONE (toll-free) CUSHING’S DISEASE,or CONGENITAL ADRENAL HYPER- http://www.osteo.org PLASIA. ovarian cancer 183

Symptoms of Ovarian Androgen Overproduction table). Ovarian cancer appears to be on the The key symptoms of this disorder are as follows: increase. The American Cancer Society estimated that about 25,580 women were diagnosed with • Hirsutism (body hair similar to patterns found ovarian cancer in 2004. Ovarian cancer represents among men, such as on the chest and face) about 6 percent of all cancer deaths in women. The National Cancer Institute reports that an estimated • Oily skin one in every 57 women in the United States will be • Acne diagnosed with ovarian cancer. • Decreased breast size in comparison with past The five-year survival rate for ovarian cancer in breast size the United States is 52 percent (which means that • Increased muscle mass without exercising 48 percent will die before five years have passed). However, if the disease is treated in the early • Amenorrhea (absence of menstrual periods) stages, when cancer is still localized to only the • Balding or thinning hair ovary, the five-year survival rate is much higher: 95 percent. Unfortunately, many cases are not Diagnosis and Treatment identified in the early stages because most women If physicians suspect ovarian androgen overpro- have few or no symptoms at that point. Some pre- duction, they order tests to measure the levels of liminary research on tests that may be able to total and free testosterone and possibly detect ovarian cancer in the early stages is promis- androstenedione. Other tests are also ordered to ing and, if efficacious, will be a welcome break- determine if the adrenal glands are overproducing through for many women and their families. androgens. These tests include measures of adrenocorticotropic hormone (ACTH), 17-hydroxyproges- Risk Factors terone, and DHEA-S (dehydroepiandrosterone). Some women have a greater risk of developing The treatment depends on the cause of the over- ovarian cancer than others. Some women carry a production. If it is an ovarian or adrenal tumor, rare genetic risk for developing ovarian cancer that removal of the tumor should correct the problem. can be detected as a BRCA1 or BRCA2 mutation. In If there is a benign cause and the ovary is felt to such cases, some women have their ovaries be the culprit, ORAL CONTRACEPTIVES can be used to removed, before any cancer develops, to reduce the decrease the stimulation of the ovaries by the pitu- risk of developing cancer later on. itary hormones FOLLICLE-STIMULATING HORMONE Other risk factors are as follows: (FSH) and LUTEINIZING HORMONE (LH). If INSULIN RESISTANCE SYNDROME is the cause, then metformin • A first-degree relative (sister, mother, or daugh- (Glucophage, Glucophage-XR) can be used, ter) who has had ovarian cancer; the risk is although it is not currently approved by the Food greater still if two or more first-degree relatives and Drug Administration (FDA) for this purpose. If have been diagnosed with ovarian cancer the adrenal gland is causing the ovarian androgen • Childlessness; the risk declines with the number overproduction, small doses of GLUCOCORTICOIDS of children that a woman has borne can be used, such as dexamethasone (Decadron). In • Age; women over age 50 have a greater risk of low doses, dexamethasone will decrease the adrenal developing ovarian cancer, and the risk increas- glands’ production of the androgens but still allow es further for women over age 60 the needed amounts of cortisol to be produced. • A previous history of cancer; women who have previously had breast cancer or colon cancer have ovarian cancer A malignant tumor of an ovary. an increased risk for developing ovarian cancer About 20,000 cases of ovarian cancer were diag- • Race; Caucasian women have the greatest risk for nosed in the year 2000, with a high of 2,646 cases developing ovarian cancer although the reason in California and a low of 37 cases in Alaska (see why is unknown 184 ovarian cancer

Protective Factors Against tum. Sometimes the doctor may find cause for sus- Developing Ovarian Cancer picion during a pelvic examination although he or Some studies have shown that some women have she is unable to diagnose ovarian cancer. In that a decreased risk for developing ovarian cancer, case, the doctor will order an internal ULTRASOUND including those women who have had their uterus test. If any tumors are present, they should show (but not their ovaries) removed or women who up on the ultrasound. Some doctors may order a have had a tubal ligation to prevent future preg- COMPUTERIZED TOMOGRAPHY (CT) test to check for nancies. Some studies have also found that using possible ovarian cancer. oral contraceptives (birth control pills) decreases If a tumor is identified, the physician will take a the risk for a woman later developing ovarian can- biopsy, which is a sample of tissue that will be cer, although other studies have not found this checked by a pathologist for cancer cells. The biop- decreased risk. Interestingly, some studies have sy is obtained through a small incision in the belly shown that women who breast-fed their babies called a laparotomy. This procedure is performed had a lower risk of developing ovarian cancer than under anesthesia and causes the woman no pain women who never breast-fed. other than the minor pain involved with inserting an intravenous line through which anesthesia can Symptoms of Ovarian Cancer be administered. Most women have no symptoms, which is why By using the biopsy and other tests, the doctor ovarian cancer has such a high mortality rate. In will stage the cancer, which means that he or she general, if symptoms do occur, they appear in the will determine how advanced the tumor is and later stages of cancer, although any woman should whether it has spread beyond the ovary. These find- see a physician if she has the following symptoms: ings will help determine what treatment is recommended. If the tumor is contained within the ovary, • Generalized abdominal pain or discomfort it may be curable by surgical excision of the ovary. (pressure, gas, bloated feeling) If the tumor has metastasized (spread) to other organs, the tumor will be treatable but not curable. • Early satiety (feeling full after eating very little food) Treating Ovarian Cancer • Weight gain or loss with no apparent cause Most women undergo surgery to treat ovarian can- • Unusual bleeding from the vagina (for example, cer. Usually both ovaries, the uterus, the cervix, in a postmenopausal women who is no longer and the fallopian tubes will be removed. This sur- menstruating) gery will render the woman unable to have chil- • Poor appetite dren. Preserving some eggs before the procedure may be possible, should the woman opt for a sur- • Diarrhea or constipation rogate mother to carry a baby at some later point. • Frequent urination However, most women who have ovarian cancer are worried about surviving, and reproduction is The above symptoms are vague and could be not a major issue to them. In some cases, particu- caused by many other medical problems. This is larly if the woman is young and the cancer is local- why women who experience such symptoms ized and low grade, the doctor may remove only should really see their physicians. Ruling out a seri- the cancerous ovary so that the woman may be ous problem is best. able to become pregnant later on. Some women with ovarian cancer may be treat- Diagnosing Ovarian Cancer ed with radiation therapy, which irradiates the area Many women have annual checkups with their that has been stricken with cancer in an attempt to gynecologist, which is a good idea. The doctor will kill the cancer cells. Radiation therapy may cause perform a pelvic examination to check the some side effects, such as nausea and vomiting, as woman’s ovaries, uterus, vagina, bladder, and rec- well as fatigue and diarrhea. ovarian cancer 185

CANCER OF THE OVARY. INVASIVE CANCER INCIDENCE COUNTS BY U.S. CENSUS REGION AND DIVISION, STATE AND METROPOLITAN AREA AND RACE, UNITED STATES, 2000 (NOT ALL STATES REPORTED DATA.) African African All Races Caucasian All Races Caucasian American American Northeast Georgia 526 410 104 New England Atlanta 175 120 48 Connecticut 311 293 * Maryland 390 294 66 Maine North Carolina 661 547 101 Massachusetts 625 586 * South Carolina 284 213 63 New Hampshire 101 99 * West Virginia 188 182 * Rhode Island 96 92 * Vermont 45 44 * East South Central Alabama 364 302 56 Middle Atlantic Kentucky 366 342 23 New Jersey 851 754 64 New York 1,665 1,412 167 West South Central Pennsylvania 1,314 1,214 62 Louisiana 316 237 68

Midwest West East North Central Mountain Illinois 1,015 898 75 Arizona 380 352 * Indiana 519 495 20 Colorado 345 334 * Michigan 860 780 66 Idaho 105 104 * Detroit 364 299 57 Montana 83 82 * Ohio 935 848 60 Nevada 154 145 * Wisconsin 428 411 * New Mexico 128 111 * Utah 144 143 * West North Central Wyoming 53 53 * Iowa 300 292 * Kansas 225 220 * Pacific Minnesota 412 381 * Alaska 37 29 * Missouri 477 435 37 California 2,646 2,284 115 Nebraska 154 145 * San Francisco-Oakland 344 261 28 North Dakota 57 57 * San Jose-Monterey 157 127 * Los Angeles 753 604 58 South Hawaii 84 24 * South Atlantic Oregon 306 292 * District of Columbia 52 17 32 Washington 556 529 * Florida 1,630 1,497 98 Seattle-Puget Sound 401 380 *

*Counts not given if fewer than 16 cases in a category Source: U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2000 Incidence. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute, 2003. 186 ovarian cyst

If the cancer is an advanced one, the patient may Modan, Baruch, M.D., et al. “Parity, Oral Contraceptives, also be treated with chemotherapy. Chemotherapy and the Risk of Ovarian Cancer Among Carriers and refers to cancer-killing drugs. Most chemotherapy Noncarriers of BRCA1 or BRCA2 Mutation.” New used to treat ovarian cancer are administered intra- England Journal of Medicine 345, no. 4 (July 26, 2001): venously. Chemotherapy also usually has side 235–240. effects, most notably nausea and vomiting. Rebbeck, Timothy R., et al. “Prophylactic Oophorectomy Women may opt to join a clinical trial on ovari- in Carriers of BRCA1 or BRCA2 Mutations.” New an cancer, which would provide the opportunity to England Journal of Medicine 346, no. 2 (May 23, 2002): be a part of a study that is testing treatments or 1,616–1,622. medications not available to the general public. After treatment for ovarian cancer, women should see their physicians at least every three ovarian cyst Fluid-filled and usually noncancer- months for two years or longer, depending on the ous growth that occurs on an ovary. Many cysts doctor’s recommendations. With this follow-up cause no symptoms, while others are painful. schedule, the doctor may be able to detect any When cysts are large and painful, physicians (usu- recurrences of disease and provide immediate ally gynecologists) may remove such cysts and may treatment. biopsy surrounding ovarian tissue to rule out the Many women may find it helpful to join a sup- presence of CANCER. The presence of an ovarian port group composed of other women who have or cyst may impair a woman’s fertility. Ovarian cysts have had ovarian cancer. Although their spouses can be detected upon a pelvic examination and and family members can sympathize and try to help confirmed by pelvic and/or vaginal ultrasound. As women diagnosed with ovarian cancer, they cannot the technology improves, the diagnostic criteria for truly know what the experience is like. The ovarian cysts continue to be refined. In one study, woman’s physician should be able to recommend up to 23 percent of women volunteers who were support groups in the local area. considered “normal” and had not been previously See also CANCER. diagnosed with any cysts prior to the study met the For further information, contact the following criteria for polycystic ovaries, or 10 or more cysts at organizations: least two to eight millimeters in diameter. See also OVARY. Gilda Radner Familial Ovarian Cancer Registry Rosewell Park Cancer Institute Elm and Carlton Streets ovarian failure, premature The cessation of the Buffalo, NY 14263 function of the ovary before it would normally (716) 845-4503 or (800) 682-7426 (toll-free) occur, or in a woman’s 30s or early 40s. This does http://www.ovariancancer.com not include cases in which the ovary was removed National Ovarian Cancer Coalition, Inc. because of an ovarian cyst, ovarian cancer, or for 500 NE Spanish River Boulevard other medical conditions. Premature ovarian fail- Suite 8 ure will cause infertility because eggs will no longer Boca Raton, FL 33431 be produced. (561) 393-0005 or (888) OVARIAN (toll-free) See also OVARY. http://www.ovarian.org

Altman, Robert, and Michael J. Sarg. The Cancer ovary A female reproductive organ located within Dictionary. New York, N.Y.: Facts On File, Inc., 2000. the abdominal/pelvic cavity. Normal females have Knopf, Kevin, and Elise Kohn. “Ovarian Cancer.” In two ovaries. The ovary is the female counterpart to Bethesda Handbook of Clinical Oncology. Philadelphia, the male testis (also known as the testicle). The Pa.: Lippincott Williams & Wilkins, 2001. ovary releases eggs in a process called ovulation. ovary 187

One of these eggs may be combined with male ovaries is also tied to the normal operation of other sperm to create a human embryo. In a normal pre- endocrine organs, such as the HYPOTHALAMUS, PITU- menopausal adult woman, the monthly ovulation ITARY, and the ADRENAL GLANDS. process continues unless it is interrupted by ORAL If the ovaries malfunction, women may experi- CONTRACEPTIVES, natural or surgically induced ence problems with infertility. Some women devel- MENOPAUSE, or illness. op OVARIAN CYSTS or OVARIAN CANCER. Others The ovaries also produce female hormones, experience ovarian failure, such as with TURNER including ESTRADIOL and progesterone. These hor- SYNDROME. POLYCYSTIC OVARY SYNDROME is another mones, particularly estradiol, are responsible for example of an ovarian disorder, and it is likely to be female sexual characteristics, such as breast devel- induced by INSULIN RESISTANCE SYNDROME. Other opment, the pattern of body hair, fat distribution, disorders may also lead to ovarian malfunctions; and other key aspects of female sexuality. In addi- for example, the EARLY PUBERTY that is characteris- tion, the ovaries are linked to the woman’s month- tic of MCCUNE-ALBRIGHT SYNDROME is often caused ly menstrual cycle. The normal operation of the by estrogens generated by ovarian cysts.

Paget’s disease A bone disease primarily charac- femur, and tibia are the most common sites for terized by an enlarged and abnormal bone struc- these sarcomas. The patient with a malignant bone ture and caused by an overproduction of poor- sarcoma generally experiences increased bone pain quality bone. First described by Sir James Paget in and/or tissue swelling in the area. No treatment is 1877 (he called the disease osteitis deformans), available for this complication. Paget’s disease causes joint dysfunction in most patients and may also cause bone pain. When the Risk Factors disease occurs in children or adolescents, it is called The risk for developing Paget’s disease increases juvenile Paget’s disease, hyperostosis corticalis with age. The disease is found in about 3 percent of deformans juvenilis, or hereditary hyperphos- all individuals in Europe and North America who phatasia. Some experts believe that the great com- are older than age 55. Men are more likely to have poser Ludwig van Beethoven suffered from Paget’s Paget’s disease than women, in a three-to-two disease, causing his hearing loss. ratio. The disease is more common in people in Paget’s disease most commonly affects the hip, eastern and northern Europe and in places where spine, pelvis, skull, tibia (a leg bone), and humerus Europeans have migrated to, such as to the United (an arm bone). Some experts believe that a virus States, Australia, and New Zealand. Conversely, the may cause Paget’s disease, although no virus has disease is rare in Scandinavia, Asia, and Africa. been isolated to date. Racial differences also occur. Caucasians are much more likely to have Paget’s disease than African Phases of the Disease Americans. In the early phases of Paget’s disease, bone resorp- The disease also appears to have genetic factors. tion (loss) mediated by overactive OSTEOCLASTS is a Certain studies have shown that the risk of a first- key feature. This is followed by a phase in which degree relative (parent or child) having Paget’s dis- both the osteoblasts and osteoclasts become over- ease is seven times greater than it is among active. The next phase is one of bone remodeling individuals who do not have first-degree relatives and sclerosis. At that point, because of the extreme with the disease. Other studies have demonstrated bone changes, physicians may mistakenly believe that the risk for developing Paget’s disease, up to that the patient has advanced cancer rather than the age of 90 years, is 9 percent for people with a Paget’s disease. Making the diagnosis even more first-degree relative, compared with only a 2 per- difficult, it is also possible for an individual to have cent risk for the general population. Paget’s disease and bone cancer at the same time. Signs and Symptoms of Paget’s Disease A Rare Complication Although some patients have pain with Paget’s dis- One rare complication of Paget’s disease, occurring ease, many do not. In fact, most patients have no in about 1 percent of all patients with the disease, signs or symptoms. The disease is often discovered is the development of a malignant bone sarcoma. accidentally when X-rays are taken for another These tumors are fast growing, and few patients purpose and the radiologist notes the characteristic survive for longer than a year. The pelvis, humerus, skeletal abnormalities of Paget’s disease. Patients

189 190 Paget’s disease with Paget’s disease also have an elevated alkaline may show indications of the disease in the inter- phosphatase blood level. Sometimes a test for alka- mediate-to-later stages. line phosphatase levels is ordered for another pur- Patients with Paget’s disease can be treated with pose and thus the disease is discovered. BISPHOSPHANATE drugs such as etidronate (Didronel), Paget’s disease may cause difficulty with walking alendronate (Fosamax), risedronate (Actonel), tilu- and gait abnormalities because of the bone remodel- dronate (Skelid), and pamidronate (Aredia). These ing that has occurred in the spine, a common site for are all oral medications, except for pamidronate, Paget’s disease. Often osteoarthritis is present along which must be administered intravenously. These with Paget’s disease, making the diagnosis more dif- drugs can often suppress the disease process for ficult. Some doctors will assume that the problem is years. Medications such as salmon calcitonin solely one of osteoarthritis rather than a combina- (including Calcimar and Miacalcin) are also some- tion of both osteoarthritis and Paget’s disease. times used to treat patients with Paget’s disease. Paget’s disease may also cause a hearing loss by Salmon calcitonin can be administered either intra- compressing the eighth cranial nerve or affecting muscularly or subcutaneously in an injection. It is the middle ear ossicles. A survey of 958 patients also available as a nasal spray (Miacalcin), although with Paget’s disease revealed that 37 percent had the nasal spray is generally not as effective as are some hearing loss, and 31 percent had bowed the injections. limbs. Other cranial nerve problems, leading to If patients with Paget’s disease have bone pain, facial drooping and eye movement disorders, may it is usually treated with acetaminophen (Tylenol) also be seen with Paget’s disease. or with one among many different brands of non- If the base of the skull is affected, hydrocephalus steroidal anti-inflammatory medications (NSAIDs). may occur (the disruption of the normal flow of Nonarthritis pain in the joint is usually responsive cerebrospinal fluid in the brain), necessitating a to a bisphosphonate medication. shunt procedure to prevent coma and/or death in See also CALCIUM BALANCE, OSTEOBLASTS. the patient. Fortunately, this complication is rare. For further information on Paget’s disease, con- In severe cases of Paget’s disease, congestive heart tact the following organization: failure may also occur due to the large amount of Paget Foundation for Paget’s Disease of Bone and blood diverted to the hypermetabolic bones. Related Disorders If pain does occur with Paget’s disease, it is usu- 120 Wall Street ally described as a dull and aching pain that is often Suite 1602 worse at night. New York, NY 10005 Other disorders often associated with Paget’s dis- (800) 23-PAGET (toll-free) or (212) 509-5335 ease include the following: http://www.paget.org • Arthritis Delmas, Pierre D., M.D., and Pierre J. Meunier, M.D. • Fractures “The Management of Paget’s Disease of Bone.” New England Journal of Medicine 336, no. 8 (February 20, •HYPERPARATHYROIDISM 1997): 558–566. •OSTEOPOROSIS Duncan, William E., M.D. “Paget’s Disease of the Bone,” • Thyroid disease in Endocrine Secrets. Philadelphia, Pa.: Hanley & Belfus, • Kidney stones Inc., 2002. Gold, D. T., et al. “Paget’s Disease of Bone and Quality of Life.” Journal of Bone Mineral Research 11, no. 12 (1996): 1,897–1,904. Diagnosis and Treatment Leach, Robin J., Frederick R. Singer, and G. David Physicians who suspect that a patient may have Roodman. “The Genetics of Paget’s Disease of the Paget’s disease should order imaging tests and Bone.” Journal of Clinical Endocrinology & Metabolism 86, radionuclide studies, although even simple X-rays no. 1 (2001): 24–28. pancreatic cancer 191

Siris, E. S. “Epidemiological Aspects of Paget’s Disease: (from neurons in the gastrointestinal tract), and Family History and Relationship to Other Medical somatostatin and gastrin (from D cells). Conditions.” Seminars in Arthritis and Rheumatism 23, no. 4 (1994): 222–225. Exocrine Function Whyte, Michael P., M.D., et al. “Oseoprotegerin In its role as an exocrine gland, the pancreas Deficiency and Juvenile Paget’s Disease.” New England excretes a number of enzymes into the duodenum, Journal of Medicine 347, no. 3 (July 15, 2002): via two ducts, in response to ingested meals. Any 175–184. obstruction of these ducts or the small ducts within the pancreas, especially by gallstones and/or “sludge” from the bile, will lead to PANCREATITIS. pancreas A gland, about six inches in length, These enzymes include lipases, pancrealipase, amy- that performs several essential functions. The pan- lase, trypsins, and others. Most of these enzymes creas has both endocrine and exocrine functions. are stored in an inactive form to prevent the pancreas from digesting itself. Endocrine Functions When the pancreas malfunctions, as with dia- For its endocrine functions, the pancreas secretes betes mellitus and pancreatitis, the results are seri- insulin from the beta cells in the islets of ous. PANCREATIC CANCER is nearly always fatal Langerhans. These insulin-rich beta cells make up unless diagnosed in the early stages. about 50–60 percent of the pancreas. INSULIN is a hormone that helps the body appropriately assimilate carbohydrates (sugar) so it may pancreatic cancer A dangerous and usually fatal be stored as glycogen in the liver and muscle. It form of cancer. According to the American Cancer also helps to transfer fat (as fatty acids) into triglyc- Society, an estimated 31,860 new cases were erides and store energy, and it allows amino acids expected in the United States in 2004. An estimat- to be incorporated into protein. Without insulin, ed 31,270 people were expected to die of pancreat- the disease known as DIABETES MELLITUS occurs. ic cancer in 2004, including 15,440 men and 15,830 With a complete lack of insulin, individuals present women. Pancreatic cancer represents about two with TYPE 1 DIABETES. Prior to the discovery of percent of all cancer cases in both men and women. insulin in 1921, there was a 100 percent fatality The five-year survival rate for pancreatic cancer rate among all patients with Type 1 diabetes. is low. Only about 5 percent of patients with pan- The pancreas also secretes glucagon from the creatic cancer will survive for five years; this means alpha cells (which make up about 25 percent of the 95 percent of patients with pancreatic cancer die pancreas). Glucagon helps release glucose from before five years have passed. the liver when the pancreas and brain perceive that Despite the dismal outlook with pancreatic can- the ambient glucose level is too low. In addition, the cer as of this writing, researchers are actively seek- pancreas secretes amylin, a peptide hormone that is ing information on causes and possible treatments. cosecreted with insulin and helps slow the emptying of the stomach (thereby smoothing out delivery of nutrients to the bloodstream). Risk Factors for Developing Pancreatic Cancer Amylin also decreases the amount of glucagons Although any individual can develop pancreatic secreted in response to eating a meal, decreasing cancer, the risk will vary depending on the follow- the rise in glucose after a meal. By acting directly ing factors: on the brain, amylin helps to increase satiety (the feeling of fullness) and decrease appetite. Several • Age: the risk increases with age and is highest amylin-like injectable products are in development among people ages 60 and older for use in the treatment of diabetes. • Smoking: people who smoke have a two to The pancreas also secretes pancreatic polypep- three times greater risk of developing pancreatic tide (from F cells), vasoactive intestinal polypeptide cancer than nonsmokers 192 pancreatitis

• Diabetes: patients with diabetes have an giopancreatography (ERCP), a test in which an increased risk endoscope is passed through the patient’s mouth • Race: African Americans have a greater risk of and into the stomach and the small intestine. The developing pancreatic cancer than Asians, doctor inserts a catheter through the endoscope to Hispanics, or Caucasians inspect the bile ducts and pancreatic ducts. The doctor may also perform a biopsy to check • Family history: the risk triples if a parent or sib- for cancer. The biopsy can be achieved during the ling had pancreatic cancer, and the risk is also ERCP or during abdominal surgery. It may also be increased if a parent or sibling had colon cancer performed using an internal ultrasound called an or ovarian cancer endoscopic ultrasound (EUS). Other options include surgery, radiation thera- Signs and Symptoms of Pancreatic Cancer py, or chemotherapy. Gemcitabine (Gemzar) is the most common drug used to treat pancreatic cancer. Although signs and symptoms often do not present It has many side effects but can be efficacious in until the disease is advanced, some indicators of some patients. Some physicians use a combination pancreatic cancer should be checked. Patients with of two therapies at a time, such as combining gem- these signs and symptoms may have another ill- citabine with radiation treatment. ness, such as hepatitis that should also be assessed If surgery is performed, and all or most of the by a physician. pancreas is removed, patients will develop diabetes The most common indicators of pancreatic can- and chronic digestive disorders, such as diarrhea cer are as follows: and cramping. Pancreatic cancer is usually diagnosed at a late • Yellow skin and eyes (caused by jaundice) stage, when it is impossible to overcome with • Dark-colored urine (also caused by jaundice) mainstream treatments. For this reason, many • Nausea and vomiting patients are encouraged to join a clinical trial when • Appetite loss they are diagnosed, in which they may have an opportunity to try medications and treatments that • Unintended weight loss are not available to most patients. • Pain in the upper abdomen or the upper back • Fluid buildup in the abdomen (ascites) pancreatitis Inflammation of the pancreas, which may be acute or chronic. If acute, the condi- Diagnosis and Treatment tion may be life threatening, and the individual If the physician suspects the presence of pancreatic should be hospitalized so that he or she can receive cancer, he or she performs a physical examination, immediate and careful treatment. Experts report checking for the presence of jaundice (pronounced that about 10 percent of cases of patients with yellowing of the skin and eyes caused by a problem acute pancreatitis become life threatening, with a with the liver or pancreas). The doctor will also high death rate. If pancreatitis is a chronic problem check the abdomen in the area of the pancreas to rather than an acute one, the patient may be treat- see if there is pain or an abnormal buildup of fluid. ed outside the hospital. Laboratory tests will show if there is an elevated The most common causes of pancreatitis are rate of bilirubin, indicating jaundice that may be gallstones or chronic alcohol abuse (together they caused by a blockage in the pancreatic duct or bile represent the etiology of about 80 percent of all the duct due to a tumor. Further information will be cases of pancreatitis). However, some metabolic provided with a COMPUTERIZED TOMOGRAPHY (CT) medical problems can also lead to pancreatitis; for scan and ultrasound procedures. A gastroenterolo- example, HYPERTRIGLYCERIDEMIA, which refers to gist may perform an endoscopic retrograde cholan- elevated blood triglycerides levels (usually greater pancreatitis 193 than 1,000 mg/dl may induce pancreatitis). In In severe cases of pancreatitis, plain X-rays will some cases, congenital defects of the pancreas or show indications of pancreatitis, such as pancreatic biliary duct system may cause pancreatitis. Very calcifications. Blood tests are also ordered to deter- infrequently, HYPERPARATHYROIDISM with its associat- mine if triglyceride levels are elevated. A special ed HYPERCALCEMIA may cause pancreatitis. In addi- type of endoscopy (ERCP) may be ordered to eval- tion, some medications may cause the condition. uate the condition of the pancreas, which may also include removal of stones or insertion of prostheses Risk Factors to widen closed ducts. This is a very specialized pro- Obesity is a major risk factor for developing pan- cedure that should be performed only by an expe- creatitis, mainly due to its association with gall- rienced gastroenterologist. stones and hypertriglyceridemia. The other major The treatment of pancreatitis depends on the risk factor is alcohol abuse. identified cause as well as the treatment for pain. Some infections are also associated with the In most cases, patients are given bowel rest, development of pancreatitis, particularly hepatitis A which means they are not allowed to eat, as this and B. Patients with acquired immune deficiency would stimulate the secretion of digestive syndrome (AIDS) have a greater risk than others of enzymes from the pancreas and worsen the situa- developing the condition. This occurs partly tion. Patients are also given intravenous fluids because AIDS patients are more likely to develop during this period infections that can affect the pancreas (such as If an infection is identified, antibiotics or other cytomegalovirus, cryptococcus, and other infec- drugs specific for the particular infection are indi- tions) and partly because AIDS patients are more cated. If gallstones have caused pancreatitis, gall- likely to take medications, such as pentamidine and bladder surgery may be indicated. If the pancreatitis sulfa drugs, that can cause pancreatitis directly. stems from chronic alcoholism, patients are urged Pancreatitis can also be genetic. Hereditary pan- to stop drinking altogether and are warned that creatitis is a rare condition that has been linked to continued consumption of alcohol could lead to chromosome 7. Symptoms and signs of hereditary their death. In some cases, medications can cause pancreatitis usually occur before the child is 10 pancreatitis. If so, they are discontinued or the years old but are often mild at first, with increas- dosages are decreased. When high triglyceride lev- ingly difficult bouts that may occur on a weekly or els are the cause of the pancreatitis, the patient is more frequent basis. given dietary recommendations and appropriate medications to lower triglyceride levels. Signs and Symptoms of Pancreatitis Acutely severe pancreatitis can lead to Severe nausea with or without vomiting and abdom- endocrine dysfunction, leading to the need for inal pain, often around the umbilicus and radiating insulin therapy to normalize glucose levels. The toward the back, are the most common indicators of chronic use of insulin and pancreatic enzyme sup- pancreatitis. Patients with pancreatitis are often so ill plements are needed when 80 percent of the pan- that they present at hospital emergency rooms. creas is damaged. See also AIDS; DIABETES MELLITUS; OBESITY; PAN- Diagnosis and Treatment CREAS. If the patient’s signs and symptoms indicate the possible presence of pancreatitis, the diagnosis can Blomgren, Kerstein B., et al. “Obesity and Treatment of be confirmed with blood tests, specifically, tests for Diabetes with Glyburide May Both Be Risk Factors for the pancreatic enzymes lipase and amylase. Acute Pancreatitis.” Diabetes Care 25, no. 2 (February Imaging tests, such as COMPUTERIZED TOMOGRAPHY 2002): 298–302. (CT) scans or ULTRASOUND tests, may help corrobo- Minocha, Anil, M.D., and Christine Adamec. The rate the diagnosis by revealing gallstones or Encyclopedia of Digestive Diseases and Disorders. New changes within the pancreas. York: Facts On File, Inc., 2004. 194 parathyroid cancer

Steinberg, William, and Scott Tenner. “Acute Pancreatitis.” Postoperatively, the patient must be watched New England Journal of Medicine 330, no. 17 (April 28, very carefully, because he or she may experience 1994): 1,198–1,210. severe HYPOCALCEMIA (unusually low levels of calcium in the blood) and may need large doses of intravenous calcium until the body stabilizes to normal. parathyroid cancer A rare form of cancer that This occurs because these patients may develop stems from the parathyroid glands and that also hungry bone syndrome, a situation that develops may cause HYPERCALCEMIA (excessive levels of cal- when there has been a long period of excessive cium in the blood). Only a few hundred cases per parathyroid hormone exposure of the bone with year of parathyroid cancer are reported in the attendant micro- and macrostructural changes. United States, at most. The five-year survival rates After recovery occurs, most patients can be among parathyroid cancer patients are variable, maintained on daily oral doses of calcium and pre- ranging from 40–86 percent. scribed CALCITRIOL (vitamin D). After all surgical Parathyroid cancer cases represent less than 1 options have been exhausted, medical treatment of percent of all cases of patients who are diagnosed parathyroid cancer revolves around the control of with primary HYPERPARATHYROIDISM. The risk for hypercalcemia, with adequate hydration and the developing parathyroid cancer appears to be slight- use of BISPHOSPHONATES and gallium nitrate. Drugs ly increased among patients who are undergoing that mimic the effects of calcium have been used treatment for end-stage renal disease (kidney fail- experimentally. Radiation therapy has also been ure). Parathyroid cancer is also associated with used, although the results have been variable. The MULTIPLE ENDOCRINE NEOPLASIA, type 1 (MEN 1). National Cancer database reported a 10-year survival rate of 49 percent in a cohort of 286 patients. Diagnosis and Treatment See also CALCIUM BALANCE; PARATHYROID GLANDS. Patients with parathyroid cancer usually have Hundahl, S. A., et al. “Two Hundred Eight-Six Cases of higher calcium levels on average than patients Parathyroid Carcinoma Treated in the U.S. Between with benign causes of hyperparathyroidism. 1985–1995: A National Cancer Data Base Report. The These patients are much more likely than American College of Surgeons Commission on Cancer patients with benign hyperparathyroidism to and the American Cancer Society.” Cancer 86, no. 3 have a neck mass, bone disease, and kidney prob- (August 1, 1999): 538–544. lems. As the calcium levels are much higher than Shane, Elizabeth. “Parathyroid Carcinoma.” Journal of normal, they can also present as parathyroid cri- Clinical Endocrinology & Metabolism 86, no. 2 (2001): sis. This occurs when the patients have severe 485–493. hypercalcemia, with mental status changes as well as dysfunction of other organ systems. The pathologist often has difficulty distinguishing parathyroid glands Refers to the four endocrine between a benign parathyroid adenoma and glands located in the neck around the thyroid parathyroid cancer. gland and that control the exchange of calcium When identified, the treatment for parathyroid into the bloodstream and the bones. On occasion, a carcinoma is the surgical removal of the cancerous person may have three or even five or six parathy- parathyroid gland and a thorough evaluation of the roid glands. At times, parathyroid glands develop other three parathyroids for any indication of can- within the thyroid gland or even migrate down cer. If cancer is found in the other glands, they into the chest. should also be surgically excised. In addition, parts Sometimes a parathyroid gland or glands may of the thyroid gland or the entire thyroid may also become cystic and these cysts may be functional (still need to be excised. Depending upon the location of able to secrete some parathyroid hormone). These the tumor, wide surgical excision may necessitate cystic glands can also form in the lateral neck as an removal of lymph nodes, the thymus gland, and embryological remnant. They can also form from the muscle tissue in the neck. degeneration of very large parathyroid adenomas. pheochromocytoma 195

They are usually discovered as small, soft neck mass- neck surgery, particularly of the thyroid gland. It es. Aspiration of these cysts may resolve them. results from damage to the parathyroid glands Parathyroid hormone can be measured in the cyst and/or to their blood supply. In addition, severe fluid from those cysts that are functional. deficiencies of magnesium, which are seen in mal- See also CALCIUM ABSORPTION; HYPERCALCEMIA; nourished patients and especially alcoholics, can HYPERPARATHYROIDISM; HYPOCALCEMIA; HYPOPARA- lead to a state of hypoparathyroidism and HYPOCAL- THYROIDISM. CEMIA (abnormally low blood levels of calcium). Recombinant PTH is now available as an injectable drug called TERIPERATIDE (Forteo) and is parathyroid hormone (parathormone or PTH) The used for the treatment of severe OSTEOPOROSIS. protein hormone, secreted by the parathyroid glands Parathormone-related peptide, or PTH-rp is a in the neck, that helps to regulate calcium and phos- protein or peptide that is secreted by some malig- phorus balance in the bloodstream. When the blood nant tumors. It can lead to the development of calcium level in the body dips even slightly, this dip HYPERCALCEMIA. PTH-rp is similar in structure to is sensed by the parathyroid glands, which then PTH, but it can be specifically measured to help increase their secretion of parathyroid hormone. At physicians determine if a patient’s elevated blood that point, PTH travels via the bloodstream to the calcium levels are due to excessive PTH (high calci- gut, bone, and the kidney to exert its effects. um, high PTH, and low or normal PTH-rp) or to Parathyroid hormone also affects the bone. At the PTH-rp (high calcium, low PTH and high PTH-rp). site of the bone, PTH activates OSTEOCLASTS and also See also PARATHYROID GLANDS. helps to remove a small amount of calcium from the bone to return the blood level to normal. Parathyroid hormone also helps to stimulate the pheochromocytoma A tumor, usually of the conversion of vitamin D to a more active form, medulla of the adrenal gland. Most (90 percent) of which works at the gut to help increase calcium pheochromocytomas occur in the adrenal gland. absorption. In the kidneys, PTH stimulates the reab- However, they can also be found anywhere along sorption of the calcium that is filtered, thus increas- the midline of the body along the sympathetic ing the amount of calcium in the bloodstream. nervous system chain, from near the bladder up to As the calcium level in the blood returns to its the carotid arteries. previous level, this change is sensed by the Most pheochromocytomas are benign (about 90 parathyroid glands, which will then decrease their percent), but some are cancerous. The pheochro- secretion of PTH. If the level of calcium in the blood mocytoma leads to secretion of excessive amounts becomes too low or too high, the parathyroid of catecholamines (adrenaline, noradrenalin), glands will react and change their secretion of PTH leading to severe paroxysms of hypertension (only hormone to normalize the blood calcium levels. 5 percent of patients with pheochromocytomas An excessive continued secretion of PTH is have normal blood pressure), ORTHOSTATIC called HYPERPARATHYROIDISM, a disease that is subdi- HYPOTENSION, headaches, and episodes of flushing. vided into primary, secondary, and tertiary hyper- Other symptoms include palpitations, rapid heart parathyroidism. rate, anxiety, chest pain, and sweating. PTH can be measured in the blood. When meas- On rare occasions, pheochromocytomas also ured, intact PTH is most frequently measured, as is secrete other hormones, including CALCITONIN, the level of calcium. The endocrinologist needs to neuropeptide y, PTH-rp, and adrenocorticotropic compare the relative values of both PTH and calci- hormone (ACTH). um in order to interpret the patient’s clinical situa- If undiagnosed, pheochromocytomas will lead tion appropriately. to death even in very healthy young individuals, Conversely, an inadequate secretion of parathy- especially if they undergo surgery with general roid hormone leads to a condition called HYPO- anesthesia and the condition is not recognized and PARATHYROIDISM. This condition may be caused by treated ahead of time. 196 physical examination

Pheochromocytomas may occur spontaneously or Klinger, H. Cristoph, et al. “Pheochromocytoma.” Urology may be associated with other endocrine and genetic 57, no. 6 (2001): 1,025–1,032. disorders, such as MULTIPLE ENDOCRINE NEOPLASIA, Young, W. F. “Pheochromocytoma and Primary type 2 syndrome, familial pheochromocytoma, von Aldosteronism: Diagnostic Approaches.” Endocrinology Hippel-Lindau disease, NEUROFIBROMATOSIS, and von and Metabolism Clinics of North America 26, no. 4 (1997): Recklinghausen disease. 801–827. The majority of these tumors are unilateral (on one side), but 5–10 percent may be bilateral. About 10 percent of the cases occur in children. physical examination The physician’s review of When they occur, pheochromocytomas most the patient’s medical history, including a history commonly appear among patients in their 40s and of the chief complaint and present illness, a review of 50s. They are a secondary cause of hypertension systems, a social history, a past medical history, and a (representing 1 percent or less of the cases of family history, as well as an examination of any parts hypertension). of the body that appear to have signs of disease or about which the patient complains. Diagnosis and Treatment Most physical examinations include annual rou- The standard approach when a patient has signs tine tests after a given age, such as a rectal exami- and symptoms suggestive of a pheochromocytoma nation, a breast check for lumps, and so forth. is to measure catecholamines and their metabolites Endocrine diseases and disorders (as well as other in a 24-hour urine collection. The measurement of medical problems) are often identified during an plasma metanephrines may become a standard test annual health check. For example, the physician in the future. When the diagnosis is in doubt, the may notice that a patient has an enlarged neck or clonidine suppression test may be ordered. This test staring, protruding eyes, which may indicate measures levels of epinephrine, norepinephrine, HYPERTHYROIDISM and ophthalmopathy caused by and dopamine. If the hormone levels are abnor- GRAVES’ DISEASE. mally high, this indicates the presence of a See also COMPUTERIZED TOMOGRAPHY; MAGNETIC pheochromocytoma. RESONANCE IMAGING; ULTRASOUND. Once a diagnosis is made, the tumor is localized with COMPUTERIZED TOMOGRAPHY (CT) scanning of the abdomen, and elsewhere if necessary. If the pineal gland An endocrine gland whose function tumor cannot be found with standard imaging is largely unknown. However, it is known that the modalities, a special nuclear medicine imaging test pineal gland secretes natural melatonin, which is called a METAIODOBENZYLGUANIDINE SCAN (MIBG involved in the sleep-wake cycles of humans. The scan) may be obtained. secretion of melatonin is mainly controlled by The ultimate treatment is excision of the tumor. cycles of light and dark (day and night). Melatonin However, prior to anesthesia and surgery, the can be taken as a supplement to prevent jet lag. excess catecholamines are controlled, usually with Some studies indicate that melatonin secreted a combination of alpha-blockers (phenoxybenza- by the pineal gland may have a protective effect mine, prazosin (Minipress), doxazosin (Cardura), against the development of some forms of cancer. terazosin (Hytrin), and phentolamine) and beta- A malfunction of the pineal gland may cause sleep blockers (labetalol, propranolol (Indera, Inderal- disorders because of the insufficient release of LA), atenolol (Tenormin) and metoprolol melatonin. Studies of elderly individuals with (Lopressor, Toprol-XL). When needed, calcium decreased melatonin levels have shown that the channel blockers and volume repletion can also be patients improved with supplemental melatonin. used prior to surgery. On rare occasions, benign and malignant tumors See also ADRENAL GLANDS; CANCER; CLONIDINE as well as cysts of the pineal gland may form. SUPPRESSION TEST. See also ELDERLY; MELATONIN. pituitary gland 197 pituitary adenomas Benign tumors of the pitu- (either due to the size of the tumor itself or sec- itary gland. The most common pituitary adenomas ondary to therapy, including surgery, medications, secrete prolactin (PROLACTINOMA) or are nonsecret- or radiotherapy). It may also be caused by trauma, ing. They are usually detected by MAGNETIC RESO- inflammation, or vascular problems including POST- NANCE IMAGING (MRI) of the pituitary gland. PARTUM PITUITARY NECROSIS (Sheehan’s syndrome). Tumors that measure between one and nine mil- There can be deficiencies of any of the six ante- limeters are called microadenomas, and those that rior pituitary hormones, including PROLACTIN, are 10 millimeters or greater are called macroade- LUTEINIZING HORMONE (LH), FOLLICLE-STIMULATING nomas. They may be detected because they make HORMONE (FSH), GROWTH HORMONE, adrenocorti- one of several hormones and cause some sort of cotropic hormone (ACTH), and THYROID-STIMULATING clinical syndrome that brings the patient to medical HORMONE (TSH). These pituitary hormones fail in a attention. Instead of secreting complete functional typical pattern. First, the gonadotropins (LH, FSH) hormones, some adenomas secrete only the alpha will fail, then growth hormone and TSH, and final- or beta subunits of pituitary hormones and they ly ACTH. Prolactin deficiency is rare unless there is have no endocrine activity. a vascular etiology. Sometimes pituitary adenomas are found when More commonly, partial failure of the pituitary an MRI or COMPUTERIZED TOMOGRAPHY (CT) scan of gland occurs. Treatment of the cause (tumor, trau- the brain is performed for another reason. These ma to the pituitary, and so forth) may enable the tumors are often referred to as incidentalomas, and patient to recover. Because pituitary failure will often they cause no symptoms. result in the inability of the body to produce need- In some autopsy series, as many as 25 percent of ed hormones, patients will need to take supple- the deceased patients had a small pituitary adenoma, ments of LEVOTHYROXINE (to replace thyroid not usually one that was not detected prior to death. produced by the thyroid), hydrocortisone (to Treatment of these tumors is directed at the replace cortisol not produced by the adrenal underlying disorder and can include medications, glands), and other medications. surgery, and radiation therapy. Much modern pitu- See also HYPOPITUITARISM. itary surgery is performed via the transsphenoidal approach. This surgery requires the cooperation of a neurosurgeon as well as an otorhinolaryngologist pituitary gland An endocrine gland that is com- (a specialized ear, nose, and throat doctor). posed of two lobes: the anterior pituitary (the ade- With this procedure, the pituitary is approached nohypophysis) and the posterior pituitary (the neu- from below, through the sinuses that are centered rohypophysis). Many experts call the anterior pitu- above the upper teeth. Mortality rates range from itary the master gland because it produces hormones 0.25–3 percent, depending upon the type and size used by another endocrine gland. For example, it of the tumor as well as other illnesses that the releases adrenocorticotropic hormone (ACTH), patient has. Complications can include bleeding, which is used by the adrenal glands, and thyroid- infection (meningitis), cerebrospinal fluid leak, stimulating hormone (TSH), which is used by the visual disturbance, and taste and smell changes. thyroid gland. The pituitary gland also releases See also HYPOPITUITARISM; PITUITARY FAILURE; luteinizing hormone (LH), follicle-stimulating hor- PITUITARY GLAND. mone (FSH), prolactin (PRL), growth hormone (GH), and pro-opiomenalnocortin (POMC). These seven hormones are essential to normal functioning. pituitary failure A total breakdown of the pitu- If the pituitary malfunctions, it can cause a sec- itary gland. Pituitary failure is also known as ondary endocrine disorder in another endocrine hypopituitarism. The failure can be partial or total. gland, because it causes that gland to malfunction This clinical syndrome is rare. The most common also. (A primary endocrine disorder occurs when causes of pituitary failure are PITUITARY ADENOMAS the disease originates in the endocrine gland itself.) 198 pituitary insufficiency

See also ACROMEGALY; ACTH; FOLLICLE-STIMULAT- concentrations in their blood. This is seen in ING HORMONE; GROWTH HORMONE; HYPOPITUITARISM; patients with insulin resistance syndrome. PROLACTIN; THYROID-STIMULATING HORMONE. Risk Factors Women with Type 2 diabetes are at greater risk for pituitary insufficiency See HYPOPITUITARISM; PITU- developing PCOS than those without glucose intol- ITARY FAILURE. erance. PCOS is also found more commonly among women who are overweight or obese. Other diseases that may present along with PCOS are ACAN- polycystic ovary syndrome (PCOS) A metabolic THOSIS NIGRICANS and hypertension. syndrome that affects about 8 percent of women of Many women with PCOS also have abnormal reproductive age. Its clinical manifestations range cholesterol and triglyceride levels, typically mildly from minimal to severe. It is characterized by men- increased low-density lipoprotein (LDL) levels, low strual irregularities, hyperandrogenism (excess high-density lipoprotein (HDL) levels, and elevated male hormones, leading to acne, alopecia, and/or triglyceride levels (hyperlipidemia). These risk hirsutism), anovulation with infertility, and mis- associations may signify that the underlying cause carriages. Polycystic ovary syndrome appears to be is insulin resistance, as these risk factors are all caused by or tightly associated with insulin resist- associated with or caused by insulin resistance. ance syndrome. Thus those affected with PCOS are predisposed to IMPAIRED GLUCOSE TOLERANCE, DIA- Signs and Symptoms BETES MELLITUS, OBESITY, and HYPERLIPIDEMIA, with PCOS usually comes to the attention of physicians all the attendant risks of these health problems. when their female patients present to them with Women with PCOS also have a much higher- menstrual irregularities, hirsutism, and/or infertili- than-average risk of developing cardiovascular ty. As mentioned, these women are often over- problems; the risk of a heart attack is seven times weight, and may have acanthosis nigricans. The greater among patients with PCOS compared with two main conditions necessary to diagnose PCOS women who do not have this syndrome. In addi- are hyperandrogenism and anovulation. In severe tion, patients with PCOS have an increased risk for cases of PCOS, the physician may find large ovari- developing endometrial cancer and breast cancer. an cysts during a pelvic examination, although Polycystic ovary syndrome was originally cysts are not necessary to make the diagnosis. known as Stein-Leventhal syndrome and was first discussed in 1935. At that time, the diagnosis Hyperandrogenism required hirsutism (unusual hairiness), obesity, The excessive levels of male hormones found and amenorrhea (failure to menstruate). Later, a among women with PCOS are mainly synthesized National Institute of Health consensus revised the by the ovaries, although the adrenal glands may diagnostic criteria to include hyperandrogenism also contribute. Most women with PCOS have ele- with ovulatory dysfunction as well as the exclusion vated blood levels of testosterone, with the mani- of CUSHING’S SYNDROME, nonclassical CONGENITAL festations of acne and/or hirsutism. However, some ADRENAL HYPERPLASIA, hyperprolactinemia, and racial groups, such as Asians, may not present with androgen-secreting tumors. In 2004, the presence acne or hirsutism. Physicians will typically measure of polycystic ovaries were considered consistent the patient’s levels of total and free testosterone as with the diagnosis of PCOS but were not necessary well as dehydroepiandroesterone sulfate (DHEAS) to make the diagnosis. that is made by the adrenal glands. The condition may present as early as puberty. Some studies indicate that women with PCOS have Anovulation a low-grade chronic inflammation of the lining of Many patients with PCOS do not menstruate at all. their blood vessels as measured by the increased However, some women continue to menstruate yet levels of high-sensitivity C-reactive protein (CRP) do not ovulate, while others have irregular men- postpartum pituitary necrosis 199 struation without ovulation. Anovulation can be For further information, contact the following ascertained by the measurement of hormone levels, organization: such as LUTEINIZING HORMONE (LH), FOLLICLE-STIMU- Polycystic Ovarian Syndrome Association LATING HORMONE (FSH), and ESTRADIOL. It can also be P.O. Box 3403 determined by measuring basal body temperature. Englewood, CO 80111 Polycystic ovaries (877) 775-PCOS http://www.pcosupport.org The third historic sign of PCOS is the polycystic ovary, which is diagnosed with ultrasound. The Diamanti-Kandarakis, Evanthia, et al. “Increased ovary is usually enlarged as well as cystic. This sign Endothelin-1 Levels in Women with Polycystic Ovary is not necessary to make the diagnosis. Syndrome and the Beneficial Effect of Metformin Therapy.” Journal of Clinical Endocrinology & Metabolism Diagnosis and Treatment of PCOS 86, no. 10 (2001): 4,666–4,673. Blood tests can determine if androgen levels are Franks, Stephen, M.D. “Polycystic Ovary Syndrome.” unusually high, and doctors also note the presence New England Journal of Medicine 333, no. 13 of hirsutism. An ultrasound will reveal the pres- (September 28, 1995): 853–861. ence of polycystic ovaries. Anovulation is more dif- Kelly, Chris C. J., et al. “Low Grade Chronic ficult to pinpoint. Inflammation in Women with Polycystic Ovarian Treatment is aimed at lowering insulin resist- Syndrome.” Journal of Clinical Endocrinology & ance (the body’s inability to use the body’s natural Metabolism 86, no. 6 (2001): 2,453–2,455. insulin). Medication, nutritional therapy, and exer- Lobo, Rogerio A., M.D., and Enrico Carmina, M.D. “The cise are tried first. After that, medications are used, Importance of Diagnosing the Polycystic Ovary such as metformin, rosglitazone, or pioglitazone, Syndrome.” Annals of Internal Medicine 132, no. 12 although none of these drugs are approved by the (2000): 989–993. Food and Drug Administration (FDA) for this indi- Tsilchorozidou, T., C. Overton, and G. S. Conway. “The cation. An overweight woman who has not men- Pathophysiology of Polycystic Ovary Syndrome.” struated or who has menstruated only erratically Clinical Endocrinology 60, no. 1 (2004): 1–17. and is then placed on one of these drugs is advised to use birth control unless pregnancy is her inten- tion because sometimes the drugs may alleviate postpartum pituitary necrosis Pituitary failure years of infertility. Some women have been known caused by severe hypotension during or after giv- to ovulate and become fertile within one month of ing birth, usually due to severe blood loss. This initiating metformin therapy. condition is also known as Sheehan’s syndrome or Some patients are treated with low doses of postpartum hypopituitarism. Because an end ORAL CONTRACEPTIVES to stabilize their menstrual artery nourishes the pituitary gland, when blood cycle and lower their androgen levels. The excess pressure drops significantly, only a minimal androgen effects can also be treated with spirono- amount of blood may reach the pituitary, causing lactone (Aldactone), which blocks the androgen the gland to die. This rare condition may occur in receptor, or with dexamethasone (Decadron), an estimated one in 10,000 deliveries. which decreases the synthesis of adrenal andro- When a woman is pregnant, her pituitary gland gens. Neither of these drugs is FDA approved for nearly doubles in size and thus is at risk for post- these particular indications, although both have partum complications. If tissue within the anterior been used clinically in this manner for years. pituitary is destroyed because of severe postpartum Obese women are advised to lose weight, which bleeding from a vaginal delivery or caesarean sec- may help to normalize hormonal function. In some tion, the woman’s hormones are thrown into dis- cases, weight reduction may resolve anovulation. array, including her thyroid hormone, adrenal See also AMENORRHEA; HIRSUTISM IN WOMEN; hormone, growth hormone, prolactin, and all the INFERTILITY. other hormones that the pituitary normally over- 200 postpartum thyroid disease sees. The posterior pituitary usually survives, and In many cases, however, the condition is not ini- in most cases, the patient does not need replace- tially severe and dramatic. Some patients develop a ment of the antidiuretic hormone desmopressin chronic form of hypopituitarism that occurs weeks acetate (DDAVP). or even years after giving birth. In such cases, According to author Mark E. Molitch, M.D., assessment of the pituitary’s ability to secrete its although the frequency of postpartum pituitary hormones in appropriate amounts, which is per- problems is not known for certain, an estimated 25 formed immediately in the case of acute postpar- percent of women who die in the first 30 days after tum necrosis, is done at a later date. Typically, a delivery have indications of pituitary infarction. cortrosyn stimulation test is also administered and levels of free T4, TSH, estradiol, FSH, LUTEINIZING Diagnosis and Treatment HORMONE, and IGF-1 are measured. An acute case of this syndrome should be suspect- See also HYPOPITUITARISM; PITUITARY FAILURE; ed in a woman who has had severe blood loss PITUITARY GLAND. and/or hypotension in the peripartum period. She Molitch, Mark E., M.D. “Sheehan Syndrome,” in NORD may have persistent low blood pressure, headache, Guide to Rare Diseases. Philadelphia, Pa.: Lippincott nausea, and vomiting and may develop fluid and Williams & Wilkins, 2003. electrolyte abnormalities. Within several weeks, Sheehan, H. L. “The Recognition of Chronic the patient may be unable to lactate (fail to pro- Hypopituitarism Resulting from Postpartum Pituitary duce breast milk) and experience malaise, fatigue, Necrosis.” American Journal of Obstetrics and Gynecology nausea, and a loss of both underarm (axillary) hair 111, no. 6 (November 1971): 852–854. and pubic hair. If women are successful at lactating after delivery, then postpartum pituitary necrosis can usually be ruled out. postpartum thyroid disease Thyroid disease that The diagnosis of postpartum pituitary necrosis is diagnosed after giving birth. An estimated 5–10 can be confirmed by a computerized tomography percent of new mothers develop some form of (CT) scan and/or magnetic resonance imaging postpartum thyroid disease, including THYROIDITIS, (MRI) of the pituitary as well as by measurement of GRAVES’ DISEASE, and thyroid adenomas. appropriate hormone levels (CORTISOL, THYROXINE, Because so many women also develop postpar- THYROID-STIMULATING HORMONE (TSH), ESTRADIOL, tum depression, researchers have studied whether FOLLICLE-STIMULATING HORMONE (FSH), insulin-like there was a link between the development of thy- growth factor 1 (IGF-1), and PROLACTIN). Because roid disease and depression in the postpartum peri- there is total infarction of the anterior pituitary od. They reported on their findings in a 2001 issue gland, this syndrome is also a cause of EMPTY SELLA of Clinical Endocrinology. SYNDROME. The researchers studied 641 women who did In acute cases of postpartum pituitary necrosis, not have either thyroid disease or diabetes initially patients are treated with intravenous doses of and followed up with them before and after deliv- hydrocortisone as well as normal saline with dex- ery until one year after their babies were born. The trose solution. When the patient’s condition has researchers found that 11 percent of the women stabilized, treatment for the chronic illness can developed postpartum thyroid disease. be started. Hydrocortisone, cortisone acetate, or Interestingly, the researchers found that women prednisone is given to replace glucocorticoids. with postpartum thyroid disease did not experience Thyroxine is given to replace natural thyroid an increased risk for developing depression com- hormone. Estrogen and progesterone that were pared with women without thyroid disease. formerly produced by the body may be replaced See also HYPERTHYROIDISM; HYPOTHYROIDISM; with oral contraceptives or medications that are PREGNANCY; THRYOID NODULES; THYROTOXICOSIS. given to women during menopause. Growth hormone may also be replaced if it is found to be defi- Lucas, A., et al. “Postpartum Thyroid Disease Is Not cient, although its use is considered controversial Associated with Postpartum Depression.” Clinical in adults. Endocrinology 55, no. 6 (2001): 809–814. Prader-Willi syndrome 201

Prader-Willi syndrome (PWS) An inherited med- Short stature is another common feature of ical condition characterized by mental develop- PWS. Most patients (90 percent) are below normal mental delay, behavioral problems (irritability and in height. They also generally experience a DELAYED tantrums), OBESITY, short stature, decreased muscle PUBERTY due to hypogonadatropic hypogonadism. mass, and genital abnormalities (hypogonadatropic When they do experience puberty, their voices will hypogonadism). Prader-Willi syndrome was named usually not change. after the Swiss pediatricians Andrea Prader and H. Many patients with Prader-Willi also have Willi, who first described this condition in 1956. abnormal glucose tolerance or diabetes mellitus, at Prader-Willi syndrome occurs in one in least in part because of their extreme obesity. About 10,000–16,000 births. Most adult patients with a third of patients with this syndrome are about PWS cannot live independently. Consequently, twice the expected normal weight for their height. they live with their families or in group homes. Other common characteristics of Prader-Willi syn- In many patients with PWS (as many as 75 per- drome include the following signs and symptoms: cent), the syndrome is caused by a genetic defect: the deletion of a segment on chromosome 15q11-q13, • Sleep disorders, especially sleep apnea which was inherited from the father. In some cases, • Poor muscle tone the genetic problem is inherited from the mother. • Almond-shaped eyes • Small mouth Signs and Symptoms of Prader-Willi Syndrome Infants with Prader-Willi syndrome have symp- Some patients also have kyphosis or scoliosis toms as newborn babies. They have poor sucking (skeletal deformities), OSTEOPOROSIS, and body reflexes and difficulties with swallowing, and they temperature control problems. It has also been may require tube feeding. Babies with PWS also reported that some patients are unusually adept at have poor muscle tone and below-normal weight, putting together jigsaw puzzles. partially due to their feeding problems. Most children and adults with Prader-Willi syn- Treatment of Prader-Willi Syndrome drome have small hands and feet. They often Until recent years, the symptoms of patients with exhibit constant scratching because of a severe this syndrome could not be treated but only man- itching problem and may be physically scarred aged, which was extremely difficult for both the because of their chronic scratching behavior. individual and the families, particularly in the case Individuals with this syndrome may also have an of hyperphagia behavior. Some studies indicate unusually high tolerance to pain. that treatment with growth hormone may help Most patients with Prader-Willi are also devel- some patients with PWS. For example, the findings opmentally delayed, with intelligence quotients in of a two-year study of 54 children with the syn- about the 70s. (An IQ of 100 is considered normal drome, ages four to 16 years old when they joined in the general population.) the study, was reported in a 2002 issue of Pediatrics. Prader-Willi syndrome is also characterized by Some of the children (35 children) were given an extreme and ravenous appetite, which leads to growth hormone, while the rest were used as a obesity. This excessive appetite usually starts in control group. early childhood, around the age of three years old, In all but one child who received growth hor- and is generally attributed to a disorder in the cen- mone, the children showed considerable improve- tral nervous system. The compulsive overeating ment. The treated children became more energetic (hyperphagia) is so extreme and intense that indi- and active, and their moods improved markedly. viduals with PWS will seek out food that has been The memory of most of the treated children (85 left in the garbage or will eat the food of their percent) improved. In addition, 89 percent of the household pets. In many households, the refrigera- children became much more sociable. Growth hor- tor and the kitchen cabinets must actually be locked mone did not make the children become “normal,” up because of this complete lack of appetite control. but it did dramatically improve the lives of both the 202 precocious puberty children and their families. Some families said that For further information on Prader-Willi syn- their other children, who did not have PWS, drome, contact the following organizations: reported that they were no longer embarrassed to The Foundation for Prader-Willi Research be seen by others in the company of their sibling 6407 Bardstown Road who had Prader-Willi syndrome. Suite 252 Growth hormone therapy was also found to accel- Louisville, KY 40291 erate growth and decrease the percentage of body fat (502) 254-9375 in the PWS patients. Unfortunately, no increase http://www.pwsresearch.org occurred in the resting energy expenditure. Patients who were given growth hormone therapy had Burman, Pia, E. Martin Ritzen, and Ann Christin increased respiratory muscle strength as well as an Lindgren. “Endocrine Dysfunction in Prader-Willi increase in their overall physical strength and agility. Syndrome: A Review with Special Reference to GH.” Growth hormone treatment is not without risk. Endocrine Reviews 22, no. 6 (2001): 787–799. A study reported in a 2004 issue of the Journal of Carrel, A. L., et al. “Growth Hormone Improves Body Pediatrics discussed the case of a four-year old boy Composition, Fat Utilization, Physical Strength and with Prader-Willi syndrome who was being treated Agility in Prader-Willi Syndrome.” Journal of Pediatrics with growth hormone and who suddenly died 134, no. 2 (1999): 215–221. from bronchopneumonia while asleep. Before his Vliet, G. V, et al. “Sudden Death in Growth Hormone- death, the boy’s snoring had become worse. Treated Children with Prader-Willi Syndrome.” Several other cases have indicated that growth Journal of Pediatrics 144, no. 1 (2004): 129–131. hormone may increase the risk of respiratory infec- Whitman, Barbara Y. “The Behavioral Impact of Growth tion, obstructive apnea, and sudden death. More Hormone Treatment for Children and Adolescents research needs to be done on the use of growth with Prader-Willi Syndrome: A 2-Year, Controlled hormone with Prader-Willi patients. Study.” Pediatrics 109, no. 2 (February 2002). Available Preliminary research indicates that some patients online. URL: http://pediatrics.aappublications.org/cgi/ with PWS have abnormal levels of GHRELIN, a weight- content/full/109/2/e35?maxtoshow=&HITS=10&HITS= and appetite-regulating hormone. Manipulation of 10&RESULTFORMAT=&fulltext=PraderWilli&searchid=1 the ghrelin levels may help to improve the uncon- 093574871920_18858&storedsearch=&FIRSTINDEX= trollable eating, although more research needs to be 0&sortspec=relevance&journalcode=pediatrics. performed on this aspect of the illness. The lives of Downloaded November 15, 2003. many families that include a child with PWS would be much happier if the excessive eating could be brought under greater control. precocious puberty See EARLY PUBERTY. Because patients with Prader-Willi have hypogonadism, experts suggest that sex hormone replacement, including testosterone for males and prediabetes A new term created by the estrogen for females, should be administered. These AMERICAN DIABETES ASSOCIATION and the NATIONAL drugs could protect against bone mineral diseases INSTITUTES OF HEALTH to distinguish abnormalities of such as osteoporosis. In one study of patients with blood glucose from normal levels and from overt PWS, 41 percent of males and 18 percent of females DIABETES MELLITUS. The previously used and techni- received hormone replacement. Families of the cally correct terms of impaired fasting glucose and patients who did not receive hormone replacement impaired glucose tolerance were not well understood may not have wished to encourage sexuality among by the public. As a result, the American Diabetes their developmentally delayed relatives with Prader- Association and the National Institutes of Health Willi syndrome. Physicians may also be reluctant to sought to impress upon the general public the fact provide hormone replacement drugs because of the that these metabolic abnormalities were quite seri- health controversies that surround these drugs. ous and should not be ignored. The newly created See also GROWTH HORMONE; TYPE 2 DIABETES. term prediabetes was believed to convey this concept. prolactin 203

Not all patients with prediabetes syndrome will the close supervision of an obstetrician as well as an actually develop diabetes. However, even those ENDOCRINOLOGIST during their pregnancies. who do not develop overt diabetes have an extremely high risk of suffering from heart attack, Screening During Pregnancy stroke, other atherosclerotic abnormalities, and Virtually all obstetricians screen women for diabetes premature death. Patients with prediabetes who mellitus between the 24th and 28th weeks of preg- have a family history of diabetes are more likely to nancy. Screening pregnant women for thyroid dis- develop the disease. However, many patients who ease would also be advisable (which is not routinely are diagnosed with prediabetes may either prevent done). Significant numbers of pregnant women are or delay the development of diabetes by losing hypothyroid or hyperthyroid, both conditions that weight (if they are overweight), exercising, and could be harmful to mother and child if not treated. adopting a healthy and nutritious diet. In the Diabetes Prevention program, a study in Endocrine Diseases May Prevent Pregnancy the United States that ended in 2001, patients with Women with some endocrine diseases may have impaired glucose tolerance were treated with diet difficulty achieving a pregnancy, such as women and exercise or with the medication metformin to with HYPOTHYROIDISM, POLYCYSTIC OVARY SYNDROME, determine the effects on their progression to dia- and hyperprolactinemia. The elevated prolactin betes. The diet and exercise group lost an average levels can be treated with bromocriptine during of 7 percent of their baseline weight and walked an pregnancy to decrease the levels of prolactin as average of 150 minutes per week, and they well as the size of the pituitary microadenoma. decreased their risk of progressing from prediabetes See also BREAST-FEEDING; FERTILITY; HYPERTHY- to overt diabetes by 58 percent. ROIDISM; INFERTILITY; POSTPARTUM PITUITARY NECRO- The group treated with about 1,700 mg of met- SIS; PROLACTIN. formin decreased their risk of progression to dia- Kovacs, Christopher S., and Henry M. Kronenbergy. betes by 31 percent. The results achieved with this “Maternal-Fetal Calcium and Bone Metabolism study regarding diet and exercise have been dupli- During Pregnancy, Puerperium, and Lactation.” cated in similar trials in China and Finland. Data Endocrine Reviews 18, no. 6 (1997): 832–872. also suggests that the use of other drugs, such as thiazolidinediones, angiotensin-converting enzyme inhibitors, alpha glucosidase inhibitors, and statins may also lower the rate of progression from predi- prolactin A hormone produced by the anterior abetes to diabetes mellitus. pituitary gland that is directly involved in stimulating breast milk for breast-feeding infants. Men and nonlactating women produce very low levels of prolactin, but these levels become elevated in pregnancy Gestation of an infant. Some pregnant breast-feeding and pregnant women. Pregnant women have endocrine diseases or disorders before women do not lactate, despite their high levels of they become pregnant (such as diabetes, thyroid prolactin, because their levels of estrogen and prog- disease, and many other medical problems). Some esterone are high enough to block milk production. women develop endocrine diseases or disorders After the baby is born, the estrogen and proges- during pregnancy or the postpartum period directly terone levels in the mother drop dramatically, after the delivery of the baby. These endocrine ill- enabling her milk production to commence, which nesses need to be identified and treated for the usually occurs within three days from the child’s health of both the mother and the child. For exam- birth. Lactation is further stimulated by the infant’s ple, women with GESTATIONAL DIABETES (a form of suckling on the breasts. diabetes mellitus that occurs only during pregnan- Prolactin is unusual in that its production is inhib- cy) are at risk for having many medical problems, as ited by the hypothalamic secretion of dopamine. This are their children. Such women need to be under is in contrast to all the other anterior pituitary cells, 204 prolactinoma where the hypothalamus secretes hormones that who are not pregnant or nursing an infant may stimulate the secretion of pituitary hormones develop breast milk production (galactorrhea), rather than inhibit them. which is seen in four out of five women with pro- Prolactin levels may become elevated in non- lactinomas. nursing individuals who are hypothyroid or who Other indicators of excessive levels of prolactin have a benign tumor of the pituitary (prolactino- are a decreased interest in sex and an increase in ma). Patients with kidney failure or liver failure vaginal dryness. Since all of these signs and symp- may experience elevated levels of prolactin. toms are common to other medical problems, with Medications may also increase the blood levels of the exception of the production of breast milk, prolactin. These medications include psychiatric diagnosis can be difficult for most physicians. A medications (haloperidol, risperidone, and medica- prolactinoma may be diagnosed after oral contra- tions in the tricyclic antidepressant and monoamine ceptives are discontinued, but there is no evidence oxidase (MAO) inhibitor categories of medications) that the use of birth control pills leads to the devel- and antinausea drugs such as metoclopramide opment of these tumors. (Reglan). Verapamil, a blood pressure and heart Among males with prolactinomas, symptoms medication, may also increase prolactin levels. include eye problems or headaches because the Typically, these medications increase the levels of pituitary gland, which is located in the head, begins prolactin from the normal range to the range of to press on the optic nerves. Men may also have a 30–100 mcg/l. decreased sex drive (libido). Often these tumors are High levels of prolactin may cause decreased diagnosed much later in men than in women; even libido and infertility in men as well as headaches small increases in prolactin will lead to changes in and cranial nerve abnormalities. It may cause some menstruation, which women generally notice. No secretion of milk in nonnursing women (galactor- corresponding sign occurs in men. rhea). Unusually low levels of prolactin do not appear to cause any disease or disorder other than Diagnosis and Treatment a woman’s inability to breast-feed a child. Patients are treated based on their signs, symptoms, See also BREAST-FEEDING; HORMONES; PREGNANCY; and laboratory results, specifically, their blood lev- PROLACTINOMA. els of prolactin. Initially, prolactin can be measured at any time. If the level is only mildly increased, the laboratory test should be repeated in the morning prolactinoma A benign tumor of the pituitary prior to the patient eating any meals since proteins gland and the most common form of tumor in the (amino acids), exercise, and breast stimulation can pituitary. The prolactinoma accounts for 40 percent all increase prolactin levels. of all pituitary tumors. It is so-named because the Some drugs may increase the production of pro- pituitary gland produces a hormone called PRO- lactin in the absence of tumors, such as the LACTIN, which is at low levels in most individuals antipsychotic drugs Stelazine (trifluoperazine) and except nursing mothers, in whom prolactin pro- Haldol (haloperidol) as well as the antinausea drug motes the production of breast milk. Prolactinomas Reglan (metoclopramide). The doctor will also test are estimated to be a significant problem in only for thyroid function levels because sometimes peo- about 14 of 100,000 people, according to the ple with HYPOTHYROIDISM have elevated prolactin NATIONAL INSTITUTES of HEALTH. Both men and levels. Magnetic resonance imaging (MRI) of the women may develop prolactinomas. pituitary gland will identify the tumor in the pituitary as well as any other lesion that may be com- Signs and Symptoms pressing the pituitary stalk. Women with prolactinomas may develop problems The lactotroph cells that secrete prolactin are such as irregular menstruation, AMENORRHEA (fail- different from the other pituitary cells in that they ure to menstruate), or infertility. Some women are inhibited by dopamine that comes from the pseudohypoparathyrodism 205 hypothalamus. In contrast, hormones from the prolactin-secreting tumors See PROLACTINOMA. hypothalamus stimulate all the other pituitary hormones. Thus, any lesion that interrupts the flow of dopamine from the hypothalamus can lead to an pseudohypoparathyrodism A condition that increased level of prolactin. As a result, other dis- resembles HYPOPARATHYROIDISM, which is caused by orders, such as ACROMEGALY, granulomatous disor- abnormally low levels of parathyroid hormone. ders, and craniopharyngiomas may lead to However, with pseudohypoparathyroidism, the hyperprolactinemia. In many cases, however, no body is actually producing sufficient amounts of specific cause can be determined. In such patients, parathyroid hormone but is unable or resistant to one of every three will become normal without use all that is produced. Patients may present with any therapy. low serum calcium levels (HYPOCALCEMIA) and high When a prolactinoma is diagnosed, endocrinolo- phosphate levels (HYPERPHOSPHATEMIA). gists use medications to decrease the amount of pro- Pseudohypoparathyroidism is primarily caused lactin secreted. Typically, BROMOCRIPTINE or by one of two abnormal genes and occurs in two CABERGOLINE is used. These medications are not anti- forms: type Ia and type Ib. Individuals with type Ia tumor agents, although they seem to help stabilize pseudohypoparathyroidism present with round the size of the tumor and, in some cases, to shrink it. faces, short hand and foot bones (and they often If the medication does not work to reduce pro- appear to be missing a knuckle), and short stature. lactin levels and the tumor, other means will be This condition is also known as Albright’s heredi- used, such as surgery or radiation therapy. tary osteodystrophy. Transsphenoidal surgery should not be the therapy Individuals with type Ib pseudohypoparathy- of choice, because it does not reliably lead to a cure. roidism have normal physical appearances and Surgery is often used for macroadenomas (tumors experience a resistance of their kidneys to parathy- greater than 10 millimeters in size), especially if the roid hormone. If a father with an abnormal gene tumors are pushing on the optic nerve or are transmits the gene to a child who also gets a nor- extending into the cavernous sinuses and other mal gene from the mother, the child can have what cranial nerves. Patients who need surgery or radia- is known as pseudopseudohypoparathyroidism, tion therapy for a prolactinoma will usually need to with the Albright’s hereditary osteodystrophy and receive this treatment from a neurosurgeon who no hypocalcemia. operates on many pituitary tumor patients. In most There is also a type II form of pseudohy- cases, such neurosurgeons practice at major med- poparathyroidism, which is very rare. It causes ical centers rather than at local hospitals. hypocalcemia, hyperphosphatemia, and increased Doctors should also monitor the estrogen levels levels of serum parathyroid hormone levels. The of women who have had prolactinomas because mechanism of action of parathyroid hormone in hyperprolactinemia (excess levels of prolactin in the kidney is different from what is seen with the bloodstream) can lead to reduced estrogen lev- patients with type Ib. els and then to OSTEOPOROSIS. For further information, contact the following organization: Diagnosis and Treatment If the physician suspects the patient has pseudohy- Pituitary Network Association poparathyroidism, he or she will order laboratory P.O. Box 1958 tests. Indications of pseudohypoparathyroidism Thousand Oaks, CA 91360 include low serum calcium, elevated serum phos- (805) 499-9973 phorus, elevated intact parathyroid hormone, and http://www.pituitary.com an abnormal urinary cAMP (cyclic adenosine Schlette, J. A. “Prolactinoma.” New England Journal of monophosphate) response to a parathyroid chal- Medicine 349, no. 21 (2003): 2,035–2,041. lenge test. In addition, a COMPUTERIZED TOMOGRAPHY 206 pseudohypoparathyrodism

(CT) scan or a MAGNETIC RESONANCE IMAGING (MRI) HORMONE (TSH), FOLLICLE-STIMULATING HORMONE scan will show calcification of the basal ganglia. (FSH), and LUTEINIZING HORMONE (LH). Patients with pseudohypoparathyroidism are Vlaeminck-Guillen, Virginie, et al. “Pseudohypopara- treated with supplements of calcium and vitamin thyrodism Ia and Hypercalcitoneinemia.” Journal of D. Doctors should also check for other endocrine Clinical Endocrinology & Metabolism 86, no. 7 (2001): disorders, such as HYPOGONADISM or HYPOTHY- 3,091–3,096. ROIDISM, because the defective response to hormones can also include THYROID-STIMULATING R radioactive iodine A substance used for both and/or nonfunctional hot nodules are present. diagnostic purposes and therapeutic reasons in sus- Nodules that take up iodine or technetium are pected or known cases of thyroid disease. The known as hot nodules and are rarely malignant. iodine isotopes I-123, I-125, and I-131 can all be Nonfunctional or cold nodules may have a 5–15 used for radioactive iodine uptake studies and percent risk of malignancy. scans of the thyroid gland. Typically I-123 is chosen, although technetium pertechnetate is also Radioactive Iodine as a Therapy often used as it is less expensive and more readily Radioactive iodine is also used as a therapy. For this available. For uptake purposes, only an iodine iso- application, I-131 is used, as it emits enough ener- tope can be used. gy to damage and kill thyroid cells. It is the most commonly used form of therapy for Graves’ disease The Procedure in the United States, although it is less favored in Radioactive iodine is given orally. It is absorbed Europe and other parts of the world. I-131 can also from the gut and then trapped by the thyroid be used to ablate toxic hyperfunctioning thyroid gland. The more active the thyroid is, the more nodules as well as attempt to decrease the size of iodine trapped in the gland. Thus, a radioisotope large, multinodular GOITERS. uptake scan will provide an excellent measure of It is a safe and effective therapy but can cause the physiological activity of the thyroid. some acute tenderness in the thyroid, which can The patient is brought into the nuclear medicine often be treated with simple analgesics or anti- department, and the amount of radioactive activity inflammatory medications, up to and including taken up by the thyroid is counted and reported as GLUCOCORTICOIDS. If a patient with hyperthyroidism a percentage. The typical normal range in the is treated with radioactive iodine, damage to the United States is from 15–30 percent. With GRAVES’ gland can cause the release of already-synthesized DISEASE, the percentages usually range from 40–100 thyroid hormones and thus can temporarily exacer- percent. In THYROIDITIS, however, the percentage is bate the hyperthyroidism. usually very low, in the 0–5 percent range. The amount of iodine that is trapped by the thy- Effects of Radioactive Iodine roid depends on the diet and the amount of iodine The major, long-term effect of radioactive therapy available in the food supply, and it also varies great- is HYPOTHYROIDISM that necessitates the use of life- ly around the world; however, it is fairly consistent long thyroid hormone therapy. Concern has been throughout the United States. raised that the use of radioactive iodine therapy Technetium is more often used to scan the thy- may lead to an exacerbation of Graves’ ophthal- roid gland or, in essence, to obtain a picture of the mopathy (bulging eyes), although most endocri- thyroid. It can also help to determine if a palpable nologists do not feel this is a significant problem. abnormality is a nodule; whether the activity in the When there is concern about the possible worsen- thyroid gland is homogenous or heterogeneous; if ing of these EYE PROBLEMS, patients are often pre- there is other active thyroid tissue around the thy- treated with a glucocorticoid medication, such as roid gland or elsewhere; and whether functional prednisone, to help minimize the impact.

207 208 recombinant thyroid-stimulating hormone

Very large doses of radioactive iodine can be while they concentrate on their careers. When used to ablate thyroid tissue left behind in a THY- they decide they wish to start a family in their 30s ROIDECTOMY performed for THYROID CANCER. It can or 40s, they may be shocked to learn that it is dif- also be used to treat metastases (cancer spread) ficult and sometimes impossible to achieve a preg- from papillary and follicular thyroid cancers. nancy. For this reason, they consult with reproductive specialists to see if the cause of the infertility can be determined and corrected. recombinant thyroid-stimulating hormone (thyro- Most of these physicians are obstetricians with gen) A hormone available for the evaluation of extra training in endocrinology, and they often patients with THYROID CANCER. In the past, after a work together with internal medicine endocrinolo- near-total or total THYROIDECTOMY, patients had to gists. Evaluation of an infertile couple includes a be taken off thyroid hormone replacement medica- medical history and a physical examination. The tion to allow their thyroid-stimulating hormone physician may order imaging tests, initially made to (TSH) to increase, typically to greater than 30 look for structural abnormalities, if indicated by the microunits/ml. These patients developed symptoms physical examination. He or she will also conduct of HYPOTHYROIDISM and felt poorly. Now when a laboratory tests to determine whether the individ- RADIOACTIVE IODINE thyroid scan is planned as a uals’ hormone levels are normal. Hormones tested follow-up for thyroid cancer patients, in order to may include estradiol, progesterone, testosterone, look for thyroid cells in the neck or elsewhere, thy- prolactin, thyroxine, and others. Women are tested roid hormone can be introduced. The patient can for evidence of ovulation, while men receive eval- be given recombinant TSH by injection. uations to test for the normal function of sperm This synthetic TSH increases TSH levels in the and for the numbers of spermatozoa. blood and helps to improve the uptake of iodine Physicians who are expert at resolving infertility into the thyroid cells, if any are present. Thus, the problems will perform in-depth analyses to try to scan can be performed without the necessity of pinpoint where the problem lies. Sometimes a sim- causing hypothyroid symptoms. In addition to the ple surgical procedure can resolve the infertility. iodine scan, endocrinologists will often measure Other times, women or men who are infertile must the patient’s thyroglobulin levels to help determine undergo complex surgery. In some cases, physi- if any thyroid cells remain behind. Typically, cians are unable to determine the cause of the Thyrogen is given in two or three intramuscular infertility. In other cases, doctors know what the doses over the course of three to five days. problem is but are unable to correct it. See also FERTILITY; INFERTILITY; PREGNANCY; TURNER SYNDROME. reproductive endocrinology The science of studying endocrine conditions that may impede fertility. For example, women with hypothyroidism reverse T3 (rT3) An inactive thyroid hormone may have difficulty becoming pregnant, as may derived from thyroxine (T4). T4 is usually convert- women with disorders of the ovaries such as POLY- ed to the physiologically active form of thyroid hor- CYSTIC OVARY SYNDROME. Men with TESTOSTERONE mone T3 by the removal of specific iodine from one deficiencies are often unable to create a pregnancy of the tyrosine rings. If the iodine is removed with their wives. It is also true that for most men instead, then reverse T3 is created. Some reverse and women, fertility declines with age. For women, T3 is always present. When more than normal lev- fertility ends with the onset of MENOPAUSE. Men els are present, however, it may indicate a nonthy- may continue to have the ability to father a child for roid illness, such as pneumonia or heart attack. the rest of their lives, although with a less robust Typically, T4 (thyroid hormone) is converted to T3 facility than was present in their earlier years. by the body at rates that allow adequate T3 to be Many individuals in the United States and other present, such that individuals have just enough developed countries choose to delay childbearing thyroid hormone present to function normally. rickets 209

When people become ill, however, their bodies pain, sweat excessively, and are more prone to convert more T4 to reverse T3 instead of to T3. developing infections. Many experts believe this happens because the Vitamin D-Dependent Rickets body is trying to slow itself down and preserve itself in times of increased stress. Type 1 and type 2 rickets are caused by rare con- In addition to nonthyroid illnesses, the medica- genital errors of vitamin D metabolism. With type tion amiodarone, which is used to treat irregular 1 rickets, there is a defect in the enzyme in the kid- heart rhythms, can also increase the levels of ney that coverts vitamin D stores to its most active reverse T3. With EUTHYROID SICK SYNDROME, levels form. Children with type 1 rickets typically have of rT3 can also be elevated. symptoms in their first two years of life. Calcium Reverse T3 levels typically mirror the T3 levels. and 1,25-dihydroxyvitamin D levels are low, while For instance, in a nonthyroid illness, T3 levels will parathyroid hormone levels are elevated. Large usually begin to fall, while rT3 levels will rise. doses of vitamin D preparations are used to treat Reverse T3 levels are rarely needed to diagnose and this condition. treat patients and are typically measured in complex In children with type 2 rickets, the children are ill patients who are hospitalized for other reasons. resistant to the effects of vitamin D. Their vitamin If measurement of rT3 is taken, it can help D blood levels are normal or elevated. This disorder physicians determine the exact thyroid state of the is usually diagnosed in children before they reach patient and whether further treatment is needed. age two. Rarely, this condition has been diagnosed With significant medical illness, both T3 and T4 levin adults. Very large doses of vitamin D are needed els decline and rT3 levels increase. by patients to correct their low calcium levels and to lead to normal bone mineralization. Camacho, Pauline M., M.D., and Arcot A. Dwarkanathan, M.D. “Sick Euthyroid Syndrome.” Postgraduate Medicine Hypophosphatemic Rickets 105, no. 4 (April 1999): 215–228. Another form of rickets is hypophosphatemic rickets. This disorder causes an abnormal reabsorption of phosphorus from the kidneys. Typically, male children are affected. They present with growth rickets A bone abnormality of childhood. The problems, low blood phosphorus levels, and lower- term refers to a group of disorders in which there is leg abnormalities. The abnormal gene that causes a defect in the mineralization of bone matrix or this disorder has been named PHEX. There have osteoid. In adults, the disorder is referred to as been rare reports of females with a mild form of OSTEOMALACIA, as the defect occurs only in the this disorder. Growth hormone has been effective- matrix and the growth plates have already sealed. In ly used with patients to improve growth, although children, the disorder is referred to as rickets because these children are not growth hormone deficient. the mineralization abnormality is located at the See also BONE AGE; BONE DISEASES; BONE MASS growth plate. Rickets is often classified as calcium- or MEASUREMENT; OSTEOPENIA; OSTEOPOROSIS; VITAMIN phosphate-deficient rickets. D; VITAMIN D RESISTANCE. The major skeletal problems are seen at sites in the body where there is rapid bone growth, such as Carpenter, T. O., et al. “24-25-Dihydroxyvitamin D in the forearm, knee, and the costochondral junc- Supplementation Corrects Hyperparathyroidism and tions. Thus, the child with rickets may have bone Improves Skeletal Abnormalities in X-Linked abnormalities, such as a bowing of the legs and the Hypophosphatemic Rickets: A Clinical Research wrists. Abnormalities may also be seen at the ends Center Study.” Journal of Clinical Endocrinology & of ribs, such as a beading known as rachitic rosary. Metabolism 81, no. 6 (1996): 2,381–2,388. Rickets can cause growth abnormalities as well as Seikaly, M. G., et al. “The Effect of Recombinant Human be associated with abnormalities of nerve and mus- Growth Hormone in Children with X-Linked cle function, depending on the cause. Children Hypophosphatemia.” Pediatrics 100, no. 5 (1997): with severe metabolic abnormalities have bone 879–884. 210 risk factors risk factors Genetic or environmental conditions Sometimes gender alone is a risk factor. Women that predispose an individual to illness. Race, for or men are more likely to develop a particular example, plays a role in risks for many diseases. For endocrine disease and disorder. For example, instance, African Americans have a higher risk for women are more likely to develop hypothyroidism. developing TYPE 2 DIABETES than Caucasians. Family medical history is another key factor in Obesity is a condition also linked to the develop- the development of many endocrine problems. ment of diabetes (and some experts believe that it People whose parents or siblings have had thyroid has a genetic basis as well). Thus, if a person is disease or cancer usually face an increased risk for African American and also obese, he or she has a these diseases themselves. This is why doctors usu- higher risk for developing diabetes than Caucasians ally ask patients about other family members and or than nonobese African Americans. their problems so they can be alert to possible signs Age is another factor in the likelihood of devel- and symptoms of this disease in the patient. oping a range of illnesses. The probability of devel- See also GENETIC RISKS. oping many different endocrine diseases and disorders, such as osteoporosis, Type 2 diabetes, and other medical problems, usually increases with age. S secondary hypothyroidism Hypothyroidism skin The largest organ of the body. Many (low thyroid levels) caused by a defect or problem endocrine diseases and disorders have a direct and at the level of the PITUITARY GLAND. If there is a noticeable effect on the patient’s skin. For example, problem at the level of the HYPOTHALAMUS that a key feature of ADDISON’S DISEASE is to cause causes hypothyroidism, that condition is referred hyperpigmentation, typically causing the skin to to as tertiary hypothyroidism. change to a darker color. This color change is due to Secondary hypothyroidism causes the same the excess of pro-opiomelanocortin (POMC) secret- symptoms as primary hypothyroidism, although ed from the brain, stemming from the glucocorti- here, symptoms may be more subtle. Patients with coid deficiency that the disease causes. Undiagnosed secondary hypothyroidism must be treated as if and poorly controlled DIABETES MELLITUS may cause they had primary hypothyroidism with loss or the skin to itch. It may also cause a thickening of destruction of the thyroid gland. The usual treat- the skin (waxy contractures or scleroderma) due to ment is the replacement of thyroid hormone with excess deposits of carbohydrate/protein complexes. LEVOTHYROXINE (T4). People with HYPOTHYROIDISM may have very dry, Patients with secondary hypothyroidism may coarse, and thickened skin that can be cold to the have a low or a normal level of THYROID-STIMULATING touch. The skin may also appear yellow due to HORMONE (TSH) when their blood is tested. As a excess carotene. These patients may also have result, the diagnosis must be suspected based on decreased perspiration. Patients with HYPERTHY- the totality of the patient’s clinical symptoms, the ROIDISM may have warm, moist skin and excessive physician’s clinical observations, and some labora- sweating. tory testing. Free thyroxine levels may be low nor- The skin of the patient with CUSHING’S DISEASE is mal or just below normal. thin and subject to easy bruising. This is due to the Once diagnosed with secondary hypothyroidism, effects of the excess glucocorticoids on the protein patients are given levothyroxine supplements, start- synthesis of collagen that is needed to strengthen ing at a low level, with the dosage titrated based on and stabilize the subcutaneous layers of capillaries the patient’s clinical symptoms as well as the free thy- and tissues. Patients with Cushing’s disease may roxine level. Patients are evaluated clinically before also have severe acne, alopecia (balding), fungal any increases in the medication are prescribed. Once infections of the skin, and HIRSUTISM (excessive clinically stable levels are reached, the patient should hairiness). The patient with ACROMEGALY has be rechecked once every six to 12 months. The sweaty and oily skin and may also have excessive physician must also be alert to other symptoms that skin tags (loose pieces of skin). Women with POLY- might indicate other pituitary deficiencies, because CYSTIC OVARY SYNDROME (PCOS) often have acne. typically patients have more than one problem. Another condition, ACANTHOSIS NIGRICANS, caus- See also HYPOTHYROIDISM. es a fine, velvety hyperpigmentation of the skin, often seen at the back of the neck, under the arms, and in the breast and groin creases. Acanthosis Sheehan’s syndrome See POSTPARTUM PITUITARY nigricans is often seen in patients with INSULIN NECROSIS. RESISTANCE SYNDROME.

211 212 somatostatin

Sometimes the appearance of the skin is the first VIPomas, insulinomas, and glucagonomas. It has clue to the patient or the physician that an illness also been used to treat diabetic diarrhea. is present, because there are few or no other symp- Some endocrine tumors have somatostatin toms or signs of disease. Upon further exploration receptors on their surface. Radioactive somato- with a physical examination and the careful taking statin can be used to attempt to image these tumors of the patient’s medical history, as well as the (an octreotide scan). ordering of laboratory or imaging tests, as needed, the physician may be able to identify an illness that would otherwise have gone undetected had the subclinical hypothyroidism/hyperthyroidism skin changes not been observed. Recently discovered entities in which thyroid function tests are abnormal but the patient is clin- Levin, Nikka A., and Kenneth E. Greer. “Cutaneous ically well and without obvious signs and symp- Manifestations of Endocrine Disorders.” Dermatology toms of thyroid disease. This condition has become Nursing 13, no. 3 (June 1, 2001): 189–196. more common as the measurement of THYROID- STIMULATING HORMONE (TSH), the gold standard somatostatin A pancreatic protein hormone syn- thyroid test, has become more sensitive, with thesized and secreted from endocrine-like D cells. third-generation assays now able to measure TSH When first discovered, somatostatin was found to levels as low as 0.01 microunit/ml of blood. inhibit growth hormone release, thus its name In the case of subclinical hypothyroidism, these somato, referring to growth, and statin referring to patients have elevated TSH levels and free T4 and stopping or inhibiting. It is now known to affect a total T3 levels that are normal or only minimally variety of gastrointestinal secretions and to affect abnormal. In the hyperthyroid state, patients have the secretion of a number of hormones in addition a lower-than-normal or even a completely sup- to growth hormone. Somatostatin is produced in pressed (immeasurable) TSH level and normal or paracrine cells throughout the gastrointestinal tract slightly elevated free T4 and T3 levels. as well as in nervous tissue, including the hypo- A review of this topic in 2004 in the Journal of thalamus. In the gut, somatostatin generally the American Medical Association noted that TSH lev- decreases secretions. Most of its effects are els that were minimally elevated to greater than 10 paracrine in nature—secreted in a tissue—and they microunits/ml were associated with elevated cho- have local effects. lesterol levels but that the benefits of treating with When synthetic somatostatin is injected intra- thyroid hormone were unproven. venously, 50 percent is gone within two to three In the situation in which the TSH was lower than minutes. Somatostatin inhibits the secretion of 0.01 microunits/ml (indicating hyperthyroidism), DDAVP (desmopressin acetate), growth hormone, there was good evidence suggesting that there was thyroid-stimulating hormone (TSH), insulin, a high prevalence of atrial fibrillation (rapid irregu- glucagons, gastrin, and many other hormones. lar heart rate) as well as a greater rate of progression Somatostatin has also been artificially synthe- to overt hyperthyroidism. Unfortunately, again the sized as octreotide acetate (Sandostatin and study could find no evidence that early therapy Sandostatin LAR) and is used as a growth hormone impacted outcomes. suppressant in treating ACROMEGALY. It is often used Because little data supports routine treatment in to treat carcinoid syndrome and chronic secretory the general population when a patient is diagnosed diarrhea syndromes when other therapies have with subclinical hyperthyroidism or hypothy- failed. In addition, it has been used to treat TSH and roidism, the authors advised against routine adrenocorticotropic hormone (ACTH)-secreting screening with THYROID BLOOD TESTS in the general tumors, Zollinger-Ellison syndrome, vasoactive population. However, they said, “Aggressive case intestinal peptide (VIP)-producing tumors or finding is appropriate in pregnant women, women surgery 213 older than 60 years, and others at high risk for thy- material is excised. Some endocrine diseases may roid dysfunction.” require surgery, particularly OVARIAN CANCER, TES- See also GRAVES’ DISEASE; HYPERTHYROIDISM; TICULAR CANCER, and other forms of cancer. Patients HYPOTHYROIDISM. with ADDISON’S DISEASE may need to have their adrenal glands surgically excised. Some patients Surks, M. I., et al. “Subclinical Thyroid Disease: Scientific with thyroid disease have near-total thyroidec- Review and Guidelines for Diagnosis and tomies, although this surgery is rarely done except Management.” Journal of the American Medical in cases of THYROID CANCER. Association 291 no. 2 (January 13, 2004): 228–238. See also THYROIDECTOMY. surgery Procedure involving an incision and some action taken on the body, usually when

Tanner stages Five stages of adolescent sexual Tanner, J. M., M.D. Growth at Adolescence with a General development, originally derived by J. M. Tanner in Consideration of the Effects of Hereditary and Environmental 1962. For example, with Stage 1, the preadoles- Factors Upon Growth and Maturation from Birth to Maturity, cent, there is no pubic hair present in either males 2d ed. Springfield, Ill.: Charles C. Thomas, 1962. or females. In Stage 2, males have some slightly pigmented hair around the base of the penis, while females have some sparse, slightly pigmented hair teriparatide (Forteo) A recombinant human around the labia. In addition, at Stage 2, the male’s parathyroid hormone, approved by the Food and testes and scrotum begin to enlarge, as does the Drug Administration (FDA) in November 2002, for penis. In the female, breast buds start to form. In the treatment of postmenopausal women who are stage 3, the male penis has an increased growth in at high risk of developing fractures as a result of length, as do the scrotum and testes. The pubic hair osteoporosis. Teriparatide is also used to treat men of the male becomes coarser and curlier. In females who are experiencing primary hypogonadism and at stage 3, the breast mound becomes enlarged fur- who are at high risk for developing fractures. ther, and the pubic hair is darker and coarser than Teriparatide is given as a daily subcutaneous at stage 2. At stage 4, the male penis has grown fur- injection via a penlike device. The standard dose of ther from stage 3, and the testes and scrotum have teriparatide as of this writing is 20 mcg, and also enlarged. The male pubic hair is at the adult patients also must take adequate oral dosages of level. Among females at stage 4, the areola and calcium and vitamin D. papilla together form a mound above the breast The drug has been successful in decreasing frac- and the pubic hair is at the adult level. Stage 5 is tures in osteoporotic women by 65 percent and the most mature stage of development. In this increasing their bone mineral density by nearly 10 stage, the genitalia have a fully adult appearance. percent in the spine. Tanner stages are also known as Tanner scales. In general, the side effects of teriparatide are Some individuals experience a puberty that is mild and do not cause most patients to discontinue precocious (EARLY PUBERTY), while others have a the drug. DELAYED PUBERTY. The Tanner stages chart enables See also FRACTURES; HYPOGONADISM; PARATHYROID physicians to determine the stage of development GLANDS. of a particular patient, despite his or her chronological age. testes/testicles Refers to the reproductive organs See also ADOLESCENTS. in men that are located in the scrotum, the sac Marshall, W. A., and J. M. Tanner. “Variations in the beneath the penis, and that make the sperm need- Pattern of Pubertal Changes in Boys.” Archive of Disease ed to create a pregnancy when combined with a in Childhood 45, no. 239 (1970): 13–23. woman’s egg from her ovary. (One testicle is a testis, ———.“Variations in Pattern of Pubertal Changes in while two are referred to as testes. Most males have Girls.” Archives of Disease in Childhood 44, no. 235 two testes.) The testes also create most of the (1969): 291–303. TESTOSTERONE, a hormone needed by the male

215 216 testicular cancer body. (The ADRENAL GLANDS generate about 5 per- means that their bodies are unable to use all of the cent of a man’s testosterone.) androgens (male hormones) they produce. In the male, testosterone is responsible for sex See also HYPOGONADISM; HYPOGONADOTROPISM; drive, muscle mass, the male pattern of hair distri- KLINEFELTER SYNDROME; MALE REPRODUCTION. bution (such as facial hair and chest hair), and other key aspects of masculinity. In addition to testosterone, the testes produce other hormones, testicular cancer Malignant tumor of the testi- such as dehydroepiandrosterone (DHEA) and cle. According to the American Cancer Society, an androstenedione. The testes are made up in part of estimated 8,980 men were diagnosed with testicu- Leydig’s cells, which provide enzymes that enable lar cancer in 2004 in the United States. The death androgens to be synthesized by the body. The testes rate is relatively low, and only about 360 men were also secrete limited amounts of estrogen hormones. predicted to die of testicular cancer in 2004. The Very rarely, the testes are unseen and are locat- five-year survival rate for men diagnosed with tes- ed in the intra-abdominal area, resulting in an ticular cancer is 99 percent for men with localized infant of indeterminate sex and who may have a cancer and 76 percent for testicular cancer that has MICROPENIS. Sometimes the child may have the spread, both very favorable rates. Testicular cancer sexual characteristics of both sexes, which is called represents less than 1 percent of all cancers diag- HERMAPHRODITISM. nosed in the United States. During puberty, the male undergoes a variety of In Canada, according to the National Cancer body changes, including enlargements of the testes Institute of Canada, 800 men were diagnosed with (the first sign of puberty in boys) and the penis, as testicular cancer in 2003. In addition, about 35 well as other changes. Some males may experience men died of testicular cancer in 2003 in Canada. a DELAYED PUBERTY, undergoing puberty several years later than their peers, while others may have an Risk Factors EARLY PUBERTY, also known as precocious puberty. Caucasian males have a greater risk for developing testicular cancer than men of other races, although Examination of the Testes why this is true is unknown (see table). Testicular Upon physical examination, the testes should be of cancer is most common among men between the a certain size, shape, and consistency. Typically, they ages of 20 and 35 and is very rare among men over are 15–25 cubic centimeters each. Endocrinologists age 40. use a device known as an orchidometer to compare Studies have also revealed that men who have the sizes of the testes. It is a chain of sphere-shaped had testicular cancer also face an increased risk for beads that range from one to 30 cubic centimeters the next 20 years of developing another form of in size. cancer, such as prostate cancer, colon cancer, blad- Most testes are firm and smooth to the touch, der cancer, pancreatic cancer, thyroid cancer, kid- and they are not tender. ney cancer, and other cancers. In a study reported in a 1997 issue of the Journal of the National Cancer Infertility and the Testes Institute, researchers analyzed 29,000 testicular Some adult males experience problems with INFER- cancer survivors and found that 1,406 men had TILITY related to insufficient sperm production or the developed second cancers. absence of sperm altogether. In some cases, such problems can be resolved through treatment. Males Signs and Symptoms may also develop cancer in the testicle area. TESTIC- Men with early testicular cancer may have no ULAR CANCER is highly treatable, in most cases, symptoms or may experience swelling in the scro- when it is identified. Some men also have problems tum. They may also have pain and a feeling of with partial or total ANDROGEN RESISTANCE, which heaviness and hardness in the area. testicular cancer 217

CANCER OF THE TESTES: INVASIVE CANCER INCIDENCE COUNTS BY U.S. CENSUS REGION AND DIVISION, STATE AND METROPOLITAN AREA AND RACE, 2000 African African All Races Caucasian All Races Caucasian American American Northeast Atlanta 80 72 * New England Maryland 125 112 * Connecticut 105 96 * North Carolina 189 173 * Massachusetts 198 189 * South Carolina 81 73 * New Hampshire 61 60 * West Virginia 46 44 * Rhode Island 31 21 * Vermont 21 21 * East South Central Alabama 82 72 * Middle Atlantic Kentucky 103 101 * New Jersey 230 215 * New York 440 387 25 West South Central Pennsylvania 350 337 * Louisiana 90 79 *

Midwest West East North Central Mountain Illinois 292 272 * Arizona 139 133 * Indiana 165 157 * Colorado 160 158 * Michigan 252 235 * Idaho 44 44 * Detroit 96 88 * Montana 35 33 * Ohio 299 280 * Nevada 53 51 * Wisconsin 160 152 * New Mexico 44 41 * Utah 71 70 * West North Central Wyoming 19 19 * Iowa 96 93 * Kansas 70 67 * Pacific Minnesota 220 207 * California 928 854 23 Missouri 113 109 * San Francisco–Oakland 126 103 * Nebraska 37 37 * San Jose–Monterey 54 44 * North Dakota 20 20 * Los Angeles 243 227 * Hawaii 24 * * South Oregon 119 113 * South Atlantic Washington 211 193 * Florida 356 330 18 Seattle–Puget Sound 146 136 * Georgia 168 154 *

* Fewer than 16 cases in this category Note: Data is not available for all states in the U.S. Source: U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2000 Incidence. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute, 2003. 218 testosterone

Patients with advanced testicular cancer may and cure the cancer. If the cancer has advanced, experience the following signs and symptoms: which is unusual, chemotherapy may be necessary to extend life. • Abdominal pain See also CANCER; TESTES/TESTICLES.

• Unintended weight loss Bishop, Philippe C., and Barnett S. Kramer. “Testicular •GYNECOMASTIA (growth of excess breast tissue in Carcinoma,” in Bethesda Handbook of Clinical Oncology. men and seen in 5 percent of men with germ Philadelphia, Pa.: Lippincott Williams & Wilkins, cell tumors and 25 percent of males who have 2001. Leydig’s cell tumors) Travis, Lois B., et al. “Risk of Second Malignant • Urinary obstruction Neoplasms Among Long-term Survivors of Testicular Cancer.” Journal of the National Cancer Institute 89, no. • Headaches 19 (October 1, 1997): 1,429–1,439. • Seizures Tseng, A. Jr., et al. “Gynecomastia in Testicular Cancer Patients: Prognostic and Therapeutic Implications.” Gynecomastia is the most common endocrine Cancer 56, no. 10 (1985): 2,534–2,538. abnormality seen in men with testicular cancer. With the Leydig’s cell form, when seen in boys ages five to 12 years old, gynecomastia is usually associated with testosterone The male sex hormone and the EARLY PUBERTY. It is also seen in men ages 25–35 who most important androgen. It is synthesized by the have erectile dysfunction in addition to the testicular testes and is converted in target tissues by 5-alpha mass. The gynecomastia is often associated with reductase to dihydrotestosterone, a more potent increased levels of human chorionic gonadatropin form of testosterone. Testosterone production (HCG). In addition, the hormone levels of prolactin, increases at the beginning of puberty and con- estrogens, and androgens, may be altered. tributes to the changes in androgen-dependent tis- Interestingly, men with very high levels of HCG may sues such as beard growth, pubic hair growth, develop HYPERTHYROIDISM due to the ability of the increased muscle mass, deepening of the voice, and HCG to interact with the thyroid-stimulating hor- decrease in body fat content. Testosterone is mone (TSH) receptor on the surface of the thyroid believed to be the primary determinant of libido. gland, which then subsequently leads to an overpro- Testosterone affects many aspects of a man’s life, duction of thyroid hormone. including sex drive, energy levels, and physical attributes such as muscle mass and strength. Diagnosis and Treatment Low levels of testosterone partially define HYPO- If the physician suspects that a man has testicular GONADISM. The other part of the definition is the cancer, he or she will usually order an imaging inability to produce adequate levels of spermatozoa. test—either a COMPUTER TOMOGRAPHY (CT) scan or a Women also have low levels of testosterone. MAGNETIC RESONANCE IMAGING (MRI) scan. The doctor will also order laboratory tests, such as blood Testosterone Declines with Aging tests for serum alpha-feto protein (AFP) and serum In general, testosterone production declines with beta-HCG, both of which are markers for testicular aging. The Baltimore Longitudinal Study of Aging cancer. A biopsy is usually not performed. revealed that hypogonadal levels of testosterone are The treatment for testicular cancer is an inguinal present in 20 percent of men over 60 years of age, orchiectomy, which is the removal of the testis and 30 percent of men over 70 years of age, and 60 per- spermatic cord. If only one testis is removed, the cent of men over 80 years of age. The numbers are man may continue to be fertile. It may be advisable, higher if the measurement is of free testosterone as however, to store his sperm before the surgery so opposed to total bound testosterone. Whether phys- that it can be used later to create a pregnancy, if iological declines in testosterone levels should be desired. In most cases, surgery is sufficient to treat treated remains an area of controversy. thymus gland 219

Treatment of Low Testosterone Levels tetany will worsen and the individual will die, If treatment for low testosterone levels is given, although this cause of death occurs very rarely. testosterone may be replaced by the intramuscular Hypocalcemic tetany is usually reversed by admin- (injection) or topical (applied to the skin) route. istering intravenous calcium. After the patient is The intramuscular form is given every 10–28 days stabilized, the parathyroid glands may resume par- in the form of testosterone enanthate or cypionate. tial function. If the hypoparathyroidism does not With this method, the levels of testosterone are improve, patients may need to take lifelong doses often high for the first week and then below nor- of both calcium and vitamin D. mal after two or three weeks. As a result, dosing See also CHVOSTEK’S SIGN; HYPOCALCEMIA. every 10–14 days is best. The topical forms of Tohme, J. F., and J. P. Bilezikian. “Hypocalcemic testosterone, either by patch or gel, provide much Emergencies.” Endocrinology and Metabolism Clinics of more stable and normal levels. North America 22, no. 2 (1993): 363–375. Raising hypogonadal levels through testosterone replacement therapy will increase energy, a sense of well-being, muscle strength, libido, and general thirst The need for fluid. Constant thirst may be a sexual function. Side effects of this therapy include sign of dehydration or of a disease such as uncon- irritation, impatience, acne, oily skin, increased trolled TYPE 1 DIABETES or TYPE 2 DIABETES, caused by prostate size, and a greater risk for prostate cancer high levels of glucose in the bloodstream. Excessive and polycythemia (increased red blood cell mass). thirst may also be seen in DIABETES INSIPIDUS,in See also ANABOLIC STEROIDS; HORMONES. which there is a lack of the hormone DDAVP Harman, S. Mitchell, et al. “Longitudinal Effects of Aging (desmopressin acetate) or a lack of effectiveness of on Serum Total and Free Testosterone Levels in the kidney, which leads to constant urination Healthy Men.” Journal of Clinical Endocrinology & (polyuria). Thirst can also be a consequence of pitu- Metabolism 86, no. 2 (2001): 724–731. itary or hypothalamic lesions caused by tumors or after neurosurgery or radiation therapy to the brain. See also DIABETES MELLITUS. tetany A form of uncontrollable muscle spasms that can be focal or diffuse. It is a form of severe neuromuscular irritability caused by repetitive, thymus gland A small, anterior mediastinal gland high-frequency discharges from the nerve endings, (a gland in the upper anterior chest cavity) that muscles, and spinal cord. Tetany may be caused by weighs about 15 grams at birth and increases to 40 extremely low levels of calcium, magnesium, or grams by puberty. It then decreases in size over time potassium in the bloodstream. Thus, hypocalcemia to an atrophic state. The thymus (from the Greek for tetany can be seen in HYPOPARATHYROIDISM (a con- “life force”) assists the immune system by helping dition of low levels of parathyroid hormone in the the development of T lymphocytes, which are used blood) or a hypocalcemic form of RICKETS. in cell-mediated immunity to fend off infection. The Tetany often leads to what is known as carpal- thymus gland contains thymic epithelial cells and pedal spasm, which is severe muscle contractions lymphocytes. The epithelial cells may sometimes in both the hands and feet. The condition can be become cancerous. The thymus also contains neu- quite painful. TROUSSEAU’S SIGN is a form of limited roendocrine cells that may release hormones. tetany, in which hand and forearm tetany is Sometimes these cells may also become cancerous. induced by raising the blood pressure of a patient Until the 1960s, researchers had no idea what and changing the local acid-base balance (pH) so function, if any, was performed by the thymus. It is that the calcium level is low. now known that the thymus is important in the Tetany may occur shortly after a THYROIDECTOMY immune system of the fetus and the young infant. or other neck surgery. If the condition causing However, some researchers believe the thymus may tetany is not treated immediately, the symptoms of continue to be more important than is currently 220 thyroid blood tests known or generally accepted. Chemotherapy for often spreads to other parts of the body. Thymic cancer can impede the actions of the thymus in tumors do not usually cause any symptoms until producing T lymphocytes. they begin to compress the trachea and cause Some infants have DiGeorge syndrome, a disor- shortness of breath. Sometimes facial swelling is der that affects the thymus, the parathyroid glands, also noted. According to the American Cancer and the heart. In the worst case of DiGeorge syn- Society, patients may also experience flushing, drome, the infants have significantly impaired asthma, and diarrhea. immune systems because of their reduced T cell Most patients are treated with surgery. function related to the thymus malfunction. This is Radiation therapy may also be used. The oncologist a very rare disease. However, in one case, (cancer doctor) may employ chemotherapy and/or researchers transplanted postnatal thymus tissue hormone therapy to treat thymic tumors. into five infants with complete DiGeorge syn- Carcinoid tumors may also develop in the thymus. drome. Two of the patients survived and their Khavison, Vladimir Kh., and Vyacheslav Morozov. immune system was restored. The researchers con- “Peptides of Pineal Gland and Thymus Prolong cluded, in their 1999 article in the New England Human Life.” Neuro Endocrinology Letters 24, no. 3/4 Journal of Medicine, “In some infants with profound (June/August 2003): 233–240. immunodeficiency and complete DiGeorge syn- Markert, M. Louise, M.D., et al. “Transplantation of drome, the transplantation of thymus tissue can Thymus Tissue in Complete DiGeorge Syndrome.” restore normal immune function.” New England Journal of Medicine 341, no. 16 (October The Thymus and Longevity 14, 1999): 1,180–1,189. Some researchers believe that the thymus and the pineal gland together have significant effects in extending longevity and that they are geroprotective. thyroid blood tests Generally refers to blood Researchers in Russia and the Ukraine, who tests obtained to determine the level of thyroid reported on their findings in a 2003 issue of hormone in the patient’s bloodstream. These tests Neuroendocrinology Letters, treated subjects with thy- help the physician to know whether disease is pres- malin, a peptide regulator from the thymus, and ent and if the thyroid is functioning at an appro- also with epithalamin, another peptide regulator priate level. They may be used to diagnose illness that stems from the pineal gland. They adminis- or to follow-up with patients already known to tered these drugs to 266 elderly individuals who have thyroid disease to determine whether the were older than age 60 over the course of six to medical treatment is appropriate and effective. eight years. The researchers found a significant Patients may receive blood tests to check their THY- decrease in respiratory disease, heart disease, ROID-STIMULATING HORMONE (TSH) levels, T3 or T4 hypertension, osteoarthritis, and osteoporosis com- levels, as well as their “free” thyroid levels of T3 pared with subjects in the control group. They also and T4. found a decreased mortality rate among the treat- The TSH test, described in more detail in this ed subjects. Further research is needed to confirm entry, is the primary test employed when a physi- or refute these findings. cian is screening for a thyroid disorder. It is also the test of choice when determining whether a patient Cancer of the Thymus is taking an appropriate amount of thyroid hor- The thymus can become cancerous, which is mone replacement for the treatment of any one of known as thymoma and thymic carcinoma. the many causes of HYPOTHYROIDISM. For other con- Thymoma is usually a slow-growing tumor that ditions, the TSH level must be measured and other remains inside the thymus gland. Most people with tests performed to make a determination of the thymoma have another immune system disease, patient’s status. such as myasthenia gravis, a disease that causes Helpful though they are, thyroid blood tests weak muscles. Thymic carcinoma, in contrast, should not be the only tool doctors rely upon to thyroid blood tests 221 diagnose thyroid disorders. Prior to making a diag- duced in the hypothalamus. The usual feedback nosis, an experienced ENDOCRINOLOGIST will always loop is that T4 and T3 thyroid hormones travel via take into account the patient’s history, the findings the blood to the pituitary and the hypothalamus. In from the physical examination, as well as any thy- both places, if the thyroid hormone levels are inad- roid function tests, ultrasounds, nuclear scans, or equate, the synthesis of TRH and, in turn, TSH are biopsy data. increased. This increased TSH travels via the blood Nonetheless, researchers using thyroid blood to the thyroid to stimulate more thyroid hormone tests have clearly demonstrated that thyroid dis- production. ease is very common. For example, in 2000, the When thyroid hormone levels are adequate, the researchers in the Colorado Thyroid Disease hypothalamus and the pituitary detect them, and Prevention Study reported findings of elevated TSH the TRH and the TSH levels both return to baseline. levels in 9.5 percent of nearly 26,000 patients who The body modulates the amount of thyroid hor- had not previously been diagnosed with thyroid mones from minute to minute as well as over the disease. Thus, they found a significant number of course of an individual’s life. people who were biochemically hypothyroid and Note that some individuals who are ill may have untreated. TSH levels within the normal range. For example, This study is even more compelling when con- patients with EUTHYROID SICK SYNDROME often have sidering that the researchers used an upper limit of a normal TSH. Many ELDERLY individuals with 5.1 microunits/ml as the top normal TSH value. As hypothyroidism may have a normal TSH level. of 2003, based on recent data, the American Thus, as previously discussed, the doctor must con- Association of Clinical Endocrinologists narrowed sider the patient’s medical history, physical exami- the normal range for TSH levels to between about nation results, as well as the laboratory findings in 0.3 and 3.04 microunits/ml. Thus, if the Colorado order to make an appropriate diagnosis. Thyroid Disease Prevention team had repeated Because increased TSH levels indicate underac- their study using current guidelines for the diagno- tive thyroid function (hypothyroidism) while low sis of hypothyroidism, utilizing a tighter TSH range, TSH levels are usually seen with HYPERTHYROIDISM,a they would have found an even greater percentage discussion with patients about TSH levels often of undiagnosed people with hypothyroidism. causes confusion. This apparent contradiction is due Additionally, the researchers in this study found to the FEEDBACK LOOP that is in play involving the below-normal TSH levels (indicating hyperthy- thyroid gland, the pituitary, and the hypothalamus. roidism) among about 2 percent of the individuals If either low or high levels of TSH are found in a tested, using lower limits of 0.3 microunits/ml. This blood test for the first time, the test should be per- value is about what most laboratories continue to formed again to make sure that the findings were use today for a lower normal limit of TSH. not in error. Administering thyroid hormone to a A variety of laboratory tests other than the TSH person based on one TSH test alone would be a bad test are used to help physicians determine if a idea. Some medications can affect the TSH blood patient has thyroid disease and to assess the sever- test result, such as dopamine, glucocorticoid drugs, ity of any existing illness. These tests include the T3 and octreotide. test, the T4 test, the TSI test, and the anti-TPO test. The T3 Test The TSH Test The T3 test measures the concentration of total T3, The most commonly used thyroid test is the TSH which is all T3 that is bound to proteins in the blood test. This is a measurement of a hormone blood and consists mainly of albumin and thyroid- produced by the pituitary gland. As the name bonding globulin. Typically, T3 is measured with a implies, this hormone stimulates the thyroid gland. process known as radioimmunoassay. An estimat- TSH is necessary in small amounts for the thyroid ed 20 percent of T3 is synthesized in the thyroid to function well at baseline. TSH is under the con- gland, and the balance is created in nonthyroid trol of thyrotropin-releasing hormone (TRH), pro- tissues. Total T3 is not commonly measured but is 222 thyroid blood tests useful in the assessment of hyperthyroidism. It is Normal values for total T4 vary slightly from not helpful at all in the diagnosis of hypothy- laboratory to laboratory, but the typical normal roidism. range is approximately 4.5–11 micrograms per In the most common form of hyperthyroidism, deciliter (mcg/dl). Greater-than-normal levels of T4 GRAVES’ DISEASE, T3 can be preferentially produced may indicate the patient has a form of hyperthy- in the thyroid gland. Production of T3 can also be roidism, such as Graves’ disease. It may also indi- seen in toxic multinodular goiters as well as with cate elevated levels of binding proteins, as is seen in single toxic nodules or adenomas (also called women taking oral contraceptives or patients who autonomously functioning thyroid nodules). Very have liver disease. Thus, these patients have high low levels of T3 can be seen in severe hypothy- concentrations of total T4, but they are clinically roidism, chronic illness, or starvation. euthyroid (normal). They have normal TSH levels Physicians may also request a test of free T3 and no signs or symptoms of hyperthyroidism. level. This refers to the concentration of unbound Other drugs in addition to oral contraceptives T3 able to get into cells and move to the nucleus to may cause elevated total T4 levels, including estro- interact with that cell’s DNA and to cause its myri- gens, methadone, amiodarone, and clofibrate. ad effects. Free T3 is rarely measured as it is more Some medications decrease T4 absorption, such as difficult to assay and because free T3 tests are more aluminium hydroxide, ferrous sulfate, sucralfate, expensive than other thyroid tests. It is occasional- cholestyramine, and colestipol. Other drugs affect ly ordered by endocrinologists when there is a the metabolism of both T3 and T4, including phe- complex issue involving binding proteins and an nobarbital, rifampin, phenytoin, and carba- attempt to determine the level of hyperthyroidism. mazepine, and cytokines such as interferon or interleukin-2. The effects will show up on thyroid The T4 Test tests, but only the physician can determine poten- The physician may order a test for total T4, or thy- tial causes for the laboratory results. This is why it roxine. Nearly 100 percent (99.7 percent) of T4 is is very important for the doctor to obtain a com- found in the bound form. Thyroxine is produced plete medical history, including all medications that solely by the thyroid gland. In patients who are the patient takes for any reason. hypothyroid, synthetic thyroxine, known as Lower-than-normal levels of total T4 may indi- levothyroxine (T4), enables them to achieve a nor- cate the patient has a form of hypothyroidism, such mal level of thyroid functioning. as a later stage of HASHIMOTO’S THYROIDITIS. It may Some patients take preparations of DESSICATED also indicate malnutrition or a serious systemic ill- THYROID, which is a prescribed drug that includes ness that has caused a decrease in proteins that both T3 and T4. The TSH test can be used regard- bind to T4. In addition, some medications cause less of the type of thyroid supplement (if any) that below-normal T4 levels, such as lithium, iodine, is taken by patients, although the interpretation of methimazole, interferon alpha, interleukin-2, thyroid function is more complicated when amiodarone, dexamethasone, propranolol, and patients are taking a combination of T4 and T3 propylthiouracil. medications than when they are taking just T4 Many radioimmunoassay kits now allow labora- alone. Note that three prospective studies have tories to measure the amount of free thyroxine failed to show any advantage to the use of the com- (free T4) in the blood. They are relatively easy to bination of T4 and T3 medications versus the use of use but have some variability from laboratory to T3 alone. laboratory and are not as precise, as of this writing, Researchers have made assessments based on as the TSH test. objective and subjective parameters, such as These radioimmunoassay kits are helpful in patient strength, energy levels, sense of well-being, sorting out issues related to illness, especially when weight, blood pressure, and cognitive function. that illness affects the levels of thyroid binding. Patients on T4 alone did as well as those on combi- These assays have made it less common for labora- nation therapy. tories to have to measure the total T4 as well as thyroid cancer 223 some measure of binding proteins and then to cal- crosomal antibody test and the antithyroglobulin culate a free T4 level. In various laboratories, these test. The antiglobulin test still has some value when free T4 tests have been given different names, such monitoring patients with THYROID CANCER. as the free thyroxine index, calculated free thyrox- See also HASHIMOTO’S THYROIDITIS; THYROIDITIS. ine, effective thyroxine, or estimated free thyrox- Canaris, Gay J., M.D., et al. “The Colorado Thyroid ine. Individuals with a lower-than-normal level of Disease Prevalence Study.” Archives of Internal Medicine free T4 may have hypothyroidism, while above- 160, no. 4 (2000): 526–534. normal levels often indicate hyperthyroidism. Demers, Lawrence M., and Carole A. Spencer. Laboratory The TSI Test Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease. National The thyroid-stimulating immunoglobulin (TSI) Academy of Clinical Biochemistry, 2002. Available test, also known as the TSH receptor antibody test, online. URL: http://www.nacb.org/lmpg/thyroid lmpg may also be ordered for patients who are suspected pub.stm. Downloaded January 15, 2004. of or known to have Graves’ disease. It provides a Surks, Martin I., M.D., and Rubens Sievert, M.D. “Drugs rough estimate of how much of this antibody is and Thyroid Function.” New England Journal of present as well as how active it is. Medicine 333, no. 25 (1995): 1,688–1,694. The TSI test is most commonly used for women in their third trimester of pregnancy to help predict neonatal Graves’ disease in the fetus. In cases in which it is unclear whether the patient has Graves’ thyroid cancer Malignant tumor of the thyroid disease, a positive TSI assay may indicate the diag- gland. Thyroid cancer is not a rare form of cancer, nosis of this autoimmune illness. The test is also and most patients with the disease have a very given to infants, children, and adolescents to pre- good prognosis. According to the American Cancer dict thyroid disease. Society, an estimated 22,000 new cases of thyroid cancer were diagnosed in the United States in The Anti-TPO Test 2003, 16,300 females and 5,700 males. Clearly, The most commonly assayed thyroid antibody test thyroid cancer is a greater risk for women, and it is the anti-thyroid peroxidase antibody, or anti- represents 3 percent of all cancers in women. An TPO test. Peroxidase is a protein, specifically an estimated 1,400 people died of thyroid cancer in enzyme, that is present in thyroid cells. As a pro- 2003, including 800 women and 600 men. In con- tein, it can function as an antigen, which means sidering middle-aged adults with thyroid cancer, the immune system can respond to it. In patients from 80–95 percent of them will survive 10 years with Hashimoto’s thyroiditis, the body mistakenly or more. makes an antibody (also known as an immunoglob- There are four major types of thyroid cancer, ulin) to combat the peroxidase protein. This anti- including papillary thyroid cancer, follicular thy- body binds to the thyroid. If enough of these roid cancer, medullary thyroid cancer, and anaplas- antibodies bind, they can damage the thyroid gland. tic thyroid cancer. Of these, papillary thyroid This can cause transient hyperthyroidism and then cancer is the most common, representing from eventually cause hypothyroidism. 70–80 percent of all thyroid cancers. The least com- The anti-TPO test is now the gold standard for mon is anaplastic thyroid cancer, which represents determining whether a patient has Hashimoto’s less than 3 percent of all thyroid cancers. There are thyroiditis. However, test results may also show also rare lymphomas of the thyroid gland as well as mild elevation for other forms of thyroiditis as well metastases (spread) to the thyroid from other pri- as for Graves’ disease. After many years of damage mary tumors. to the thyroid gland, the levels of anti-TPO antibod- In the Surveillance, Epidemiology and End ies can be quite low. Thus its absence does not com- Results (SEER) government database of nearly pletely rule out autoimmune thyroid disease. This 16,000 patients, the 10-year survival rate for the test has replaced the older and less specific antimi- epithelial thyroid cancers were as follows: 98 percent 224 thyroid cancer for papillary type, 92 percent for the follicular type, People who have goiters have an increased risk and 13 percent for the anaplastic type. for developing thyroid cancer. The incidence In a study of 336 patients whose thyroid cancer among such patients is 10–15 percent. was known to have spread, reported in a 2003 A lack of iodine in the diet may lead to thyroid issue of the Journal of the American College of Surgery, cancer. Because iodine is added to salt in the United researchers found that those with the best survival States, thyroid cancer is rarely caused by iodine outcomes were patients who were under age 45 deficiencies in this country. years old. Thyroid cancer may also have a genetic basis. According to the National Cancer Institute of Some researchers have found that an alteration in Canada, thyroid cancer has the most rapidly the RET gene may be transmitted from a parent to increasing rate of incidence among both men and a child, causing medullary thyroid cancer. If sever- women in Canada, although the reasons for this is al people in a family are diagnosed with thyroid unknown. cancer, other members may wish to be tested for a mutation of the RET gene. This syndrome, when Risk Factors present, is also called familial medullary thyroid can- Thyroid cancer occurs among all age groups, cer or multiple endocrine neoplasia, type 2 (MEN although it is more commonly found among indi- 2). Individuals who have MEN 2 syndrome are also viduals over age 30. Women have about a two to at risk for developing other types of cancer. three times greater risk of developing thyroid cancer than men. Distinctive racial differences occur in Symptoms of Thyroid Cancer the incidence of thyroid cancer. As with many other forms of cancer, most people In the United States, high rates have been iden- in the early stages of thyroid cancer have no symp- tified among Asian women, with Filipino women toms or signs of disease. When symptoms or signs (14.6 per 100,000 women) experiencing the high- occur, they may include the following: est rates, followed by Vietnamese women (10.5 per 100,000) and Hawaiian women (9.1 per 100,000). • Hoarseness Caucasians are more likely than African Americans • A lump near the Adam’s apple of the neck to develop thyroid cancer. The lowest rates of thy- • Swollen lymph nodes in the neck or nearby roid cancer occur among African-American women (3.3 per 100,000). • Dysphagia (difficulty swallowing) People who were exposed to excessive radiation • Pain in the neck or throat have an increased risk for developing thyroid cancer. From the 1920s to the 1950s, many doctors Medullary carcinoma of the thyroid secretes routinely used X-rays to diagnose and treat children CALCITONIN and thus can cause symptoms due to with tonsillitis, acne, an enlarged thymus, and other the presence of this hormone, such as flushing, medical problems of the head and neck. According nausea, and diarrhea. In addition, medullary carci- to the National Cancer Institute, scientists later dis- noma of the thyroid is often inherited. Family covered that this increased radiation exposure made members can be screened by measuring their calci- patients more vulnerable to thyroid cancer. tonin levels or by looking for abnormal chromo- (Experts report that radiation from dental X-rays is somes, such as RET. not risky for children and adults, although shields Anaplastic carcinoma typically presents in older should be used to protect the body below the head, men as a very hard mass in the neck. It is often whenever possible.) Experts are currently studying incurable at the time of diagnosis, as it does not con- patients who were exposed to radioactive fallout in centrate iodine, and thus radioactive iodine (RAI) Hanford, Washington, and Chernobyl in the therapy cannot be used. It is poorly responsive, if at Ukraine in the former Soviet Union. all, to chemotherapy and external radiation therapy. thyroid cancer 225

Diagnosis and Treatment To stage the cancer (determine how advanced it is If symptoms are present (though in the early stages and whether it has spread to other organs), whole- of thyroid cancer, they usually are not), the doctor body radioactive iodine scans are used to look for will perform a physical examination of the neck to thyroid tissue in the thyroid bed and elsewhere. check for nodules or swelling. (Most patients with Other imaging techniques such as ULTRASOUND, COM- thyroid nodules do not have thyroid cancer, but it PUTERIZED TOMOGRAPHY (CT) scans, MAGNETIC RESO- needs to be ruled out.) NANCE IMAGING (MRI) scans, or positron emission When a thyroid nodule is discovered, the first tomography (PET) scans are required for some thy- step should be a fine needle aspiration biopsy of the roid cancers and may be used to help determine the thyroid gland. In this procedure, a very small needle, extent of the spread of the tumor. usually 21–27 gauge, is inserted into the thyroid in The treatment of the cancer depends on the order to obtain small numbers of thyroid cells that severity of the disease. Severity is a function of the can be viewed under a microscope. This procedure type of cancer (papillary being the least aggressive can be done in the doctor’s office. Ultrasound guid- and anaplastic being the most aggressive), the size ance may be used if the nodule is difficult to palpate of the tumor, and whether or not there is metas- or if multiple nodules are present. tases. For small, nonaggressive cancers, a hemithy- The ultrasound can also be used to follow up roidectomy, which is a near-total thyroidectomy, and check on the size of a nodule accurately. If a may suffice. If there is concern that small amounts specific kind of calcification is seen on the ultra- of cancer may have been left behind in the thyroid sound, it can be a marker for a malignancy, bed or if there are metastases, then radioactive although the presence of this calcification is not iodine is used to kill the remaining cells. A thy- sensitive or specific enough to be used as a screen- roidectomy must be done prior to the use of RAI ing technique. therapy. Giving a dose that is large enough to wipe If the biopsy results are unclear, the endocrinol- out the entire thyroid is not practical or safe. Thus ogist may order a technetium or iodine scan of the the majority of the thyroid cells (most of which are thyroid to determine if the nodule is functional benign) must be removed surgically prior to the (warm), nonfunctional (cold), or hyperfunctional use of RAI. (hot). Cold nodules have the highest risk of malig- The isotope iodine-131 is used. It is very safe in nancy, although the majority of them (70–85 per- small-to-moderate doses with little risk to the cent) are still benign. Hot nodules are very rarely recipient. However, when large doses are used, malignant. such as greater than 200 millicuries, bone marrow Blood tests may also indicate the presence of is affected. Its ability to function must be monitored thyroid cancer. For example, calcitonin is consid- by physicians. In addition, if there is a large ered a tumor marker for medullary carcinoma of amount of metastases in the lung, large doses of the thyroid. It is always elevated when the patient RAI can cause scarring (fibrosis) of the lung, dam- has thyroid cancer. aging its ability to function. With papillary and follicular thyroid cancers, In the past, in order to use RAI therapy effec- measurement of serum thyroglobulin is used to tively, thyroid hormone therapy was withdrawn to help physicians track the disease. Thyroglobulin is allow the body’s endogenous level to rise. This a protein that is composed of only thyroid cells. If a would then maximize the efficacy of the RAI ther- person has had his or her entire thyroid removed apy, and an elevated thyroid-stimulating hormone as well as follow-up RAI therapy, then usually no (TSH) level would help drive the RAI into the detectable thyroglobulin is in the blood. If thy- remaining thyroid cells. However, the patients nec- roglobulin is detected, this is an indication of can- essarily became very hypothyroid during this time cer spread that should be treated with further and felt miserable. Recombinant TSH (thyrogen) is radiation therapy. now used. 226 thyroidectomy

In most cases, two or three doses of Thyrogen Results (SEER) Program 1973–1991.” Cancer 79, no. 3 are given to the patient intramuscularly several (1997): 564–573. days prior to the RAI uptake scan and therapy. The Shoup, M., et al. “Prognostic Indicators of Outcomes in Thyrogen increases the overall level of TSH in the Patients with Distant Metastases from Differentiated system while the patient is still taking thyroid hor- Thyroid Carcinoma.” Journal of the American College of mone replacement. Both the scan and the treat- Surgery 197, no. 2 (August 2003): 191–197. ment can be done effectively without causing the patient to become hypothyroid. For tumors that do not concentrate iodine, other thyroidectomy Partial or total surgical removal of forms of chemotherapy may be used, although most the diseased thyroid gland, often due to nodular thy- are fairly ineffective. Another option for patients roid disease, GRAVES’ DISEASE, or THYROID CANCER. with advanced thyroid cancer is to join a clinical The thyroidectomy is described as partial (any study, in which they may have the opportunity to part), hemi (half), isthmusectomy (excision of the try a new drug or treatment that is under study and isthmus), and total or near-total thyroidectomy. that otherwise would not be available to them. Thyroid surgery is best done by a surgeon with See also CANCER; MULTIPLE ENDOCRINE NEOPLASIA. extensive experience in performing this procedure. For further information on thyroid cancer, con- Typically, a necklace-type incision is used. As with tact the following organizations: all surgeries, complications are possible as well as possible complications due to anesthesia, blood American Cancer Society loss, and infection, although complications from 1599 Clifton Road NE blood loss and infection are rare. Atlanta, GA 30329 The thyroid must be carefully excised by the (404) 320-3333 or (800) 227-2345 (toll-free) surgeon because the parathyroids can be temporar- http://www.cancer.org ily or permanently damaged or disrupted by the Light of Life Foundation surgery. (If the parathyroids are damaged or P.O. Box 163 destroyed, the resulting HYPOPARATHYROIDISM will Manalpan, NJ 07726 necessitate the use of vitamin D and calcium, and (877) 565-6325 (toll-free) possibly of magnesium supplement, for the http://www.lightoflifefoundation.org remainder of the patient’s life.) In addition, the recurrent laryngeal nerves are located very close to National Cancer Institute the thyroid gland and can become damaged during Building 31, Room 11A16 surgery, which would lead to partial or complete 9000 Rockville Pike vocal cord paralysis. Rockville, MD 20892 If a total or near-total thyroidectomy is per- (800)-4-CANCER (toll-free) formed, the patient will need to take replacement http://www.cancer.gov thyroid medication for the rest of his or her life. ThyCa: Thyroid Cancer Survivors Association, Inc. See also THYROID GLAND. P.O. Box 1545 New York, NY 10159 (877) 588-7904 (toll-free) thyroid gland A very important, butterfly- http://www.thyca.org shaped organ, located in the neck, that controls the body’s overall METABOLISM and energy levels Abraham, Jame, and Tito Fojo. “Endocrine Tumors.” in through its production of thyroid hormone. Bethesda Handbook of Clinical Oncology. Philadelphia, The thyroid has two lobes and a connecting sec- Pa.: Lippincott Williams & Wilkins, 2001. tion called the isthmus. Embryologically, the thy- Gilliland, F. D., et al. “Prognostic Factors for Thyroid roid descended from an area near the tongue. Carcinomas: A Population Based Study of 15,698 Sometimes, remnants of thyroid tissue can be left Cases from the Surveillance, Epidemiology and End behind and can form what is known as a thy- thyroiditis 227 roglossal duct cyst in the middle of the neck. In thyroid hormone. Thyroid hormone should be addition, this migration of the thyroid as the fetus thought of as a permissive hormone, or one that is develops also causes the recurrent laryngeal nerves required in appropriate amounts to allow each cell to be pulled along. A surgeon performing thyroid and organ system to function properly. It is not that surgery must be very careful to avoid damaging these systems will not function at all without thy- these vital structures that control the vocal cords roid hormone but, rather, that they will not func- and the ability to speak and sing properly. tion as well as they should function. The thyroid gland can be inspected from the The most common forms of thyroid disease are front of the neck. The endocrinologist will check it two autoimmune disorders: Graves’ disease, which by palpating the thyroid from the front and often causes hyperthyroidism, and HASHIMOTO’S THYROIDI- from the rear. The thyroid is fairly superficial, but it TIS, which causes hypothyroidism. Some individuals is partially covered by a thick layer of the anterior develop THYROID NODULES, which might need to be neck strap muscles. evaluated for the presence of thyroid cancer. During an examination, the physician will often See also GOITER; THYROID BLOOD TESTS; THY- want the patient to swallow to see that the thyroid ROIDECTOMY; THYROIDITIS; THYROID-STIMULATING moves properly up and down. Sometimes it is situ- HORMONE; THYROXINE. ated a bit lower than usual and is behind the man- nerism (the top part of the sternum, or the breastbone), and thus it can be felt only when the thyroiditis A general term indicating an inflamma- person swallows. At times, the thyroid gland is tion of the thyroid gland. Thyroiditis may cause completely behind the breastbone and can be seen excessively low (hypothyroid) or high (hyperthy- only with imaging techniques. roid) levels of thyroid hormone. HASHIMOTO’S A substantial goiter is not uncommon in the THYROIDITIS, the most common cause of hypothy- thyroid gland. The four parathyroid glands are roidism, is also the most common cause of chronic located close to the right and left thyroid lobes and thyroiditis. Other forms of thyroiditis, which may be at times actually lie within the thyroid gland itself. acute or subacute, include painless lymphocytic thy- The thyroid gland has active transporters to take roiditis (which is the cause of the thyroiditis and is up iodine from the circulation and combine it with also known as painless sporadic thyroiditis and post- tyrosine, an amino acid, in order to make various partum thyroiditis), subacute thyroiditis (which is thyroid hormones. The thyroid gland synthesizes T4 painful), suppurative thyroiditis, and drug-induced (LEVOTHYROXINE), T3 (tri-iodothyronine), thyroglob- thyroiditis. The treatment of the thyroiditis depends ulin, and various other forms of thyroid hormone on the particular cause. that are relatively unimportant. The thyroid’s ability to take up iodine from the circulation actively is uti- Hashimoto’s Thyroiditis lized in thyroid scanning with radioactive iodine and An autoimmune disorder that can occur at any age, technetium to create images of the gland and to Hashimoto’s thyroiditis is most common among measure its biological activity. In addition, the patients between the ages of 30 and 50 years. It is ENDOCRINOLOGIST can use this ability of the gland to more frequently found among smokers. Hashimoto’s import iodine actively to treat patients with GRAVE’S thyroiditis may also cause a GOITER (enlargement of DISEASE and THYROID CANCER with the appropriate the thyroid gland). therapeutic dosages of radioactive iodine. In the early phases of the illness, the patient When the thyroid gland functions normally, the maintains normal thyroid function. As the gland energy levels of a person are consistent with the enlarges, portions of it become damaged and do needs of the individual and the overall metabolism not function as well. Thus, early on, the thyroid is within normal ranges. When it malfunctions, gland may be slightly enlarged and firmer than individuals may have HYPOTHYROIDISM, with low usual. The patient may have increased levels of levels of thyroid hormone, or they may have antithyroid peroxidase antibodies but yet have HYPERTHYROIDISM, with excessively high levels of completely normal levels of thyroid hormone. 228 thyroiditis

Many endocrinologists choose to treat patients thyroiditis from GRAVES’ DISEASE. With painless early in the course of this disease with prescribed lymphocytic thyroiditis, the iodine uptake is very thyroid hormone. They hope that the thyroid hor- low. In contrast, with most patients with Graves’ mone, which decreases the amount of thyroid- disease, it is high. stimulating hormone (TSH), will prevent the Painless sporadic thyroiditis is essentially the thyroid gland from enlarging. They prefer to avoid same disease as painless postpartum thyroiditis, waiting for the overt symptoms of hypothyroidism without a pregnancy having occurred. The therapy to occur. is the same as well. Later in the course of the disease, due to ongo- Many patients do not require any medication for ing damage to the thyroid gland, it may shrink and painless lymphocytic thyroiditis. Symptoms of become fibrotic (scarred). hyperthyroidism, such as rapid heartbeat (tachycar- Hashimoto’s thyroiditis is chronic and slow dia), nervousness, palpitations, tremors, and anxi- developing. Consequently, it is painless, causing no ety can be diminished with the use of beta-blockers tenderness nor redness. Patients with Hashimoto’s such as propranolol (Inderal), atenolol (Tenormin), thyroiditis are at an increased risk for developing a and metoprolol (Lopressor and Toprol-XL). lymphoma of the thyroid, although such a development is very rare. Painful Subacute Thyroiditis This disease is also an autoimmune disorder. Painless Lymphocytic Thyroiditis (Postpartum Painful subacute thyroiditis is rare and represents Thyroiditis and Painless Sporadic Thyroiditis) only about 5 percent of all diagnosed thyroid dis- Postpartum thyroiditis, also an autoimmune disor- eases. It is most commonly seen in the summer- der, is fairly common and occurs in as many as 10 time after the patient has had an upper-respiratory percent of women within several months of child- viral infection. Patients present with a sore throat birth. It is more common among women with TYPE 1 and neck, general body aches and pains, fatigue, DIABETES, other autoimmune disorders, or a family and low fevers. history of autoimmune disorders, especially autoim- Many patients are misdiagnosed because the mune thyroid disorders. THYROTOXICOSIS may occur condition is not considered or the gland is not pal- within one to six months after the delivery and may pated, nor is it noted to be tender. As many as half last for one to four months, although most patients of these patients may also have thyrotoxicosis for who experience thyrotoxicosis have it for one to two several weeks, after which their thyroid function months. The patient then enters a euthyroid (nor- will be normal for several months, possibly fol- mal thyroid phase) for one to two months. lowed by the patient becoming hypothyroid for After this phase, the patient may then become about four to six months. About 95 percent of hypothyroid (underactive thyroid) for four to six patients with painful subacute thyroiditis ultimate- months. About 80 percent of women with painless ly regain normal thyroid function. postpartum thyroiditis eventually regain normal Patients with painful subacute thyroiditis have thyroid function. an elevated level on the erythrocyte sedimentation With all the many changes that women face rate (ESR) blood test, antithyroid antibodies, and after delivering a child (fatigue, disrupted sleep, also have high rates of C-reactive protein blood hair loss, and other symptoms), this thyroid condi- concentration. tion can be misdiagnosed or missed completely. If Treatment is aimed at helping the patient cope diagnosed, the physician needs to be fully aware of with pain. Most patients are treated with aspirin or the course of postpartum thyroiditis since sequen- nonsteroidal anti-inflammatory medications tial thyroid tests can give confusing results and may (NSAIDs) to provide pain relief. If the pain is be elevated, then normal, and finally, low. extreme, patients may be treated with corticos- Physicians may elect to use a 24-hour iodine teroids such as prednisone, which are generally uptake test to differentiate painless lymphocytic tapered down over four to six weeks. thyroiditis 229

Suppurative Thyroiditis with antithyroid medications, such as methimazone This form of thyroid inflammation is usually caused or propylthiouracil, can be attempted but often fails. by a bacterial infection, but it may also be caused Type II thyroiditis may be treated with high doses of by fungal, mycobacterial, or parasitic infections. corticosteroids, which may help. In addition, per- Infections of the thyroid gland are rare. They may chlorate may be used to try to discharge the excess be found in patients with preexisting thyroid dis- iodine from the thyroid gland. However, this is not ease as well as among those who are immunocom- a Food and Drug Administration-approved use of promised, such as elderly individuals, patients with perchlorate. In resistant cases, the symptoms can be acquired immune deficiency syndrome (AIDS), diminished with beta-blockers and the patient can and recipients of organ transplants. undergo a thyroidectomy. Patients with suppurative thyroiditis have trouble swallowing (dysphagia), fever, and neck pain. Lithium-Induced Thyroiditis Their sedimentation rates and white blood cell Thyroiditis caused by a patient taking lithium usu- counts are elevated. The illness is usually diagnosed ally causes hypothyroidism. In a few cases, the with a fine-needle aspiration and a culture of the lithium may induce Graves’ disease, the dominant tissue. Antibiotics are used, and the thyroid is form of hyperthyroidism. When hypothyroidism drained of any abscess that may be present. occurs, treatment with thyroid hormone is usually used. When hyperthyroidism occurs, and if it can- Medication-Induced Thyroiditis not be successfully treated, patients must confer The primary types of medications that may cause with their psychiatrist, neurologist, or primary care thyroiditis are amiodarone (a heart medication), physician to consider therapies other than lithium lithium (a psychiatric medication), and interferon to treat their underlying disorders. alpha or interleukin-2 (medications given to boost the immune system). Immune Medication-Caused Thyroiditis Interferon alpha, when used as therapy to treat Amiodarone-Induced Thyroiditis hepatitis B and hepatitis C, can cause thyroid dys- Thyroid disease caused by taking amiodarone is function within three months of beginning thera- often very difficult to treat. Amiodarone may cause py. This form of thyroiditis is most likely to occur hypothyroidism (may be treated with thyroid hor- among patients with a preexisting thyroid abnor- mone) and hyperthyroidism. However, when mality, such as those who have a predisposition to hyperthyroidism is induced by amiodarone, life developing an autoimmune thyroid disease and becomes very difficult for patients, their cardiologist, who have only positive thyroid peroxidase anti- and their endocrinologist. This is because amio- bodies. Interferon alpha can induce both hypothy- darone is used to treat significant heart arrythmias roidism and hyperthyroidism. (such as atrial fibrillation, ventricular tachycardia, Interleukin-2, which is used in the treatment of and other life-threatening heart rhythm distur- leukemia and other malignancies, can cause thyroid bances), and must be maintained for life. dysfunction in about 1–3 percent of those treated. Because amiodarone is 37 percent iodine by Patients with thyroiditis who continue on the weight, antithyroid drugs and radioactive iodine interferon alpha or interleukin-2 may also receive will not work. Antithyroid drugs work by blocking beta-blocker medications or corticosteroids. If they the uptake of iodine and decreasing thyroid hor- are hypothyroid, they will also be treated with mone synthesis. Radioactive iodine kills thyroid levothyroxine. cells. Neither works because the amiodarone has filled the thyroid full of iodine. Other Forms of Thyroiditis Two types of amiodarone-induced thyrotoxicosis Radiation-induced thyroiditis can occur after the occur. Type I is more commonly seen among use of radioactive iodine for the treatment of patients with preexisting thyroid disease. Treatment hyperthyroidism, at which point there is elevated 230 thyroid nodules thyroid iodine uptake. The destructive effects of Endocrinologists will assess the individual’s can- radioactive iodine can lead to a brief exacerbation cer risk based on the patient’s medical history and of hyperthyroidism that can usually be treated risk factors. Cancer is more likely to be found in symptomatically with beta-blockers. Pain that has nodules in patients who are younger than age 30 as been caused by damage to the thyroid gland can be well as in male patients and in those who have treated with simple analgesics (painkillers), non- experienced radiation exposure. steroidal anti-inflammatory medications (NSAIDs), and sometimes corticosteroids. Single or Multiple Nodules Palpation-induced thyroiditis is caused by an There may be a solitary nodule or multiple nod- overly vigorous palpation of the thyroid gland. It is ules. A solitary nodule, if greater than one cen- rare and usually mild and can be treated with over- timeter in diameter, is considered to be a clinically the-counter analgesics, ice, and NSAIDs. significant nodule. (This definition continues to Fibrous thyroiditis is a very rare condition that is evolve as imaging modalities become better and are part of a primary fibrosing (scarring) syndrome. It able to detect smaller and smaller nodules.) In is treated with corticosteroids and surgery to avoid cases of multiple nodules, if one nodule is clearly compressive symptoms that prevent swallowing or larger than the others, it is considered a dominant breathing properly. nodule. Dominant nodules have a higher risk of cancer. On occasion, when multiple nodules are Pearce, Elizabeth N., M.D., Alan P. Farwell, M.D., and present and two are much larger than all the rest, Lewis E. Braverman, M.D. “Thyroiditis.” New England these two nodules are considered to be codomi- Journal of Medicine 348, no. 26 (June 26, 2003): nant. Thus, if nodules were present that were five 2,646–2,655. millimeters, three millimeters, six millimeters, seven millimeters, three millimeters,15 millimeters, and 19 millimeters in diameter, the 15-millimeter thyroid nodules Any focal enlargement of a por- and 19-millimeter nodules would be considered tion of the thyroid gland as detected by palpation codominant. upon physical examination, ULTRASOUND, or another Nodules may be simple or complex and solid or imaging modality such as nuclear thyroid scanning, cystic. They may also be consistent throughout COMPUTED TOMOGRAPHY (CT) scan, or MAGNETIC (homogeneous) or partially cystic, containing some RESONANCE IMAGING (MRI). fluid and partly solid (heterogeneous). Thyroid nodules are very common. In a study from Framingham, Massachusetts, the prevalence Growth of Nodules Does Not of clinically detected nodules was 6.4 percent in Ensure Cancer Presence women and 1.5 percent in men. Most thyroid nodules grow, whether they are benign or malignant. So increased growth is not Concern About Cancer necessarily an indication of thyroid cancer. The biggest fear when patients have thyroid nod- In a study reported in a 2003 issue of the Annals ules is whether they represent cancer. Up to about of Internal Medicine, researchers analyzed the out- 90 percent of thyroid cancers in the United States comes for all patients referred to the Brigham and are papillary, follicular, or mixed thyroid cancers, Women’s Hospital Thyroid Nodule Clinic in Boston, (usually papillary-follicular) all of which have very Massachusetts, between 1995 and 2000 who good long-term survival rates. requested a follow-up ultrasound examination The incidence of cancer in nonselected nodules within one month to five years after their initial (nodules that are randomly detected) is in the 3–6 examination. There were a total of 268 patients with percent range in the United States. The presence of 338 nodules. The majority were female patients. microcarcinomas of the thyroid (less than 10 mil- The researchers found that the majority of limeters in diameter) is very common and may be patients (89 percent) had thyroid nodules that as high as 15 percent. grew by at least 15 percent. They also found that thyroid nodules 231 solid nodules were more likely to grow than cystic slide. The solution is spun down to make a small ones. Of the nodules that the researchers reaspirat- pellet of cells. The slide is examined by cytopathol- ed with fine-needle aspiration, only one in 74 was ogists much as Pap smears in women are studied. malignant. The pathologist must be experienced in this specific form of pathology, because the analysis can be Diagnosis and Treatment very tricky. If the local pathologist is not trained or The patient and/or the physician may notice the experienced in this field, the slides are usually for- presence of a single nodule, multiple nodules, or warded to another pathologist who has the requi- goiter (a general term, meaning enlargement of the site skills. thyroid gland). Many nodules are found acciden- In general, one of four conclusions can be tally by the physician. For example, a patient may reached about the biopsy sample: be sent for an ultrasound of the carotid arteries and a nodule is detected, or a patient may have a CT 1. The specimen is inadequate for analysis and scan of the neck or chest and a nodule is seen. the biopsy must be repeated Endocrinologists often refer to nodules detected in 2. The specimen is suspicious for cancer or is con- this manner as incidentalomas. However, because sistent with a cancer diagnosis, and the patient thyroid cancer is relatively common, these nodules is referred for surgery must be evaluated. 3. The specimen appears clearly benign, and the The first step in the evaluation of a single nod- patient can be followed conservatively ule, many nodules, or a dominant or codominant 4. The specimen is indeterminate, and other tests nodule should be to biopsy the patient with a fine- must be factored in to allow the physician to needle aspiration. In the past, when a multinodu- reach a treatment decision lar goiter was detected, many endocrinologists did not pursue a biopsy. However, it is now known that Laboratory tests should not be used first to eval- the presence of a multinodular goiter does not pro- uate a nodule. Laboratory tests should be obtained tect a patient from thyroid cancer. specifically when called for, especially if the patient In this procedure, which is typically performed has any signs and/or symptoms of thyroid overac- at the endocrinologist’s office without any anesthe- tivity (hyperthyroidism) or underactivity (hypo- sia, a very small needle is inserted through the skin thyroidism). Typically, the risk of cancer is lower in into the thyroid gland. The needle is usually a a hyperthyroid patient than in a patient who is 23–27 gauge needle, much smaller than the nee- hypothyroid or euthyroid (having normal thyroid dles used to draw blood. Anywhere from one to six levels), but it is still not zero. If the patient has passes are made into the nodule. The needle and hyperthyroid signs and symptoms or he or she is the syringe are also rinsed in a solution to enable found to be hyperthyroid by laboratory tests and the retrieval of as many cells as possible. also has a thyroid nodule, this does not yet rule out Sometimes a small amount of local numbing the diagnosis of cancer. medicine may be injected under the skin prior to If a fine-needle aspiration biopsy of a thyroid the fine-needle biopsy. However, most patients feel nodule gives indeterminate results, the options for that the prick and burning from this anesthetic follow-up include watchful waiting (observing and (typically a form of novocaine) is worse than the monitoring the patient but taking no action), surgi- biopsy itself. cal excision of the thyroid gland, a repeat biopsy, or If a nodule is not easily palpable (the physician a thyroid scan. The thyroid scan will determine cannot feel it with the fingers), it could be biopsied whether the nodules are functional (warm or hot) with ultrasound guidance. Often with a multi- or nonfunctional (cold). Cold nodules have a high- nodular goiter, the biopsy must be done in this way er risk of cancer. Warm nodules have a lower risk, to be sure that the appropriate nodule is biopsied. and hot nodules have a very low risk of cancer. A fairly small number of cells are shaved off by Although nodules that grow do not necessarily indi- the beveled end of the needle and squirted onto a cate cancer, patients should be carefully followed by 232 thyroid-stimulating hormone their physicians in the event that the nodule does excess thyroid function), while an above-normal become cancerous. level indicates HYPOTHYROIDISM (low levels of thy- See also GOITER; HYPERTHYROIDISM; HYPOTHY- roid hormones and inadequate thyroid function). ROIDISM; THYROID CANCER. Although the TSH assay tends to be very accurate, the test will be repeated if the results are abnormal Alexander, Erik K., M.D., et al. “Natural History of in case a laboratory error has occurred. Benign Solid and Cystic Thyroid Nodules.” Annals of The TSH is the best test to use in patients with Internal Medicine 138, no. 4 (February 2003): 315–318. primary hypothyroidism. With chronically hypo- Mortensen, J. D., L. B. Woolner, and W. A. Bennett. “Gross thyroid patients, the American Academy of Clinical and Microscopic Findings in Clinically Normal Thyroid Endocrinologists now recommends titrating the Glands.” Journal of Clinical Endocrinology & Metabolism amount of thyroid hormone given to maintain a 15, no. 10 (1955): 1,270–1,280. TSH level between 0.5 and 2.0 microunits/ml. Tan, G. H., and H. Gharib. “Thyroid Incidentalomas: See also GRAVES’ DISEASE;HASHIMOTO’S THYROIDI- Management Approaches to Nonpalpable Nodules TIS; POSTPARTUM THYROID DISEASE; THYROID BLOOD Discovered Incidentally on Thyroid Imaging.” Annals TESTS. of Internal Medicine 126, no. 3 (1997): 226–231. Vander, J. B., E. A. Gaston, and T. R. Dawber. “The Significance of Non-Toxic Thyroid Nodules. Final thyroid storm A life-threatening condition in Report of a 15-Year Study of the Incidence of Thyroid which the patient has extremely high levels of thy- Malignancy.” Annals in Internal Medicine 69 (1968). roid hormone and multiple clinical abnormalities, including fever and dysfunction of an organ system other than the thyroid gland. Thyroid storm is the thyroid-stimulating hormone (TSH) A hormone most extreme case of THYROTOXICOSIS. Because produced by the anterior pituitary to stimulate the GRAVES’ DISEASE is the most common cause of thyroid gland. It is under the control of the hypo- hyperthyroidism and thyrotoxicosis, it is also the thalamus, which stimulates the pituitary with most common cause of thyroid storm. thyrotropin-releasing hormone (TRH). Both the Thyroid storm tends to occur in patients who hypothalamus and the pituitary are part of a feed- have underlying hyperthyroidism, that is, either back loop with the thyroid gland. The hypothala- untreated or partially treated hyperthyroidism. mus and the pituitary gland can both detect low There is often a precipitating event. Some precipi- levels of thyroid hormone and then increase their tating events include infection, heart attack, sur- secretion of TRH and TSH to normalize those levels. gery, and the use of intravenous contrast material TSH also refers to an assay for thyroid-stimulat- that contains large amounts of iodine. ing hormone. This blood test is the gold standard as Thyroid storm is the extreme opposite of the a single test to measure thyroid function and indi- MYXEDEMA COMA, in which patients have so little cates whether a patient has low, normal, or high thyroid hormone that they lapse into unconscious- TSH levels. The measurement of thyroid-stimulat- ness. Both conditions are very severe. Patients are ing hormone concentration is the most sensitive usually cared for in an intensive care unit with barometer of thyroid function in the body. The input from the intensive care staff, cardiologists, usual range for TSH is 0.3–3.4 microunits/ml, pulmonologists, and endocrinologists. according to the AMERICAN ASSOCIATION OF The symptoms and signs of thyroid storm are CLINICAL ENDOCRINOLOGISTS (AACE). This is a fever, very rapid heartbeat (tachycardia), and other change from the past recommended range of 0.5–5 organ system dysfunctions. These often include but microunits/ml. are not limited to congestive heart failure, deliri- With the TSH test, a below-normal level gener- um/psychosis, or respiratory failure. ally indicates that the patient may have HYPERTHY- The treatment for thyroid storm is first aimed at ROIDISM (high levels of thyroid hormones and decreasing the patient’s rapid heart rate and con- thyroxine 233 trolling the fever. Thus, acetaminophen (Tylenol), multinodular goiter or a toxic single nodule. In rare cooling blankets, and intravenous beta-blocker cases, lithium therapy can cause thyrotoxicosis. medications are usually employed. Many patients may require invasive monitoring of their car- Signs and Symptoms diopulmonary status and may also need mechani- Patients with thyrotoxicosis typically have accentu- cal ventilation (artificial breathing devices). ated symptoms of hyperthyroidism, including rapid The underlying cause of the thyroid storm must heartbeat (tachycardia), heat intolerance, nervous- be sought and appropriate therapy begun. If the ness, disrupted sleep, tremulousness, weight loss, cause is nondestructive, such as Graves’ disease, and a variety of other symptoms. The patient may then toxic nodule or goiter antithyroid drugs are or may not have an enlarged thyroid GOITER. begun in very high doses. Occasionally, iodine is Menstruating women may have a diminished men- used in the form of a supersaturated solution of strual flow or may have no menstrual flow (AMEN- potassium iodine (Lugol’s solution) or iopanoic ORRHEA). Elderly patients with thyrotoxicosis may acid. If the cause of the thyroid storm is a destruc- present with apathy rather than with hyperactivity tive lesion of the thyroid gland, such as a form of and may appear to have an underactive gland. thyroiditis, then therapy is aimed at decreasing the effects of the excess thyroid hormone. Diagnosis and Treatment See also HYPERTHYROIDISM. Thyrotoxicosis is usually suspected based on clinical symptoms. It is diagnosed by blood samples that test for thyroid-stimulating hormone (TSH), free thyrox- Thyrolar (liotrix tablets) A thyroid hormone ine, and in some cases, triiodothyronine levels (T3). replacement medication that contains synthetic T4 Treatment of thyrotoxicosis is directed at the and T3. The 60 mg or 1-grain tablet contains about underlying cause. It generally involves watchful 50 mg of T4 and 12.5 mg of T3, or about the equiv- waiting and the use of beta-blocker medications alent of 100 mcg of LEVOTHYROXINE. (for thyroiditis), antithyroid drugs (for Graves’ disease, toxic nodule, or goiter), or surgery in any case in which the other therapies cannot be utilized safely or effectively. thyrotoxicosis The clinical syndrome resulting from an excess of thyroid hormones in the blood- Fisher, Joseph N., M.D. “Management of Thyrotoxicosis.” stream. In extreme cases, known as THYROID STORM, Southern Medical Journal 95, no. 5 (2002): 493–505. the patient is in a life-threatening situation and requires immediate medical treatment. Thyroid storm is defined as thyrotoxicosis and fever plus thyroxine (T4) Natural thyroid hormone pro- dysfunction of one other organ system. duced by the thyroid gland. It is also known as T4 Thyrotoxicosis is similar to HYPERTHYROIDISM but due to the four iodine molecules attached to the implies a more severe clinical situation with more amino acid tyrosine that make up this hormone. signs and symptoms of excess thyroid hormones. Thyroxine acts as a prehormone. The body uses an In most cases (about 80 percent) the cause of thy- enzyme to cleave one iodine and to create the rotoxicosis is GRAVES’ DISEASE. However, some more active hormone, which is T3, also known as patients with HASHIMOTO’S THYROIDITIS, a form of triiodothyronine. Most of T4 that circulates in the HYPOTHYROIDISM, can develop thyrotoxicosis. An blood is bound to proteins, mostly albumin and estimated 5–10 percent of women develop thyrotox- thyroid-binding globulin (TBG). Thyroxine can be icosis after childbirth (postpartum thyrotoxicosis), measured as the bound hormone or total T4. A typically due to postpartum thyroiditis, also known bound hormone is attached to a binding protein in as painless lymphocytic thyroiditis (see POSTPARTUM the blood to be transported around the body, as THYROID DISEASE). Other causes include a toxic well as used for storage purposes. It can also be 234 triiodothyronine measured as the unbound or free form, free T4, tingling or pins and needles) in the fingers and may which typically provides a more accurate assessment. experience an involuntary twitching of the fingers. Most patients with HYPOTHYROIDISM must rely According to author Frank Urbano in his 2000 upon supplemental LEVOTHYROXINE, a synthesized article for Hospital Practice, the Trousseau-von form of thyroid hormone, to bring their thyroid Bonsdorff test is another test that can be used in blood levels up to normal. concert with Trousseau’s sign. If Trousseau’s sign is See also DESSICATED THYROID; THYROID BLOOD positive, the Trousseau-von Bonsdorff test is per- TESTS; THYROLAR. formed directly after the sphygmomanometer (blood pressure device) is deflated. The patient will breathe deeply, at about 40 breaths per minute, and then the physician will check for the same triiodothyronine (T3) The active form of thyroid spasm that is seen in Trousseau’s sign. hormone in the body. The thyroid actually makes See also HYPOPARATHYROIDISM; TETANY. more THRYOXINE, (T4), another thyroid hormone, than T3. The body uses enzymes to take one iodine Urbano, Frank L., M.D. “Signs of Hypocalcemia: off the T4 and covert it to T3 as it is needed. This is Chvostek’s and Trousseau’s Signs.” Hospital Physician why deficient thyroid hormone is usually replaced 36, no. 3 (March 2000): 43–45. with T4; thryoxine can be dosed once a day as opposed to 2–4 times per day with triiodothryo- nine. Thyroxine also provides prove stable levels Turner syndrome A genetic disorder with and less side effects than when T3 is used to replace endocrine features that is found in about one in deficient thyroid hormone. In some disease states, 2,500 girls born in the United States. About 60,000 such as GRAVES’ DISEASE and toxic thyroid nodules, girls and women in the United States have Turner the thyroid may produce more T3 than T4 and lead syndrome. The syndrome was named after Dr. to symptoms of HYPERTHYROIDISM/THYROTOXICOSIS. Henry Turner, an American physician who reported its traits in 1938 in the journal Endocrinology. Dr. C. Ford identified the major chromosomal abnor- Trousseau’s sign An indicator of low levels of cir- mality that causes Turner syndrome in 1959. culating calcium (HYPOCALCEMIA) that was original- The most common feature of Turner syndrome, ly discovered and described by 19th-century affecting an estimated 95 percent of all patients, is French physician Armand Trousseau. It is general- short stature. The average adult height of a patient ly considered to be a more reliable indicator of pos- with Turner syndrome is four feet and eight inches. sible hypocalcemia than CHVOSTEK’S SIGN. Even if Other common features are the lack of the develop- Trousseau’s sign is positive, however, the physician ment of secondary sexual characteristics (such as should order laboratory blood levels of calcium pubic hair and breasts) and the presence of INFER- before diagnosing hypocalcemia, because there are TILITY. Most females with Turner syndrome are born false positives with this sign. In addition, without ovaries. Most patients have normal intelli- Trousseau’s sign does not screen all individuals gence and can expect to live average life spans. with hypocalcemia. Patients can test negative for Turner syndrome is usually accompanied by a Trousseau’s sign and yet still have hypocalcemia. variety of medical problems, most prominently heart To check for Trousseau’s sign and possible defects (aortic valve problems and coarctation), hypocalcemia, the physician inflates a blood pres- INSULIN RESISTANCE (an increased relative risk for sure cuff above the patient’s systolic blood pressure both TYPE 1 DIABETES and TYPE 2 DIABETES), kidney level. Patients who are positive for Trousseau’s sign defects contributing to hypertension, celiac sprue, will experience an involuntary wrist flexion and a greater risk than normal for autoimmune toward the body and flexion of the fingers, with HYPOTHYROIDISM. (An estimated 10–30 percent of the thumb moving toward the palm. The patient patients with Turner syndrome have hypothy- will also experience paresthesias (numbness and roidism.) Many patients with Turner syndrome also Turner syndrome 235 have hearing difficulties, such as hearing loss, in a 2002 issue of the Journal of Clinical chronic middle ear infections, and inner ear hearing Endocrinology & Metabolism. In this study, 232 loss. Speech problems are also common. patients with Turner syndrome who were at least five years old and had a bone age of less than 12 Signs and Symptoms years old were placed into two groups. The subjects Physical traits of females with Turner syndrome came from sites throughout the United States. include a shield-shaped chest, webbed neck, low- In one group, the patients received growth hor- set ears, a lower-than-normal hairline, eye abnor- mone and a low dose of estrogen. The other group malities (amblyopia, strabismus, ptosis, and received a placebo. The researchers found a signif- red-green color blindness, among others), and icant increase of growth among the study subjects puffy feet and hands. About 10 percent of patients who were given growth hormone, and 29 percent with Turner syndrome develop scoliosis. Patients of them achieved a height greater than five feet (60 with Turner syndrome are prone to developing inches), compared with the placebo group, in keloid scars (very puffy and raised scars) if they are which only 5 percent achieved this height. The injured or have surgery. Thus elective surgery researchers also found that subjects with younger should be used on a limited basis only. Even simple age and lower bone age were more likely to have ear piercing can create scars in a patient with increased growth. They also found that estrogen Turner syndrome. administration did not improve the growth rate. Physicians have also noted an increasing inci- Diagnosis and Treatment dence of osteoporosis and fractures in women with Turner syndrome is diagnosed based on the charac- Turner syndrome as they age. Many of these teristic signs and symptoms of this medical problem women often had not previously received estrogen and may also be confirmed by genetic testing. therapy. Patients typically lack part or all of one of the two See also GROWTH HORMONE. X chromosomes, although there are cases of For more information, contact: mosaicism in which there are a mix of some nor- The Endocrine Society mal and abnormal chromosomes, thus the syn- 8401 Connecticut Avenue drome may not be as severe or obvious. There is no Suite 900 specific genetic treatment for Turner syndrome as a Chevy Chase, MD 20815 whole, but many of the medical problems that are (301) 941-0200 caused by or are related to it can be treated. For http://www.endo-society.org example, the patient with Turner syndrome who has hypertension can be treated for this ailment. Turner Syndrome Society Hypothyroidism can be treated with thyroid sup- 14450 T. C. Jester plements. Girls and women with Turner syndrome Suite 260 who have speech and hearing difficulties should Houston, TX 77014 receive a referral to an ear, nose, and throat clinic (800) 365-9944 (toll-free) and a speech therapist. http://www.turner-syndrome-us.org Because many girls with Turner syndrome have dental abnormalities, they should see a dentist and, Quigley, Charmian A., et al. “Growth Hormone and Low if appropriate, an orthodontist as well. Dose Estrogen in Turner Syndrome: Results of a Girls with unusually short stature may be treat- United States Multi-Center Trial to Near-Final ed with growth hormone, although there are many Height.” Journal of Clinical Endocrinology & Metabolism pros and cons to administering growth hormone 87, no. 5 (2002): 2,033–2,041. therapy. Only a pediatric endocrinologist should Saenger, P., et al. “Recommendations for the Diagnosis initiate and monitor this form of therapy. and Management of Turner Syndrome.” Journal of The efficacy combining a growth hormone and a Clinical Endocrinology & Metabolism 86, no. 7 (2001): low dose of estrogen was tested in a study reported 3,061–3,069. 236 Type 1 diabetes

Saenger, Paul, M.D. “Turner Syndrome.” New England These signs can appear suddenly, and patients Journal of Medicine 335, no. 23 (December 5, 1996): who have them should see their physicians as soon 1,749–1,754. as possible for diagnosis and treatment. Turner, H. D. “A Syndrome of Infantilism, Congenital See also DIABETES MELLITUS; GESTATIONAL DIA- Webbed Neck, and Cubitus Valgus.” Endocrinology 28, BETES; TYPE 2 DIABETES. no. 23 (1938): 566–574. Petit, William A. Jr., and Christine Adamec. The Encyclopedia of Diabetes. New York: Facts On File, Inc., 2002. Type 1 diabetes One of the two prevailing forms of diabetes (the other being Type 2 diabetes). Type 1 diabetes was formerly known as insulin-dependent Type 2 diabetes The most prevalent form of dia- diabetes mellitus or juvenile-onset diabetes. Patients betes, representing about 90–95 percent of all with Type 1 diabetes represent about 5–10 percent cases. (The other most common form is Type 1 dia- of all cases of diabetes found in North America. In betes.) Type 2 diabetes was formerly called non- the United States, about 900,000 children and insulin-dependent diabetes (NIDDM) or adult-onset adults have Type 1 diabetes, and about 13,000 new diabetes. Individuals with Type 2 diabetes produce cases are diagnosed every year. The disease is more insulin, but their bodies are unable to use insulin common among Caucasians than among other effectively due to insulin resistance. racial groups. Type 2 diabetes is caused by two problems. First, Type 1 diabetes is an autoimmune disease in there is a genetic predisposition for insulin resist- which the afflicted individual’s own immune sys- ance. Second, there is beta cell dysfunction in the tem destroys the beta cells in the pancreas that pancreas, which means that the patient cannot make insulin. Consequently, patients with Type 1 make enough insulin to overcome this resistance diabetes need to administer insulin in order to live, and thus, the blood glucose level increases. either through injecting it with needle, a pen-like device, or with an insulin pump. Patients must Risk Factors carefully monitor their blood glucose levels at least Based on 2004 estimates, approximately 17 million several times daily, depending on the advice pro- patients in the United States have Type 2 diabetes. vided by their physicians. They also need to act on Type 2 diabetes is more common among certain the information the blood tests provide, in some racial groups, such as African Americans or Native cases changing their diet, getting more rest, or tak- Americans, particularly the Pima Indians of ing other actions. Arizona. The risk for developing Type 2 diabetes A landmark study published in 1993 demon- also rises with advancing age. OBESITY and lack of strated that tightly controlled blood glucose levels exercise are also linked to Type 2 diabetes. with maintenance of hemoglobin A1c levels to 7.0 There is also a hereditary aspect to Type 2 dia- percent decreased the risk of complications such as betes. If a parent or sibling has the disease, the risk DIABETIC NEPHROPATHY, DIABETIC NEUROPATHY, and is increased for other family members. DIABETIC RETINOPATHY by 30–70 percent. Typical signs of Type 1 diabetes, due to hyper- Signs and Symptoms glycemia, are as follows: The most common signs and symptoms of Type 2 diabetes are constant thirst (polydipsia), frequent • Extreme thirst urination (polyuria), blurred vision, slowly healing • Frequent urination wounds, and, on occasion, unexplained/uninten- • Unexplained weight loss tional weight loss. The lessons of the United Kingdom Prospective Diabetes Study (UKPDS), a • Extreme hunger very large clinical study of diabetes patients in the • Wounds that heal slowly United Kingdom, showed that the metabolic dys- Type 2 diabetes 237 function leading up to Type 2 diabetes generally used first. It is chosen because it does not lead to goes on for 10–12 years prior to the patient being any weight gain and sometimes leads to some diagnosed. This is why some patients can have weight loss. It decreases the liver’s production of complications of diabetes, such as DIABETIC NEU- glucose and indirectly leads to a decrease in resist- ROPATHY and DIABETIC RETINOPATHY at the same time ance to insulin. Metformin cannot be used in they are diagnosed. Thus, these patients should patients with kidney or liver dysfunction. It will begin to have their eyes checked on a yearly basis, not lead to hypoglycemia when used by itself starting at the time of diagnosis. They should also (monotherapy) as it does not increase insulin check their feet on a daily basis, because a small secretion. wound can become a severe medical problem if If the patient is of normal weight or is thin, often untreated. a sulfonylurea drug is utilized, as these patients often have decreased insulin secretion. These drugs Diagnosis and Treatment include glipizide (Glucotrol, Glucotrol XL), If physicians suspect the presence of Type 2 dia- glimepiride (Amaryl), and glyburide (Micronase, betes based on signs and symptoms, the disease Diabeta, and Glynase). They directly stimulate the may be diagnosed with a fasting blood glucose level beta cell in the pancreas to secrete more insulin. (greater than or equal to 126 mg/dl on two sepa- This can lead to hypoglycemia if not dosed appro- rate occasions) or an oral glucose tolerance test, priately. Sulfonylurea medications must be used with a two-hour glucose level that is equal to or with caution in the elderly and in patients with greater than 200 mg/dl. liver and kidney dysfunction. The cornerstone of therapy is nutritional guid- Two more rapid-acting agents also increase ance along with exercise, with the aim of weight insulin secretion, and they are repaglinide loss. Even small amounts of weight loss, such as (Prandin) and nateglinide (Starlix). These drugs are 5–10 percent of body weight, will lead to significant taken prior to each meal and act over only a short improvements in glucose levels. If possible, all time. Thus, they are useful in patients with variable patients should be referred to a registered dietitian eating habits, a susceptibility to hypoglycemia, or for education. In addition, all patients with diabetes mild kidney problems. These drugs can also cause require education about the disease, typically held hypoglycemia. in a class and lead by certified diabetes educators. The newest class of medications as of this writing Most insurance companies will reimburse for at are the glitazones or thiazolidinediones, which least some diabetes education, and Medicare will include rosiglitazone (Avandia) and pioglitazone cover all of it. (Actos). This type of medication can also be used as If Type 2 diabetes is diagnosed, patients must be initial therapy. Often one of these drugs is chosen to instructed on how to test their blood, which should treat patients with significant insulin resistance or in be done at least several times each day. They must those with kidney problems. These drugs work by also be trained about what to do based on the blood directly decreasing resistance to insulin, affecting test results. For example, if the blood sugar level is mainly muscle and fat. They are the slowest-work- low (hypoglycemia), they should raise their glu- ing medications for Type 2 diabetes and may take cose levels by eating a food high in sugar or using 12–16 weeks to get to maximal effect. They cannot a product specifically designed for patients with be used in patients with significant liver disease, diabetes. If patients find that their blood levels are those with congestive heart failure, or those with high in blood sugar, they must avoid products with any form of significant edema. high glucose contents so that the blood levels stabi- Common adverse effects with rosiglitazone and lize downward. pioglitazone are edema and some weight gain (typ- There is some controversy over which medica- ically three to eight pounds in the first year), tions to administer first. As most patients with Type although not all patients will gain weight. 2 diabetes are overweight, the biguanide met- Research indicates that these drugs also have formin drug (Glucophage, Glucophage-XR) is often direct effects on the lining of blood vessels, (the 238 Type 2 diabetes endothelium) and may help to prevent atheroscle- learn how to perform these injections from their rosis. They appear to have a wide range of effects physician or nurse. other than those on glucose, such as increasing high-density lipoprotein (HDL) or “good” choles- Preventing or Delaying Type 2 Diabetes terol, decreasing protein loss in the urine, decreas- Large clinical studies such as the Diabetes ing triglyceride levels, and decreasing levels of Prevention Program have clearly demonstrated mediators of clotting and inflammation, such as that lifestyle changes, such as a modest weight loss plasminogen activator inhibitor-1 (PAI01) and (5–7 percent) and exercise (equivalent to 150 min- interleukins. utes of brisk walking per week) will decrease the As of this writing, there are also two glucosidase risk of progression from prediabetes to overt dia- inhibitors. These drugs slow the absorption of car- betes by 58 percent. The use of metformin alone bohydrates into the bloodstream and are used by will decrease the risk by 31 percent. A study of some patients with Type 2 diabetes. Two examples women who had gestational diabetes and who are acarbose (Precose) and miglitol (Glyset). They were given thiazolidinedione medications after the are typically titrated slowly, as a rapid dose escala- pregnancy showed that the women decreased their tion will lead to significant flatulence and diarrhea. risk of developing diabetes. Another study showed These drugs will not cause hypoglycemia when about a 30 percent decrease in progression to dia- used alone. betes when patients were treated with acarbose. Most patients with Type 2 diabetes, however, The HOPE (Heart Outcomes Prevention require more than one medication. There are now Evaluation) trial, in patients at high risk for cardiac several combination medications on the market, problems, demonstrated a decrease in the risk of such as Glucovance (metformin and glyburide), diabetes using the blood pressure drug armorial Metaglip (metformin and glipizide), and (Altace). Avandamet (rosiglitazone and metformin). See also DIABETES MELLITUS; TYPE 1 DIABETES. Most patients with Type 2 diabetes can control American Diabetes Association and National Institute of their illness by taking oral medications along with Diabetes and Digestive and Kidney Diseases. “The maintaining careful control over their diets. Prevention or Delay of Type 2 Diabetes.” Diabetes Care However, approximately 7 percent of these patients 25, no. 4 (April 2002): 742–749. will require insulin each year, either because their Petit, William A. Jr., and Christine Adamec. The bodies stop making any insulin or because they are Encyclopedia of Diabetes. New York: Facts On File, Inc., no longer able to maintain adequate control using 2002. diet, exercise, and oral medications. Patients will U ultrasound A noninvasive imaging test that uses nodules are present and whether there is a domi- painless sound waves to form a shadowy picture of nant nodule (one that is significantly larger than internal organs. It is used to diagnose many differ- the others). Ultrasound can also be used to follow ent medical conditions and problems, and it some- a thyroid nodule or cyst over time to see if further times accompanies medical procedures that doctors growth or other changes occur. It can also be used perform. Ultrasound was first used to detect the to guide a fine-needle aspiration biopsy of the thy- medical status of the fetus to provide information roid when the nodule is difficult to feel by hand or to pregnant women. It was later adapted to collect if the nodule is located under the collarbone or information about virtually every internal organ. even slightly substernal (under the breastbone). Most ultrasound tests are external, but probes Ultrasound is helpful in evaluating the testes allow studies to be done within the vagina of a and ovaries for structural abnormalities. It is used woman or the rectum of man to assess for disease. on occasion to evaluate the pancreas but has gen- There are also very small probes that allow for erally been replaced in this function by computer- ultrasound within blood vessels. ized tomography (CT) scanning. Ultrasound is commonly used in the evaluation See also COMPUTERIZED TOMOGRAPHY; MAGNETIC of thyroid disorders to determine if one or many RESONANCE IMAGING.

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V vasoactive intestinal peptide producing tumor some very northern countries with long winters and (vipoma) An islet cell tumor of the pancreas that little sunshine, supplements of exposure to appropri- leads to severe watery diarrhea (80 percent of ate artificial ultraviolet light is critical. patients exceed three liters of diarrhea per day) and Vitamin D can also be obtained from foods. decreased potassium and chloride in the blood- Many foods are also fortified with vitamin D (vita- stream. Also known as pancreatic cholera syn- min D2 or ergocalciferol), such as milk and break- drome, Verner-Morrison syndrome, WDHA (watery fast cereals. Few foods are naturally high in vitamin diarrhea, hypokalemia, achlorhydria), or WDDH D. Those that are include cod liver oil, cooked (watery diarrhea, hypokalema) syndrome. A large salmon, cooked mackerel, sardines, and eels. number (40 percent) of vipomas are malignant. CALCITRIOL is a human-made form of vitamin D that is taken by people who are deficient in vitamin Diagnosis and Treatment D and/or calcium, such as patients with Patients present with generalized weakness and HYPOPARATHRYROIDISM (a rare condition in which diarrhea. They have low levels of potassium, chlo- the parathyroid glands have been damaged by an ride, and magnesium and elevated glucose levels autoimmune reaction or have been surgically dam- (likely due to the severe losses of potassium that, in aged). Supplemental vitamin D boosts the levels of turn, lead to the inability to secrete adequate calcium in the blood and bones by increasing the insulin) and calcium. On rare occasions, vipoma is absorption from the gastrointestinal tract. High associated with MULTIPLE ENDOCRINE NEOPLASIA doses are available by prescription only. (MEN) syndrome. Vipoma is difficult to detect in the plasma. Deficiencies of Vitamin D (Hypovitaminosis) Therapy is surgery to remove the tumor. If the Deficiencies of vitamin D may be more common patient has hyperplasia and not a tumor, a total than is generally realized. In one study, physicians pancreatectomy is considered. A drug called studied 290 hospitalized patients of all ages to deter- octreotide is quite useful in treating this syndrome. mine if they were deficient in vitamin D. These findings were reported in a 1998 issue of the New England Journal of Medicine. The researchers obtained vitamin D The vitamin that helps the body to information on diet and medical histories and also maintain normal levels of calcium and phosphorus obtained measures of the serum parathyroid hor- in the blood and bones, mainly by its effects in mone levels of the patients. They found that 57 per- increasing calcium absorption from the gastroin- cent of the patients had hypovitaminosis D, or very testinal tract. low levels of vitamin D. The conditions most often The body uses sunshine (specific ultraviolet rays) associated with hypovitaminosis were kidney disor- to make vitamin D (cholecalciferol or vitamin D3). It ders, glucocorticoid (steroid) therapy, cirrhosis, anti- is estimated that casual sun exposure leads to the convulsant therapy, and gastric or bowel resections. synthesis of the equivalent of ingesting about 200 IU The study also pointed out that vitamin D deficien- of vitamin D. There can be wide variations in vitamin cies are more common among acutely ill individuals D levels of individuals, depending on the season. In than had been realized in the past.

241 242 vitamin D

The researchers concluded, “Because of the • Infants without adequate Sun exposure or sup- potential adverse effects of vitamin D deficiency on plementation the skeleton and other organ systems, widespread • Strict vegetarians, especially in the winter screening for vitamin D deficiency or routine vitamin D supplementation should be considered.” Hypervitaminosis with Vitamin D People can also become deficient in vitamin D if Having too much vitamin D in the bloodstream is they have little or no sunlight exposure, although also possible. Having toxic levels of vitamin D from some people need vitamin D supplements even if diet alone is almost impossible. Instead, most peo- they obtain normal levels of sunlight. This is par- ple with excessively high levels of vitamin D are ticularly true for individuals older than age 65 taking supplements, either prescribed or over-the- and/or for hospitalized patients. It is also true that counter drugs. Too much vitamin D in the body can some people’s bodies cannot absorb vitamin D from cause the following signs and symptoms: the gastrointestinal tract. In addition, sometimes the kidney is unable to make adequate vitamin D • Nausea and vomiting (1,25-dihydroxy-vitamin D). • Constipation The most commonly known deficiencies of vitamin D are RICKETS and OSTEOMALACIA. Rickets is a • Increased thirst and urination childhood disease that causes weak bones and • Itching skeletal abnormalities. Osteomalacia involves mus- • Weakness cle weakness as well as weak bones. This condition • Poor appetite is often suspected in a high-risk group if the calcium level is low. The diagnosis can be made if a 25- • Weight loss hydroxy vitamin D level is measured. Typically, • Mental confusion healthy people have vitamin D levels greater than 30 ng/dl, even though the normal range is often Hypervitaminosis of vitamin D is treated by dis- stated to be about 9–52 ng/dl. To determine if the continuing, or at least decreasing, the supplements level is physiologically effective, the endocrinolo- of vitamin D. A low-calcium diet is another treat- gist will often measure a 24-hour urine test for cre- ment. Sometimes corticosteroid medications (such atinine (to check that the collection has been as prednisone) are given. correct and to calculate the kidney function as See also ALTERNATIVE MEDICINE. well). The calcium levels should be between two Haddad, J. G. “Vitamin D—Solar Rays, the Milky Way, or and four mg of calcium/kg body weight. Both?” New England Journal of Medicine 326, no. 18 People older than age 50 have a greater risk of (1992): 1,213–1,215. being deficient in vitamin D than younger individ- Heaney, Robert P., M.D., and Connie M. Weaver. uals and may need to take supplemental vitamin D. “Calcium and Vitamin D.” Endocrinology and Some categories of people who may become defi- Metabolism Clinics of North America 32, no. 1 (2003): cient in vitamin D include the following groups: 181–194. Lamberg-Allardt, C., et al. “Low Serum 25-Hydroxyvitamin • People with Crohn’s disease D Levels and Secondary Hyperparathyroidism in • Individuals with kidney disease Middle-Aged White Strict Vegetarians.” American • People with celiac sprue (gluten enteropathy) Journal of Clinical Nutrition 58, no. 5 (1998): 684–689. • Individuals with chronic liver diseases (cirrhosis) Lips, Paul. “Vitamin D Deficiency and Secondary Hyperparathyroidism in the Elderly: Consequences • People with pancreatic enzyme deficiencies for Bone Loss and Fractures and Therapeutic (due to pancreatitis) Implications.” Endocrine Reviews 22, no. 4 (2001): • Elderly individuals 477–501. vitamin D resistance 243

Reichler, H., H. P. Koeffler, and A. W. Norman. “The Role Vitamin D resistance may lead to the develop- of the Vitamin D Endocrine System in Health and ment of FRACTURES stemming from OSTEOPOROSIS. Disease.” New England Journal of Medicine 320, no. 15 Children with untreated vitamin D resistance have (1989): 980–991. a rickets-like appearance, with bowed legs and Thomas, Melissa K., M.D. “Hypovitaminosis D in Medical weak limbs, and they may also experience balding Inpatients.” New England Journal of Medicine 338, no. 12 (alopecia). Treatment may improve the condition (March 19, 1998): 777–783. considerably. Vitamin D resistance syndrome cannot be completely diagnosed by blood tests alone. Researchers vitamin D resistance A medical condition in performing clinical studies on normal patients as which a person has a normal level of vitamin D in well as those with Vitamin D deficiency and resist- the blood but the body is unable to use this vitamin ance report that measurement of fingernail thick- D appropriately and thus develops signs and symp- ness may correlate with each syndrome. toms of Vitamin D deficiency. The cause may be a The treatment of vitamin D resistance is usually genetic defect that prevents CALCITRIOL (a form of supplementation with calcitriol. Some patients are Vitamin D) from binding to the vitamin D receptor. more responsive to supplements of calcium, while Some elderly individuals may also have vitamin D others require both calcitriol and calcium supple- resistance, although the cause for this form is ments. unknown.

W–X

Wermer’s syndrome See MULTIPLE ENDOCRINE terolemia). Tuberous xanthomas are softer, often NEOPLASIA. seen on the buttocks and can also be seen in type IIa, type IIb, or type IV hyperlipidemia. Smaller groupings of yellowish brown to reddish eruptions xanthomas Fatty deposits in the skin that may in a variety of places on the skin are called eruptive indicate disorders of triglyceride or cholesterol lev- xanthomata, which are usually seen in patients els. They typically appear on the elbows, knuckles, with type IIa or type IV hyperlipidemia when the Achilles tendon, or other large tendons on extensor triglyceride levels are greater than 1,000 mg/dl. surfaces of the body. The cholesterol that makes up These xanthomatas will regress and disappear with these nodules is both inside and outside the cells. normalization of the lipid levels. The harder xan- Xanthomas are firm to hard and are often slightly thomas can regress with therapy but usually do not painful. regress completely. Hard tendon xanthomas are most often seen in type IIa hyperlipidemia (familial hypercholes-

245

APPENDIXES

I. Important Organizations in the United States II. Key Health Organizations in Canada III. Chart of Thyroid Medications to Treat Hypothyroidism IV. Chart of Thyroid Medications to Treat Hyperthyroidism V. Medications to Treat Diabetes VI. 13 Little-Known Facts About Endocrine Diseases VII. 10 Little-Known Facts About Diabetes Mellitus VIII. Web Sites with Information on Endocrine Diseases and Disorders IX. Frequencies of Diabetes Among Persons 18 Years of Age and Older, By Selected Characteristics: United States, 1999 X. Percent of Diabetes Among Persons 18 Years of Age and Over, By Selected Characteristics: 1999

247 XI. Frequency Distributions of Body Mass Index Among Persons 18 Years of Age and Over, By Selected Characteristics: United States, 1999 XII. Percent Distributions of Body Mass Index Among Persons 18 Years of Age and Over, By Selected Characteristics: United States, 1999 XIII. Diabetes Deaths, Rates per 100,000 XIV. Incidence of Invasive Cancers of the Endocrine System XV. State Cancer Registries XVI. Diabetes Research and Training Centers and Endocrinology Research Centers in the United States

248 APPENDIX I IMPORTANT ORGANIZATIONS IN THE UNITED STATES

AARP Alliance of Genetic Support Groups 601 E. Street Northwest 4301 Connecticut Avenue NW Washington, DC 20049 Suite 104 (888) OUR-AARP Washington, DC 20008 http://www.aarp.org (202) 966-5557 http://www.geneticalliance.org Academy for Eating Disorders 6728 Old McLean Village Drive American Academy of Family Physicians McLean, VA 22101 (AAFP) (703) 556-9222 11400 Tomahawk Creek Parkway http://www.aedweb.org Leawood, KS 66211 (800) 274-2237 Administration on Aging http://www.aafp.org Department of Health and Human Services 330 Independence Avenue SW American Academy of Neurology Washington, DC 20201 1080 Montreal Avenue (202) 619-0724 St. Paul, MN 55116 http://www.aoa.gov (800) 879-1960 http://www.aan.com Agency for Healthcare Research & Quality (AHRQ) American Academy of Ophthalmology Publications Clearinghouse P.O. Box 7424 P.O. Box 8547 San Francisco, CA 94120 Silver Spring, MD 20907 (415) 561-8500 (800) 358-9295 http://www.aao.org http://www.ahrq.gov American Academy of Pediatrics Alcoholics Anonymous 141 Northwest Point Boulevard Grand Central Station Elk Grove Village, IL 60007 P.O. Box 459 (847) 434-4000 New York, NY 10163 http://www.aap.org http://www.alcoholics-anonymous.org American Academy of Physical Medicine Alliance for Aging Research and Rehabilitation 2021 K Street NW One IBM Plaza Suite 305 Suite 2500 Washington, DC 20006 Chicago, IL 60611 (202) 293-2856 (312) 464-9700 http://www.agingresearch.org http://www.aapmr.org

249 250 The Encyclopedia of Endocrine Diseases and Disorders

American Anorexia Bulimia Association American Chronic Pain Association 165 West 46 Street, #1108 P.O. Box 850 New York, NY 10036 Rocklin, CA 95677 (212) 575-6200 (916) 632-0922 http://www.theacpa.org American Association of Clinical Endocrinologists (AACE) American College of Obstetricians and 1000 Riverside Avenue Gynecologists (ACOG) Suite 205 409 12th Street SW Jacksonville, FL 32304 P.O. Box 96920 (904) 353-7878 Washington, DC 20090 http://www.aace.com (202) 863-2518 http://www.acog.org American Association of Diabetes Educators 444 North Michigan Avenue, Suite 1240 American College of Physicians, American Chicago, IL 60611 Society of Internal Medicine (ACP-ASIM) (800) 338-3633 190 N. Independence Mall West http://www.aadenet.org Philadelphia, PA 19106 (800) 523-1546 American Autoimmune Related Diseases http://www.acpoline.org Association 22100 Gratiot Avenue American College of Rheumatology East Detroit, MI 48021 1800 Century Place (586) 776-3900 Suite 250 http://www.aarda.org Atlanta, GA 30345 (404) 633-3777 American Board of Medical Specialties www.rheumatology.org 47 Perimeter Center East, Suite 500 Atlanta, GA 36346 American College of Sports Medicine (800) 776-2378 P.O. Box 1440 http://www.abms.org Indianapolis, IN 46206 (317) 637-9200 American Board of Pediatric Surgery http://www.ascm.org/sportsmed 1601 Dolores Street San Francisco, CA 94110 American College of Surgeons (ACS) (415) 826-3200 633 North St. Clair Street Chicago, IL 60611 American Board of Physician Nutrition (312) 202-5000 Specialists http://www.facs.org University of Alabama at Birmingham 439 Susan Mott Webb Nutrition Sciences Building American Diabetes Association (ADA) 1675 University Boulevard 1701 North Beauregard Street Birmingham, AL 35294 Alexandria, VA 22311 (205) 934-5564 (800) 342-2383 http://main.uab.edu/ipnec/show.asp?durki=37725 http://www.diabetes.org American Cancer Society American Dietetic Association 1599 Clifton Road NE 216 West Jackson Boulevard Atlanta, GA 30329 Chicago, IL 60606 (800) 227-2345 or (404) 320-2408 (312) 899-0040 http://www.cancer.org http://www.eatright.org Appendix I 251

American Federation for Aging Research American Medical Association (AFAR) 515 North State Street 1414 Sixth Avenue, 18th Floor Chicago, IL 60610 New York, NY 10019 (312) 464-5000 (212) 752-2327 http://www.ama-assn.org http://www.afar.org American Medical Women’s Association American Foundation of Thyroid 801 North Fairfax Street Patients Suite 400 P.O. Box 820195 Alexandria, VA 22314 Houston, TX 77282 (703) 838-0500 (281) 496-4460 http://www.amwa-doc.org http://www.thyroidfoundation.org American Menopause Foundation American Health Assistance Foundation 350 Fifth Avenue 15825 Shady Grove Road Suite 2822 Suite 140 New York, NY 10118 Rockville, MD 20850 (212) 714-2398 (800) 437-2423 http://www.americanmenopause.org http://www.ahaf.org American Mental Health Counselor’s American Health Care Association (AHCA) Association 1201 L Street NW 801 N. Fairfax Street, Suite 304 Washington, DC 20005 Alexandria, VA 22314 (202) 842-4444 (703) 548-6002 http://www.ahca.org http://www.amhca.org American Heart Association/American American Nurses Association Stroke Association 600 Maryland Avenue SW 7272 Greenville Avenue Suite 100 West Dallas, TX 75231 Washington, DC 20024 (800) AHA-USA1 (202) 554-4444 http://www.americanheart.org http://www.nursingworld.org American Hospital Association (AHA) American Obesity Association One North Franklin 1250 24th Street NW, Suite 300 Chicago, IL 60606 Washington, DC 20037 (312) 422-3000 (800) 98-OBESE http://www.aha.org http://www.obesity.org American Fertility Association American Pharmaceutical Association 666 Fifth Avenue 2215 Constitution Avenue NW Suite 278 Washington, DC 20037 New York, NY 10103 (202) 628-4410 (888) 917-3777 http://www.aphanet.org http://www.theafa.org American Physical Therapy Association American Institute for Cancer Research (APTA) 1759 R Street NW 111 North Fairfax Street Washington, DC 20009 Alexandria, VA 22314 (800) 843-8114 (800) 999-2782, ext. 3395 http://www.aicr.org http://www.apta.org 252 The Encyclopedia of Endocrine Diseases and Disorders

American Podiatric Medical Association (202) 857-1190 9312 Old Georgetown Road http://www.asn-online.com Bethesda, MD 20814 (301) 581-9200 American Society of Ophthalmic Plastic & http://www.apma.org Reconstructive Surgery 1133 West Morse Boulevard, Suite 201 American Psychiatric Association Winter Park, FL 32789 1400 K Street NW (407) 647-8839 Washington, DC 20005 http://www.asoprs.org (202) 682-6000 http://www.psych.org American Thyroid Association 6066 Leesburg Pike, Suite 550 American Psychological Association Falls Church, VA 22041 750 First Street NE (703) 998-8890 Washington, DC 20002 http://www.thyroid.org (202) 336-5500 http://www.apa.org American Urological Association 1120 North Charles Street American Society for Bariatric Surgery Baltimore, MD 21201 7328 West University Avenue, Suite G (410) 727-1100 Gainesville, FL 32607 http://www.auanet.org (352) 331-4900 http://www.asbs.org Association for Glycogen Storage Disease American Society for Bone and Mineral P.O. Box 896 Research Durant, IA 52747 1200 Nineteenth Street NW, Suite 300 (319) 785-6038 Washington, DC 20036 http://www.agsdus.org (202) 857-1161 http://www.asbmr.org Association for Neuro-Metabolic Disorders 5223 Brookfield Lane American Society for Reproductive Medicine Sylvania, OH 43560 1209 Montgomery Highway (419) 885-1497 Birmingham, AL 35216 (205) 978-5000 Association of American Indian Physicians http://www.asrm.org 1235 Sovereign Row, Suite C-9 Oklahoma City, OK 73108 American Society of Bariatric Physicians (405) 946-7651 5453 East Evans Place http://www.aaip.com Denver, CO 80222 (303) 770-2526 Association of Asian Pacific Community http://www.asbp.org Health Organizations 1440 Broadway #510 American Society of Human Genetics Oakland, CA 94612 9650 Rockville Pike (510) 272-9536 Bethesda, MD 20814 http://www.aapcho.org (301) 571-1825 http://www.faseb.org/genetics Cancer Research Foundation of America 1600 Duke Street, Suite 110 American Society of Nephrology Alexandria, VA 22314 1200 Nineteenth Street Northwest, Suite 300 (800) 227-2732 Washington, DC 20039 http://www.preventcancer.org Appendix I 253

Centers for Disease Control and Prevention Emergency Nurses Association (CDC) 915 Lee Street 1600 Clifton Road Des Plaines, IL 60016 Atlanta, GA 30333 (800) 900-9659 (404) 639-3534 http://www.ena.org http://www.cdc.gov Endocrine Society Centers for Medicare and Medicaid Services 4350 East West Highway (Formerly the Health Care Financing Suite 500 Administration) Bethesda, MD 2081 6325 Security Boulevard (301) 941-0200 Baltimore, MD 21207 http://www.endo-society.org (410) 786-3000 Food and Drug Administration http://www.hcfa.gov (FDA) Children with Diabetes Foundation HFE88 2525 Araphoe Avenue 5600 Fishers Lane Suite E4, PMB #506 Rockville, MD 20857 Boulder, CO 80302 (888) 463-6332 http://www.cwdfoundation.org http://www.fda.org Creutzfeldt-Jakob Disease Foundation The Genetic Alliance P.O. Box 5312 4301 Connecticut Avenue NW Akron, OH 44334 Suite 404 (800) 659-1991 Washington, DC 20008 http://www.cjdfoundation.org (202) 966-5557 http://www.geneticalliance.org Cushing’s Support and Research Foundation, Inc. Harvard Eating Disorders Center 65 East India Row 22B 55 Fruit Street Boston, MA 02110 YAW 6900 (617) 723-3824 Boston, MA 02114 http://www.csrf.net (617) 726-8470 http://www.hedc.org Diabetes Action Research and Education Foundation H.E.L.P., The Institute for Body 426 C Street NE Chemistry Washington, DC 20002 P.O. Box 1338 (202) 333-4520 Bryn Mawr, PA 19010 http://www.diabetesaction.org (610) 525-1225 Diabetes Exercise and Sports Association Hepatitis Foundation 1647 West Bethany Home Road #B International Phoenix, AZ 85015 504 Blick Drive (800) 898-4322 Silver Spring, MD 20904 http://www.diabetes-exercise.org (800) 891-0707 http://www.hepfi.org Disability Rights Education and Defense Fund, Inc. Hormone Foundation 2212 Sixth Street 4350 East-West Highway, Suite 500 Berkeley, CA 94710 Bethesda, MD 20814 (800) 466-4232 (800) HORMONE http://www.dredf.org http://www.hormone.org 254 The Encyclopedia of Endocrine Diseases and Disorders

Human Growth Foundation Juvenile Diabetes Research Foundation 997 Glen Cove Avenue (JDF) International Glen Head, NY 11545 120 Wall Street (800) 451-6434 19th Floor http://www.hgfound.org New York, NY 10005 (800) 223-1138 Hypoglycemia Support Foundation, Inc. http://www.jdf.org 3822 Northwest 122nd Terrace Sunrise, FL 33345 Klinefelter Syndrome and Associates, Inc. (954) 742-3098 P.O. Box 119 http://www.hypoglycemia.org Roseville, CA 95678 (916) 773-1449 Hypoparathyroidism Association, Inc. http://www.genetic.org/ks 2835 Salmon Idaho Falls, ID 83406 La Leche League International (208) 524-3857 1400 North Meacham Road http://www.hypoparathyroidism.org Schaumburg, IL 60173-4840 (847) 519-7730 Impotence World Association http://www.lalecheleague.org 10400 Little Patuxent Parkway Suite 485 Light of Life Foundation Columbia, MD 21044 32 Marc Drive (800) 669-1603 Englishtown, NJ 07726 (732) 972-0461 Indian Health Service http://www.lightoflifefoundation.org Headquarters Diabetes Program Little People of America, Inc. 5300 Homestead Road NE 5289 Northeast Elam Young Parkway Albuquerque, NM 87110 Hillsboro, OR 97124 (505) 248-4182 (888) LPA-2001 http://www.lpaonlne.org International Association for Medical Assistance to Travellers Magic Foundation 417 Center Street 6645 West North Avenue Lewiston, NY 14092 Oak Park, IL 60302 (716) 754-4883 (708) 383-0808 http://www.iamat.org http://www.magicfoundation.org

International Diabetic Athletes March of Dimes Birth Defects Association Foundation 1647 West Bethany Home Road #B 1275 Mamaroneck Avenue Phoenix, AZ 85015 White Plains, NY 10605 (800) 898-4322 (914) 428-7100 http://www.diabetes-exercise.org http://www.modimes.org

Joslin Diabetes Center Medic Alert Foundation One Joslin Place P.O. Box 109 Boston, MA 02215 Turlock, CA 95831 (617) 732-2415 (209) 668-3331 http://www.joslin.harvard.edu http://www.medicalalert.org Appendix I 255

Metabolic Information Network Silver Spring, MD 20907 P.O. Box 670847 (888) 644-6226 Dallas, TX 75367 http://www.nccam.nih.gov (800) 945-2188 National Center for the Study The Myelin Project of Wilson’s Disease 1747 Pennsylvania Avenue Northwest, Suite 950 432 West 58th Street, Suite 614 Washington, DC 20006 New York, NY 10091 (202) 452-8994 (212) 523-8717 http://www.myelin.org National Certification Board National Adrenal Diseases Foundation for Diabetes Educators 505 Northern Boulevard, Suite 200 330 East Algonquin Road, Suite 4 Great Neck, NY 11021 Arlington Heights, IL 60005 (516) 487-4992 (847) 228-9795 http://www.medhelp.org/nadf http://www.ncbde.org National Alliance for Hispanic Health National Clearinghouse for 1501 Sixteenth Street NW Alcohol and Drug Information Washington, DC 20036 11426 Rockville Pike, Suite 200 (202) 387-5000 Rockville, MD 20852 http://www.hispanichealth.org (800) 729-6686 http://www.health.org National Association of Anorexia Nervosa and Associated Disorders National Coalition for Cancer P.O. Box 7 Survivorship (NCCS) Highland Park, IL 60035 1010 Wayne Avenue, Suite 770 (847) 831-3438 Silver Spring, MD 20910 http://www.anad.org (877) 622-7937 http://www.cansearch.org National Cancer Institute Division of Cancer Epidemiology and Genetics National Council on Aging 6120 Executive Boulevard, MSC-7224 300 D Street SW, Suite 801 Executive Plaza South, 7th Floor Washington, DC 20024 Bethesda, MD 20892 (202) 479-1200 (301) 496-1691 http://www.ncoa.org http://dceg.cancer.gov National Council on Alcoholism National Center for Chronic Disease and Drug Dependence Prevention and Health Promotion (NCADD) Division of Diabetes Translation 20 Exchange Place, Suite 2902 Mail Stop K-10 New York, NY 10005 4770 Buford Highway NE (800) NCA-CALL (24-hour Affiliate referral) or Atlanta, GA 30341 (212) 269-7797 (877) CDC-DIAB http://www.ncadd.org http://www.cdc.gov/diabetes National Diabetes Information National Center for Complementary and Clearinghouse Alternative Medicine (NCCAM) 1 Information Way Clearinghouse Bethesda, MD 20892 National Institutes of Health (NIH) (800) 860-8747 P.O. Box 8218 http://diabetes.niddk.nih.gov 256 The Encyclopedia of Endocrine Diseases and Disorders

National Digestive Diseases Information National Health Information Center (NHIC) Clearinghouse (NDIC) Office of Disease Prevention and Health National Institute of Diabetes and Digestive and Promotion (ODPHP) Kidney Diseases (NIDDK) Department of Health and Human Services National Institutes of Health (NIH) P.O. Box 1133 2 Information Way Washington, DC 20013 Bethesda, MD 20892 (800) 336-4797 (800) 891-5389 http://www.health.gov/NHIC http://digestive.niddk.nih.gov National Heart, Lung, and Blood Institute National Dissemination Center for Children P.O. Box 30105 and Youth with Disabilities Bethesda, MD 20824 P.O. Box 1492 (301) 592-8573 Washington, DC 20013 http://www.nhlbi.nih.gov (800) 695-0285 National Institute of Diabetes and Digestive http://www.nichcy.org and Kidney Diseases (NIDDK) National Easter Seal Society National Institutes of Health 230 West Monroe Street Building 31, Room 9A04 Suite 1800 31 Center Drive, MSC 2560 Chicago, IL 60606 Bethesda, MD 20892 (800) 221-6827 (301) 496-3583 http://www.easter-seals.org http://www.niddk.nih.gov National Eating Disorders National Institute of Mental Health Organization NIMH Public Inquiries 603 Stewart Street 6001 Executive Boulevard Suite 803 Room 8184, MSC 9663 Seattle, WA 98101 Bethesda, MD 20892 (800) 931-2237 (301) 443-4513 http://www.nationaleatingdisorders.org http://www.nimh.nih.gov National Eye Health Education Program National Institute on Aging (NEHEP) Building 31, Room 5C27 2020 Vision Place 31 Center Drive, MSC 292 Bethesda, MD 20892 Bethesda, MD 20892 (301) 496-5248 (301) 496-1752 http://www.nei.nih.gov http://www.nia.nih.gov National Eye Institute National Institute on Drug Abuse 2020 Vision Place National Institutes of Health Bethesda, MD 20892 6001 Executive Boulevard, Room 5213 (301) 496-5248 Bethesda, MD 20892 http://www.nei.nih.gov/nehep (301) 443-1124 http://www.nida.nih.gov National Graves’ Disease Foundation National Institutes of Health (NIH) P.O. Box 1969 P.O. Box 8218 Brevard, NC 28712 Silver Spring, MD 20907 (828) 877-5251 (888) 644-6226 http://www.ngdf.org http://www.nccam.nih.gov Appendix I 257

National Kidney and Urologic Diseases National Rehabilitation Information Center Information Clearinghouse 4200 Forbes Boulevard 3 Information Way Suite 202 Bethesda, MD 20892 Lanham, MD 20706 (800) 891-5390 (800) 346-2742 http://www.naric.com National Kidney Foundation, Inc. 30 East 33rd Street National Self-Help Clearinghouse New York, NY 10016 Graduate School and University Center of the City (800) 622-9010 University of New York http://www.kidney.org 365 Fifth Avenue, Suite 3300 New York, NY 10016 National Mental Health Association (212) 817-1822 1021 Prince Street http://www.selfhelpweb.org Alexandria, VA 22314 (703) 684-7722 National Women’s Health Network http://www.nmha.org 514 10th Street NW Suite 400 National Neurofibromatosis Foundation Washington, DC 20004 95 Pine Street, 16th Floor (202) 347-1140 New York, NY 10005 http://www.nwhn.org (800) 344-6633 http://www.nf.org Neurofibromatosis, Inc. 9320 Annapolis Road, Suite 300 National Oral Health Information Lanham, MD 20706 Clearinghouse (301) 918-4600 1 NOHIC Way http://www.nfinc.org Bethesda, MD 20892 (301) 402-3500 North American Menopause Society (NAMS) http://www.nohic.nidcr.nih.gov P.O. Box 94527 Cleveland, OH 44101 National Organization for Rare Disorders (440) 442-7550 (NORD) http://www.menopause.org 55 Kenosia Avenue P.O. Box 1968 Office of Minority Health Resource Center Danbury, CT 06813-1968 P.O. Box 37337 (203) 746-6518 Washington, DC 20013 http://www.rarediseases.org (800) 444-6472 http://www.omhrc.gov National Osteoporosis Foundation 1232 22nd Street NW Ovarian Cancer National Alliance (OCNA) Washington, DC 20037 910 17th Street NW, Suite 413 (202) 223-2226 Washington, DC 20006 http://www.nof.org (202) 331-1332 http://www.ovariancancer.org National Ovarian Cancer Coalition (NOCC) 500 NE Spanish River Boulevard Overeaters Anonymous Suite 8 P.O. Box 44020 Boca Raton, FL 33431 Rio Rancho, NM 87124 (561) 393-0005 (505) 891-2664 http://www.ovarian.org http://www.oa.org 258 The Encyclopedia of Endocrine Diseases and Disorders

Oxalosis and Hyperoxaluria Foundation The Foundation for Prader-Willi Research 20 E. 19th Street, #12 E 6407 Bardstown Road New York, NY 10003 Suite 252 (800) OHF-8699 Louisville, KY 40291 http://www.ohf.org (502) 254-9375 Paget Foundation for Paget’s Disease of Bone President’s Council on Physical Fitness and and Related Disorders Sports 120 Wall Street 701 Pennsylvania Avenue NW Suite 1602 Suite 250 New York, NY 10005 Washington, DC 20004 (800) 23-PAGET (202) 272-3421 http://www.paget.org http://www.fitness.gov Pancreatic Cancer Action Network RESOLVE: The National Infertility 2221 Rosecrans Avenue Association Suite 131 1310 Broadway El Segundo, CA 90245 Somerville, MA 02144 (877) 272-6226 (888) 623-0744 http://www.pancan.org http://www.resolve.org Pediatric Endocrinology Nursing Society Social Security Administration (SSA) P.O. Box 2933 Office of Public Inquiries Gaithersburg, MD 20886 Windsor Park Building http://www.pens.org 6401 Security Boulevard Baltimore, MD 21235 Pedorthic Footwear Association (800) 772-1213 7150 Columbia Gateway Drive http://www.ssa.gov Suite G Columbia, MD 21046 Society for Inherited Metabolic Disorders (410) 381-7278 Oregon Health Sciences University/L473 http://www.pedorthics.org 3181 Southwest Sam Jackson Park Road Portland, OR 97201 Pituitary Tumor Network Association (503) 494-5400 P.O. Box 1958 http://www.simd.org Thousand Oaks, CA 91358 (805) 499-9973 Society for Neuroscience http://www.pituitary.org 11 Dupont Circle NW Suite 500 Polycystic Ovarian Syndrome Association Washington, DC 20036 P.O. Box 3403 (202) 462-6688 Englewood, CO 80111 http://www.sfn.org (877) 775-PCOS http://www.pcosupport.org Substance Abuse and Mental Health Services Administration (SAMSHA) Prader-Willi Alliance for Research Department of Health and Human Services 28 Vesey Street Room 12-105 Parklawn Building Suite 2104 5600 Fishers Lane New York, NY 10007 Rockville, MD 20857 (212) 332-0970 (800) 729-6686 http://www.p-war.org http://www.samhsa.gov Appendix I 259

ThyCa: Thyroid Cancer Survivors’ United Network for Organ Sharing Association, Inc. P.O. Box 2484 P.O. Box 1545 Richmond, VA 23218 New York, NY 10159 (804) 330-8500 (877) 588-7904 http://www.unos.org http://www.thyca.org Veterans Health Administration Thyroid Foundation of America, Inc. 810 Vermont Avenue NW One Longfellow Place Washington, DC 20420 Suite 158 (202) 273-8490 Boston, MA 02114 http://www1.va.gov/health_benefits (800) 832-8321 Weight-Control Information Network http://www.allthyroid.org 1 Win Way Thyroid Society for Education and Research Bethesda, MD 20892 7515 South Main Street (800) WIN-8098 Suite 545 http://www.niddk.nih.gov/health/nutrit/nutrit.htm Houston, TX 77030 Weight Watchers International (800) THYROID 175 Crossways Park West Transplant Recipients International Woodbury, NY 11797 Organization, Inc. (800) 651-6000 2117 L Street NW, #353 http://www.weightwatchers.com Washington, DC 20037 Wilson’s Disease Association International (202) 293-0980 1802 Brookside Drive http://www.trioweb.org Wooster, OH 44691 United Leukodystrophy Foundation (800) 399-0266 2304 Highland Drive http://www.wilsonsdisease.org Sycamore, IL 60178 (800) 728-5483 http://www.ulf.org APPENDIX II KEY HEALTH ORGANIZATIONS IN CANADA

Canadian Cancer Society Heart and Stroke Foundation of Canada National Office, Suite 200 222 Queen Street, Suite 1402 10 Alcorn Avenue Ottawa, Ontario K1P 5V9 Toronto, Ontario M4V 3B1 (613) 569-4361 (416) 961-7223 ww2.heartandstroke.ca http://www.cancer.ca Infertility Awareness Association of Canada Canadian Diabetes Association 2100 Marlowe Avenue, Suite 39 National Life Building Montreal, Quebec H4A 3L5 1400-522 University Avenue (800) 263-2929 Toronto, Ontario M5G 2R5 http://www.iaac.ca (800) BANTING Osteoporosis Society of Canada http://www.diabetes.ca 33 Laird Drive Canadian Institutes of Health Research Toronto, Ontario M4G 3S9 410 Laurier Avenue West, Ninth Floor (800) 463-6842 (Canada) or (416) 696-2663 Address Locator 4209A http://www.osteoporosis.ca Ottawa, Ontario K1A 0W9 Thyroid Federation International (888) 603-4178 (Canada) or 613-941-2672 797 Princess Street, Suite 304 http://www.cihr.ca Kingston, Ontario K7L 1G1 Canadian MedicAlert Foundation (613) 544-8364 2005 Sheppard Avenue East, Suite 800 http://www.thyroid-fed.org Toronto, Ontario M2J 5B4 Thyroid Foundation International 800-668-1507 (English) or 800-668-6381 797 Princess Street, Suite 304 (French) Kingston, Ontario K7L 1G1 http://www.medicalert.ca (613) 544-8364 Canadian Mental Health Association http://www.thyroid.ca 8 King Street East, Suite 810 Toronto, Ontario M5C 1B5 (416) 484-7750 http://www.cmha.ca Health Canada A.L. 0900C2 Ottawa, Ontario K1A 0K9 (613) 957-2991 http://www.hc-sc.gc.ca/english

260 APPENDIX III CHART OF THYROID MEDICATIONS TO TREAT HYPOTHYROIDISM

Brand Name Generic Name Available Dosages Manufacturer

Armour thyroid Dessicated pork thyroid Many dosages, ranging Forest Pharmaceuticals (T3 and T4) from 1/4–5 grains St. Louis, MO

Cytomel Liothyronine (T4) 5–50 micrograms Jones Pharma, Inc. St. Louis, MO

Levoxyl Levothyroxine (T4) Many dosages, ranging Jones Pharma, Inc. from 25–300 micrograms St. Louis, MO

Levothroid Levothyroxine (T4) 25, 50, 75, 88, 100, 112, Forest Pharmaceuticals 125, 137, 150, 175, 200, St. Louis, MO 300 micrograms

Synthroid Levothyroxine (T4) Many dosages, ranging Abbott Laboratories from 25–300 micrograms North Chicago, IL

Unithroid Levothyroxine (T4) 25, 50, 75, 88, 100, 112, Watson Pharm. 125, 150, 175, 200, Corona, CA 300 micrograms

261 APPENDIX IV CHART OF THYROID MEDICATIONS TO TREAT HYPERTHYROIDISM

Brand Name Generic Name Available Dosages Manufacturer Generic methimazole Methimazole 5, 10 milligrams Many companies

Propylthiouracil (PTU) Propylthiouracil 50 milligrams Many companies

Tapazole Methimazole 5, 10 milligrams Jones/King Pharm. St. Louis, MO

262 APPENDIX V MEDICATIONS TO TREAT DIABETES

I. INSULIN SECRETAGOGUES 1st Generation 2nd Generation A. Sulfonylureas Tolbutamide Glyburide/ Micronized Glyburide Tolazamide Glipizide Chlorpropramide Glimepiride B. Meglitinide Repaglinide (Prandin) C. Phenylalanine Derivatives Nateglinide (Starlix) II. Thiazolidinediones (TZDs) Rosiglitazone (Avandia) Pioglitazone (Actos) III. Alpha Glucosidase Inhibitors Acarbose (Precose) Miglitol (Glyset) IV. Biguanide Metformin (Glucophage)

SULFONYLUREA MEDICATIONS AND TYPICAL DOSING Generic Name Trade Name Number of Daily Doses Typical Daily Dose Tolbutamide Orinase 2–3 500–3000 mg/day Acetohexamide Dymelor 1–2 250–500 mg/1–2 a day Tolazamide Tolinase 1–2 100–1000 mg/day Chlorpropamide Diabinese 1 100–500 mg/day Glyburide Diabeta Micronase 1 1.25–20 mg/day Micronized glyburide Glynase PresTab 1 1.5–12 mg/day Glipizide Glucotrol 1–2 2.5–40 mg/day Glipizide GITS Glucotrol XL 1 2.5–20 mg/day Glimepiride Amaryl 1 0.5–8 mg/day

SECRETAGOGUE MEDICATIONS AND TYPICAL DOSING Generic Name Trade Name Typical Dosing Repaglinide Prandin 1.5–16 mg, 3 or 4/day Nateglinide Starlix 180–360 mg/day

263 264 The Encyclopedia of Endocrine Diseases and Disorders

TZD MEDICATIONS AND TYPICAL DOSING Generic Name Trade Name Typical Dosing Rosiglitazone Avandia 2–8 mg/day, 1–2/day Pioglitazone Actos 15–45 mg/day

ALPHA GLUCOSIDE INHIBITOR MEDICATIONS AND TYPICAL DOSING Generic Name Trade Name Typical Doses Miglitol Glyset 75–300 mg/day Acarbose Precose 75–300 mg/day APPENDIX VI 13 LITTLE-KNOWN FACTS ABOUT ENDOCRINE DISEASES

1. Some people may initially have an overactive 6. Herbal remedies and supplements may be thyroid gland, often due to the autoimmune dangerous because they can boost or weaken disease Graves’ disease and then later they the effects of other drugs patients take, such become hypothyroid (underactive) due to the as insulin, thyroid supplements, and so forth. autoimmune disease known as Hashimoto’s Patients should always check with their thyroiditis. The reverse phenomenon, or the doctors before taking any herbal remedy development of Graves’ disease after or supplement. Hashimoto’s thyroiditis, can also occur but is 7. Treatments that may work well for one mem- seen infrequently. ber of the family with diabetes, thyroid dis- 2. When a person has a serious endocrine disease, or other endocrine disorders may also ease is not always obvious. Primary hyper- work well for other members with the same parathyroidism is often found by accident disease, but everyone is different. Sometimes when blood work is done for other reasons. other family members need different medica- The patient may have had kidney stones in tions for their condition to improve. the past and now has osteoporosis or a frac- 8. Some thyroid diseases, such as hypothyroidism, ture, both potentially related to hyper- are common in the general population. parathyroidism. If the patient does not share 9. Testing for most forms of thyroid disease with this past medical history with a physician, the blood tests is relatively simple. diagnosis of hyperparathyroidism might not 10. Pregnant women have an increased risk of be considered. Doctors need complete med- developing thyroid disease, both during preg- ical information from patients, and they also nancy and immediately afterward. need to take laboratory tests to help them 11. Vitamin D deficiency is extremely common in determine if an endocrine disorder is present. the elderly and is treatable. Often these 3. Most endocrine disorders are treatable, patients present with nonspecific aches and although they may not be curable. pains in the muscles and especially in their 4. Infertility may be caused by an underlying wrists and shins. Vitamin D deficiency is usual- endocrine disorder in a man or a woman ly easily treated with supplemental vitamin D. (and sometimes in both of them). This is most 12. Gastric bypass surgery for severe obesity clear- commonly caused by mild elevations of the ly has the best track record to date of all the hormone prolactin due to tiny microadenomas therapies tried for this common and difficult- of the pituitary gland that may be as small as to-treat disorder. one to two millimeters in diameter. Prior to the 13. Thyroid medication must be taken on an current imaging of the pituitary that is possible empty stomach, because various foods and with magnetic resonance imaging, these lesions medications, especially iron and other supple- could not be visualized by the physician. ments, may decrease the absorption of thy- 5. Babies and elderly people can develop treat- roid hormone and lead to hypothyroidism. able endocrine disorders, as can people of any other age. 265 APPENDIX VII 10 LITTLE-KNOWN FACTS ABOUT DIABETES MELLITUS

1. People with diabetes can eat foods with sugar the disease is sometimes diagnosed in adult- (also known as carbohydrates or starches), hood. Also, even if diagnosed during child- contrary to popular belief. Many people hood, the illness persists throughout life. Type believe that diabetes means that patients 2 diabetes was previously called adult-onset must never eat any cakes, cookies, or related diabetes or noninsulin-dependent diabetes. These items. The fact is that people with diabetes names were misleading, because adolescents can eat such foods in moderation. In addi- and even children can develop this form of tion, people with diabetes may actually devel- diabetes. Also, some people with Type 2 dia- op low blood sugar levels (hypoglycemia). betes do require insulin. When that happens, then they need to con- 5. People with diabetes have a greater risk of sume something with sugar in it in order to developing many medical complications. treat the hypoglycemia and stay healthy. This However, with good and continuous control is one of the reasons why people with dia- of their blood glucose, patients can lead nor- betes need to test their blood on a regular mal and active lives. basis—to find out whether their glucose lev- 6. Everyone with Type 1 diabetes needs insulin. els are too high or too low. The insulin may be given by injection or via 2. Not everyone with diabetes needs insulin. an insulin pump (a small catheter under the Insulin is required by people with Type 1 dia- skin). Researchers are also testing an inhaled betes. Some people with Type 2 diabetes, usu- delivery method of insulin. ally after having the disease for many years, 7. Smoking is very bad for people with diabetes, will also require insulin as well. Many and it greatly increases the risk that the patients with Type 2 diabetes will do very patient will suffer from complications, includ- well with a good nutritional program, exer- ing amputations, cancer, heart attack, stroke, cise, and oral medications. and so forth. People with diabetes who smoke 3. Some women develop diabetes only during should work with their doctors to kick the pregnancy, which is called gestational diabetes. habit. Once they deliver their babies, their blood 8. Many supermarkets and pharmacies sell sugar usually returns to normal. However, sugar-free food products for people with dia- these women are at greater risk for develop- betes and other individuals. They also sell ing either Type 1 or Type 2 diabetes later in glucose supplements for when people with life. Also, should they get pregnant again, the diabetes become low in blood sugar. gestational diabetes will often return. 9. Some schools still fail to acknowledge the 4. The names of the two primary types of dia- need of schoolchildren and adolescents to betes have been changed in recent years. self-inject insulin, and parents may need to Type 1 diabetes was once called juvenile-onset determine school guidelines about medica- diabetes, because it is often diagnosed during tions and actively work to obtain exceptions childhood. The name was changed because to them. (Multiple laws and guidelines cover

266 Appendix VII 267

these issues. Contact the American Diabetes Wearing a medical bracelet can help alert Association for further information.) medical experts and other authorities to the 10. Some hypoglycemic adults (and children) presence of diabetes and other chronic med- may appear to be in a drunken state when ical problems and may also help to increase they are, in fact, in serious need of glucose. the probability of fast and effective treatment. APPENDIX VIII WEB SITES WITH INFORMATION ON ENDOCRINE DISEASES AND DISORDERS

American Academy of Pediatrics American Thyroid Association http://www.aap.org http://www.thyroid.org American Association of Clinical Camps for Children with Diabetes Endocrinologists http://www.childrenwithdiabetes.com http://www.aace.com Canadian Cancer Society American Association of Diabetes Educators http://www.cancer.ca http://www.aadenet.org Canadian Diabetes Association American Autoimmune Related Diseases http://www.diabetes.ca Association Centers for Disease Control and Prevention http://www.aarda.org http://www.cdc.gov American Cancer Society Centers for Medicare and Medicaid Services http://www.cancer.org http://cms.hhs.gov American Diabetes Association (ADA) Children with Diabetes Foundation http://www.diabetes.org/ http://www.cwdfoundation.org American Dietetic Association Department of Veterans Affairs http://www.eatright.org http://www.va.gov/health/diabetes American Foundation of Thyroid Patients Diabetes Action Research and Education http://www.thyroidfoundation.org Foundation American Menopause Foundation http://www.diabetesaction.org http://www.americanmenopause.org Diabetes Exercise and Sports Association American Obesity Association http://www.diabetes-exercise.org http://www.obesity.org Endocrine Society American Society for Reproductive Medicine http://www.endo-society.org http://www.asrm.org Gilda Radner Familial Ovarian Cancer American Society of Human Genetics Registry http://www.faseb.org/genetics http://www.ovariancancer.com American Society of Nephrology Health Resources and Services http://www.asn-online.com Administration http://www.hrsa.gov American Society of Ophthalmic Plastic & Reconstructive Surgery Hormone Foundation http://www.asoprs.org http://www.hormone.org 268 Appendix VIII 269

Human Growth Foundation National Health Information Center (NHIC) http://www.hgfound.org http://www.health.gov/NHIC Hypoglycemia Support Foundation, Inc. National Information Center for Children http://www.hypolglycemia.org and Youth with Disabilities http://www.nichcy.org Hypoparathyroidism Association, Inc. http://www.hypoparathyroidism.org National Institute of Diabetes and Digestive and Kidney Diseases Indian Health Service http://www.niddk.nih.gov http://www.ihs.gov National Institute of Mental Health International Diabetic Athletes Association http://www.nimh.nih.gov http://www.diabetes-exercise.org National Institute of Neurological Disorders Joslin Diabetes Center http://www.ninds.nih.gov http://www.joslin.harvard.edu National Institute on Aging Juvenile Diabetes Research Foundation http://www.nia.nih.gov (JDF) International http://www.jdf.org National Kidney Foundation, Inc. http://www.kidney.org Light of Life Foundation http://lightoflifefoundation.org National Oral Health Information Clearinghouse Little People of America, Inc. http://www.nohic.nidcr.nih.gov http://www.lpaonline.org National Organization for Rare Disorders March of Dimes Birth Defects Foundation (NORD) http://www.modimes.org http://www.rarediseases.org National Cancer Institute of Canada (NCIC) National Osteoporosis Foundation http://www.ncic.cancer.ca http://www.nof.org National Coalition for Cancer Survivorship National Ovarian Cancer Coalition (NOCC) (NCCS) http://www.ovarian.org http://www.canceradvocacy.org National Rehabilitation Information Center National Diabetes Education Program http://www.naric.com http://www.ndep.nih.gov National Self-Help Clearinghouse National Diabetes Information http://www.selfhelpweb.org Clearinghouse http://www.niddk.nih.gov/health/diabetes.ndic.htm National Women’s Health Network http://www.womenshealthnetwork.org National Digestive Diseases Information Clearinghouse (NDIC) North American Menopause Society (NAMS) http://www.niddk.nih.gov http://www.menopause.org National Easter Seal Society Office of Minority Health Resource Center http://www.easter-seals.org http://www.omhrc.gov National Eye Institute Ovarian Cancer National Alliance (OCNA) http://www.nei.nih.gov http://www.ovariancancer.org National Graves’ Disease Foundation Oxalosis and Hyperoxaluria Foundation http://www.ngdf.org http://www.ohf.org 270 The Encyclopedia of Endocrine Diseases and Disorders

Paget Foundation for Paget’s Disease of Bone Society for Neuroscience and Related Disorders http://www.sfn.org http://www.paget.org ThyCa: Thyroid Cancer Survivors’ Pancreatic Cancer Action Network Association, Inc. http://www.pancan.org http://www.thyca.org Pituitary Tumor Network Association Thyroid-Cancer.net http://www.pituitary.com http://www.thyroid-cancer.net Power of Prevention (A Diabetes Web Site) Thyroid Foundation of America, Inc. www.powerofprevention.com http://www.allthyroid.org Prader-Willi Alliance for Research Transplant Recipient International http://www.pwsresearch.org Organization http://www.trio.org Prader-Willi Syndrome Association http://www.pwsausa.org United Network for Organ Sharing http://www.unos.org RESOLVE: The National Infertility Association Wilson’s Disease Association http://www.resolve.org http://www.wilsonsdisease.org APPENDIX IX FREQUENCIES OF DIABETES AMONG PERSONS 18 YEARS OF AGE AND OLDER, BY SELECTED CHARACTERISTICS: UNITED STATES, 1999

NUMBERS IN THOUSANDS

All Persons 18 and Older All Persons 18 and Older With Diabetes Total 199,617 10,755

Sex Male 95,565 5,090 Female 104,053 5,666 Age 18–44 years 108,523 1,806 45–64 years 58,617 4,678 65–74 years 17,806 2,468 75 years and older 14,671 1,803 Race Caucasian 163,210 8,177 Black or African American 22,350 1,725 American Indian or Alaska Native 1,202 114 Asian 5,786 221 Native Hawaiian or other Pacific Islander 164 3 Region Northeast 38,973 2,242 Midwest 51,107 2,587 South 71,998 4,112 West 37,540 1,814 Sex and Age Male: 18–44 years 53,460 767 45–64 years 28,342 2,289 65 years and older 13,763 2,034 Female: 18–44 years 55,063 1,039 45–64 years 30,275 2,389 65 years and older 18,714 2,237

Source: Pleis, J. R. and R. Coles. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 1999, Series 10, Number 212, National Center for Health Statistics, 2003.

271 APPENDIX X PERCENT OF DIABETES AMONG PERSONS 18 YEARS OF AGE AND OVER, BY SELECTED CHARACTERISTICS: 1999

UNITED STATES, 1999

Total 5.4 Sex Male 5.4 Female 5.5

Age 18–44 years 1.7 45–64 years 8.1 65–74 years 14.1 75 years and older 12.5

Race Caucasian 5.1 Black or African American 7.8 American Indian or Alaskan Native 9.5 Asian 3.8 Native Hawaiian or other Pacific Islander 2.0

Region Northeast 5.8 Midwest 5.1 South 5.8 West 4.9

Sex and Age Male: 18–44 years 1.4 45–64 years 8.2 65 years and older 15.1 Female: 18–44 years 1.9 45–64 years 8.0 65 years and older 12.2

Source: Pleis, J. R. and R. Coles. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 1999, Series 10, Number 212, National Center for Health Statistics, 2003.

272 APPENDIX XI FREQUENCY DISTRIBUTIONS OF BODY MASS INDEX AMONG PERSONS 18 YEARS OF AGE AND OVER, BY SELECTED CHARACTERISTICS: UNITED STATES, 1999

UNITED STATES, 1999

All Persons 18 Selected Characteristic Years of Age Underweight Healthy Weight Overweight Obese and Older Total (number in thousands) 199,617 4,220 79,876 67,974 40,692 Sex Male 95,565 830 31,985 40,537 20,306 Female 104,053 3,390 47,891 27,437 20,386 Age 18–44 years 108,523 2,684 48,049 34,061 20,264 45–64 years 58,617 617 18,831 22,162 14,693 65 years and older 32,477 920 12,997 11,751 5,735 Race and Ethnicity Caucasian 163,210 3,537 66,048 56,049 32,159 Black or African American 22,350 327 7,215 7,809 6,105 American Indian or Alaska Native 1,202 12 321 413 439 Asian 5,786 214 3,820 1,198 313 Native Hawaiian or other Pacific Islander 164 3 28 55 74 Hispanic or Latino 20,508 239 7,305 7,683 4,567 Education Less than a high school diploma 29,923 678 10,204 10,658 7,390 High school graduate/GED recipient 51,995 767 18,490 18,562 12,398 Some college 46,712 859 17,063 16,620 10,734 Bachelor of Arts, science degree, 43,365 799 19,010 16,614 6,571 or professional degree Family Income Less than $20,000 39,756 1,175 16,256 12,372 8,523 $20,000 or more 149,828 2,854 59,880 52,510 30,231 $20,000–34,999 30,471 645 12,012 10,047 7,038 $35,000–$54,999 33,956 632 13,235 11,821 7,633 $55,000–$74,999 23,603 404 9,361 8,396 4,843 $75,000 or more 35,057 746 14,597 13,018 6,006 Marital Status Married 116,328 1,782 42,766 42,642 25,200 Widowed 13,483 479 5,518 4,366 2,614 Divorced or separated 20,787 450 8,127 7,095 4,444 Never married 37,300 1,191 18,273 10,067 6,502 Living with a partner 11,085 303 4,975 3,603 1,868

(continues)

273 274 The Encyclopedia of Endocrine Diseases and Disorders

FREQUENCY DISTRIBUTIONS OF BODY MASS INDEX AMONG PERSONS 18 YEARS OF AGE AND OLDER, BY SELECTED CHARACTERISTICS: UNITED STATES, 1999 (continued)

All Persons 18 Selected Characteristic Years of Age Underweight Healthy Weight Overweight Obese and Older

Region Northeast 38,973 831 15,896 13,261 7,063 Midwest 51,107 961 20,121 17,322 11,166 South 71,998 1,687 27,842 24,581 15,668 West 37,540 742 16,017 12,810 6,795 Sex and Age Male: 18–44 years 53,460 496 19,680 21,647 10,516 45–64 years 28,342 156 7,355 12,900 7,433 65 years and older 13,763 179 4,951 5,990 2,356 Female: 18–44 years 55,063 2,188 28,369 12,414 9,748 45–64 years 30,275 461 11,476 9,262 7,260 65 years and older 18,714 741 8,046 5,761 3,379

Source: Pleis, J. R. and R. Coles. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 1999, Series 10, Number 212, National Center for Health Statistics, 2003. APPENDIX XII PERCENT DISTRIBUTIONS OF BODY MASS INDEX AMONG PERSONS 18 YEARS OF AGE AND OVER, BY SELECTED CHARACTERISTICS: UNITED STATES, 1999

UNITED STATES, 1999

Selected Characteristic Total Underweight Healthy Weight Overweight Obese

Sex Male 100.0 0.9 34.2 43.3 21.7 Female 100.0 3.4 48.3 27.7 20.6 Age 18–44 years 100.0 2.6 45.7 32.4 19.3 45–64 years 100.0 1.1 33.4 39.4 26.1 65 years and older 100.0 2.9 41.4 37.4 18.3 Race and Ethnicity Caucasian 100.0 2.2 41.9 35.5 20.4 Black or African American 100.0 1.5 33.6 36.4 28.5 American Indian or Alaska Native 100.0 1.0 27.1 34.9 37.0 Asian 100.0 3.9 68.9 21.6 5.6 Native Hawaiian or other Pacific Islander 100.0 2.0 17.6 34.3 46.1 Hispanic or Latino Education Less than a high school diploma 100.0 2.3 35.3 36.8 25.5 High school graduate/GED recipient 100.0 1.5 36.8 37.0 24.7 Some college 100.0 1.9 37.7 36.7 23.7 Bachelor of Arts, science degree, 100.0 1.9 45.3 37.2 15.6 or professional degree Family Income Less than $20,000 100.0 3.1 42.4 32.3 22.2 $20,000–$34,999 100.0 2.2 40.4 33.8 23.7 $35,000–$54,999 100.0 1.9 39.7 35.5 22.9 $55,000–$74,999 100.0 1.8 40.7 36.5 21.1 $75,000 or more 100.0 2.2 42.5 37.9 17.5 Marital status Married 100.0 1.6 38.1 37.9 22.4 Widowed 100.0 3.7 42.5 33.6 20.1 Divorced or separated 100.0 2.2 40.4 35.3 22.1 Never married 100.0 3.3 50.7 27.9 18.0 Living with a partner 100.0 2.8 46.3 33.5 17.4 Region Northeast 100.0 2.2 42.9 35.8 19.1 Midwest 100.0 1.9 40.6 34.9 22.5 South 100.0 2.4 39.9 35.2 22.5 West 100.0 2.0 44.0 35.2 18.7 (continues) 275 276 The Encyclopedia of Endocrine Diseases and Disorders

PERCENT DISTRIBUTIONS OF BODY MASS INDEX AMONG PERSONS 18 YEARS OF AGE AND OLDER, BY SELECTED CHARACTERISTICS: UNITED STATES: 1999 (continued)

Selected Characteristic Total Underweight Healthy Weight Overweight Obese

Sex and Age Male: 18–44 years 100.0 0.9 37.6 41.4 20.1 45–64 years 100.0 0.6 26.4 46.3 26.7 65 years and older 100.0 1.3 36.7 44.4 17.5 Female: 18–44 years 100.0 4.2 53.8 23.5 18.5 45–64 years 100.0 1.6 40.3 32.5 25.5 65 years and older 100.0 4.1 44.9 32.1 18.8 Source: Pleis, J. R. and R. Coles. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 1999, Series 10, Number 212, National Center for Health Statistics, 2003. APPENDIX XIII DIABETES DEATHS, RATES PER 100,000

DEATHS DUE TO DIABETES, BY SEX, 2001

Total Male Female State Number Rate* Number Rate* Number Rate* Alabama 1,344 29.3 609 33.2 735 26.6 Alaska 80 22.7 41 20.6 39 23.2 Arizona 1,057 20.1 535 23.0 522 17.7 Arkansas 756 25.8 347 28.3 409 23.7 California 6,395 21.4 3,049 23.7 3,346 19.5 Colorado 667 18.7 307 20.1 360 17.5 Connecticut 759 19.6 348 22.7 411 17.2 Delaware 218 27.1 94 27.6 124 26.0 District of Columbia 209 37.0 82 36.8 127 37.5 Florida 4,631 22.0 2,344 25.8 2,287 18.9 Georgia 1,475 21.9 684 24.1 791 19.8 Hawaii 173 13.3 93 15.8 80 11.1 Idaho 318 26.2 141 26.3 177 25.7 Illinois 3,092 25.4 1,380 28.1 1,712 23.3 Indiana 1,677 27.7 763 31.1 914 25.2 Iowa 709 20.1 310 22.4 399 18.4 Kansas 721 25.0 327 28.1 394 23.2 Kentucky 1,099 27.1 491 29.9 608 25.1 Louisiana 1,734 41.7 688 39.4 1,046 42.5 Maine 398 26.9 186 31.0 212 24.2 Maryland 1,458 29.2 689 33.4 769 26.1 Massachusetts 1,422 20.2 656 24.0 766 17.7 Michigan 2,655 26.9 1,169 28.7 1,486 25.4 Minnesota 1,213 24.3 612 30.2 601 20.0 Mississippi 661 24.1 263 24.1 398 24.1 Missouri 1,535 25.5 714 29.2 821 22.8 Montana 229 23.2 98 23.1 131 23.0 Nebraska 400 21.2 175 23.3 225 20.2 Nevada 322 17.6 180 19.6 142 14.9 New Hampshire 291 23.6 157 30.3 134 18.4 New Jersey 2,556 28.5 1,190 33.1 1,366 25.3 New Mexico 538 31.4 266 35.5 272 27.9 New York 3,844 19.4 1,770 22.3 2,074 17.3 North Carolina 2,181 27.8 964 30.0 1,217 26.0 North Dakota 196 25.7 87 27.6 109 24.1 Ohio 3,750 31.4 1,670 34.7 2,080 28.9 Oklahoma 1,065 29.5 450 29.6 615 28.9 Oregon 1,011 27.9 466 30.4 545 26.0 Pennsylvania 3,826 25.7 1,696 28.4 2,130 23.6 Rhode Island 265 21.7 120 25.2 145 19.3 South Carolina 1,088 27.5 497 29.8 591 25.4 South Dakota 212 24.2 94 26.2 118 22.8 Tennessee 1,746 30.6 786 33.3 960 28.3 (continues) 277 278 The Encyclopedia of Endocrine Diseases and Disorders

DEATHS DUE TO DIABETES, BY SEX, 2001 (continued)

Total Male Female State Number Rate* Number Rate* Number Rate*

Texas 5,456 31.6 2,445 33.5 3,011 30.0 Utah 509 31.9 235 33.9 274 30.6 Vermont 155 24.1 67 24.5 88 23.7 Virginia 1,613 24.5 741 26.9 872 22.3 Washington 1,403 25.1 687 28.6 716 22.2 West Virginia 802 37.6 358 40.6 444 34.6 Wisconsin 1,337 23.3 663 28.8 674 19.6 Wyoming 120 25.5 56 28.2 64 23.6 United States 71,371 25.2 32,840 28.0 38,531 23.0

*Deaths per 100,000 Source: Centers for Disease Control and Prevention. The Burden of Chronic Diseases and Their Risk Factors: National and State Perspectives. U.S. Department of Health and Human Services, February 2004. APPENDIX XIV INCIDENCE OF INVASIVE CANCERS OF THE ENDOCRINE SYSTEM

Males, 2000 Primary Site All Races Caucasian African American Asian/Pacific Islander All sites, all forms of cancer 560,533 483,519 52,985 11,037 Pancreas 12,229 10,510 1,290 297 Testes 6,267 5,833 194 101 Thyroid 4,200 3,726 229 147 Other endocrine, including thymus 757 628 75 37 Note: Racial information was not available in some cases. Source: U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2000 Incidence. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute, 2003.

Females, 2000 Primary Site All Races Caucasian African American Asian/Pacific Islander All sites, all forms of cancer 533,647 465,477 46,569 11,894 Pancreas 12,891 10,931 1,508 322 Ovary 20,188 17,989 1,352 493 Thyroid 13,019 11,114 932 624 Other endocrine, including thymus 677 534 96 27 Note: Racial information was not available in some cases Source: U.S Cancer Statistics Working Group. United States Cancer Statistics: 2000 Incidence. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute, 2003.

279 APPENDIX XV STATE CANCER REGISTRIES

ALABAMA 1700 Tribute Road, Suite 100 Alabama Statewide Cancer Registry Sacramento, CA 95815 Alabama Department of Public Health (916) 779-0303 P.O. Box 303017 http://www.ccrcal.org/index.htm Montgomery, AL 36130 (334) 206-5552 COLORADO http://www.adph.org/cancer_registry Colorado Department of Public Health and Environment ALASKA Colorado Central Cancer Registry Alaska Cancer Registry PPD-CR-A5 3601 C Street, Suite 540 4300 Cherry Creek Drive South P.O. Box 240249 Denver, CO 80246 Anchorage, AK 99524 (303) 692-2542 (907) 269-8000 http://www.cdphe.state.co.us/pp/cccr.cccrhom.asp http://www.epi.hss.state.ak.us CONNECTICUT ARIZONA Connecticut Tumor Registry Arizona Cancer Registry 410 Capitol Avenue Arizona Department of Health Services P.O. Box 340308 MS #13-TMR 1740 West Adams Room 410 Hartford, CT 06134 Phoenix, AZ 85007 (860) 509-7163 (602) 542-7308 http://www.dph.state.ct.us/OPPE/hptumor.htm http://www.hs.state.az.us/phs/phstats/acr/index.htm DELAWARE ARKANSAS Delaware Department of Health and Social Arkansas Central Cancer Registry Services Arkansas Department of Health Division of Public Health Division of Chronic Disease/Disability Prevention P.O. Box 637 4815 West Markham Street, Slot 7 Dover, DE 19903 Little Rock, AR 72295 (302) 739-5617 (501) 661-2392 http://www.state.de.us/dhss/dph http://www.healthyarkansas.com/arkcancer/ arkcancer.html DISTRICT OF COLUMBIA District of Columbia Cancer Registry CALIFORNIA District of Columbia Department of Health California Department of Human Services 825 North Capitol Street NE Cancer Surveillance Section Room 3145 280 Appendix XV 281

Washington, DC 20002 INDIANA (202) 442-5910 Indiana State Department of Health http://www.dchealth.dc.gov/services/special_pro- State Cancer Registry grams/cancer_control/index.shtm Two North Meridian Street Section 7-D FLORIDA Indianapolis, IN 46204 (317) 233-7158 Florida Cancer Data System http://www.in.gov/isdh/dataandstast/cancer.htm University of Miami School of Medicine P.O. Box 016960 (D4-11) Miami, FL 33101 IOWA (305) 243-4600 State Health Registry of Iowa http://fcds.med.miami.edu 250 FB Building Iowa City, IA 52242 GEORGIA (319) 335-8609 http://www.public-health.uiowa.edu/shri Georgia Department of Human Services Division of Public Health/Cancer Control Section KANSAS Two Peachtree Street NW 14th Floor, 14.283 Kansas Cancer Registry Atlanta, GA 30303 University of Kansas Medical Center (404) 657-1943 3901 Rainbow Boulevard http://www.ph.dhr.state.ga.us/programs/cancer Kansas City, KS 66160 (913) 588-2744 http://www.kumc.edu/som/kcr HAWAII Hawaii Tumor Registry KENTUCKY 1236 Lauhala Street Kentucky Cancer Registry Honolulu, HI 96813 2365 Harrodsburg Road (808) 586-9750 Suite A230 http://planet-hawaii.com/htr Lexington, KY 40504 (859) 219-0773 IDAHO http://www.kcr.uky.edu Idaho Hospital Association Cancer Data Registry of Idaho LOUISIANA 615 North Seventh Street Louisiana Tumor Registry Boise, ID 83702 Louisiana State University Health Sciences (208) 338-5100 Center—New Orleans http://www.idcancer.org 1600 Canal Street Suite 1104 ILLINOIS New Orleans, LA 70112 (504) 568-4283 Illinois State Cancer Registry http://www.lcltfb.org/registry.html Illinois Department of Public Health 605 West Jefferson Street Springfield, IL 62761 MAINE (217) 785-1873 Maine Cancer Registry http://www.idph.state.il.us/about/epi/cancer.htm Division of Family and Community Health 282 The Encyclopedia of Endocrine Diseases and Disorders

Bureau of Health 324 Clark Hall Key Bank Plaza University of Missouri—Columbia Fourth Floor Columbia, MO 65211 11 State House Station (573) 882-7775 Augusta, ME 04333 (207) 287-5272 MONTANA http://www.state.me.us/dhs/bohdcfh/mcr/index2. Montana Central Tumor Registry html Montana Department of Public Health and Human Services MARYLAND Health Policy and Services Division Maryland Cancer Registry Cogswell Building Maryland Department of Health and Mental P.O. Box 202952 Hygiene Helena, MT 59620 201 West Preston Street (406) 444-6786 Baltimore, MD 21201 http://www.dphhs.state.mt.us (410) 767-4055 http://www.fha.state.md.us/cancer/registry NEBRASKA Nebraska Department of Health and Human MASSACHUSETTS Services Regulation and Licensure Massachusetts Department of Public Health Public Health Assurance Division Massachusetts Cancer Registry Data Management Section 250 Washington Street 301 Centennial Mall South Sixth Floor Lincoln, NE 68509 Boston, MA 02108 (402) 471-0147 (617) 624-5618 http://www/hhs.state.ne.us/ced/cancer http://www.state.ma.us.dph/bhsre/mcr/canreg.htm NEVADA MICHIGAN Nevada State Cancer Registry Michigan Cancer Surveillance Program 3811 West Charleston Boulevard Division for Vital Records and Health Statistics Suite 208 Michigan Department of Community Health Las Vegas, NV 89102 3423 North Martin Luther King, Jr. Boulevard (702) 486-6260, ext. 224 Lansing, MI 48909 http://health2k.state.nv.us/cancer (517) 335-8702 http://www.michigan.gov/mdch NEW HAMPSHIRE New Hampshire State Cancer Registry MISSISSIPPI P.O. Box 186 Mississippi Department of Health Hanover, NH 03755 P.O. Box 1700 (603) 653-1032 Jackson, MS 39215 http://cancer.dartmouth.edu/nhcr (601) 576-7411 http://www.cancer.msdh.state.ms.us NEW JERSEY Cancer Epidemiology Services MISSOURI New Jersey State Department of Health and Missouri Cancer Registry Senior Services Health Management and Informatics P.O. Box 369 Appendix XV 283

Trenton, NJ 08625 (614) 466-5350 (609) 588-3500 http://www.odh.state.oh.us/ODHPrograms/CI_SU http://www.state.nj.us/health/cancer/statistics.htm RV/ci_sur1.htm

NEW MEXICO OKLAHOMA New Mexico Tumor Registry Oklahoma Central Cancer Registry 2325 Camino de Salud, NE Chronic Disease Service Albuquerque, NM 87131 Oklahoma Department of Health (505) 272-5541 1000 Northeast Tenth Street http://hsc.unm.edu/epiccpro Oklahoma City, OH 73117 (405) 271-4072, ext. 57123 NEW YORK http://www.health.state.ok.us/program/cds/can- cereg.html New York State Cancer Registry New York State Department of Health OREGON Corning Tower, Room 536 Empire State Plaza Oregon State Cancer Registry Albany, NY 12237 Department of Human Services (518) 474-2255 800 Northeast Oregon Street http://www.health.state.ny.us/nysdoh/cancer/can- Suite 730 cer.htm Portland, OR 97232 (503) 731-4858 NORTH CAROLINA http://www.ohd.hr.state.or.us/oscar/index.cfm North Carolina Central Cancer Registry PENNSYLVANIA North Carolina Department of Health and Human Services Pennsylvania Cancer Registry State Center for Health Statistics Division of Statistical Registries 1908 Mail Service Center Pennsylvania Department of Health Raleigh, NC 27699 555 Walnut Street (919) 715-4558 Sixth Floor http://www.schs.state.nc.us/dphmoved.html Harrisburg, PA 17101 (717) 783-2548 NORTH DAKOTA http://www.health.state.pa.us/stats North Dakota Department of Health PUERTO RICO Division of Health Promotion and Education 600 East Boulevard Avenue Departamento de Salud de Puerto Rico Department 301 Registro Central de Puerto Rico Bismarck ND 58505 P.O. Box 70184 (701) 328-2419 San Juan, PR 00927 http://www.health.state.nd.us/cancerregistry (787) 274-7866

OHIO RHODE ISLAND Ohio Department of Health Rhode Island Department of Health Bureau of Health Surveillance, Information, and 3 Capitol Hill Operational Support Providence, RI 02908 P.O. Box 118 (401) 222-1172 Columbus, OH 43266 http://www.health.ri.gov/disease/cancer/canreg.htm 284 The Encyclopedia of Endocrine Diseases and Disorders

SOUTH CAROLINA VERMONT South Carolina Department of Health and Vermont Cancer Registry Environmental Control Vermont Department of Health PHSIS/SCCCR P.O. Box 70 2600 Bull Street 108 Cherry Street Columbia, SC 29201 Burlington, VT 05402 (803) 898-3626 (802) 863-7644 http://www.scdhec.gov/cancer/cancer-registry.htm http://www.healthvermonters.info

SOUTH DAKOTA VIRGINIA South Dakota Cancer Registry Virginia Cancer Registry Office of Health Promotion, Health and Medical Virginia Department of Health Services P.O. Box 2448 Department of Health Room 114 615 East Fourth Street Richmond, VA 23218 Pierre, SC 57501 (804) 786-1668 (605) 773-5740 http://www.vdh.state.va.us/epi/cancer/index.asp http://www.state.sd.us/doh/stats WASHINGTON TENNESSEE Washington State Cancer Registry Tennessee Cancer Registry Department of Health Cordell Hull Building 7211 Cleanwater Lane Sixth Floor North Building 10 425 Fifth Avenue North Olympia, WA 98504 Nashville, TN 37247 (360) 236-3676 (615) 253-5937 http://www.doh.wa.gov http://www.mtmc.org/cancer/registry.htm WEST VIRGINIA

TEXAS West Virginia Department of Health and Human Resources Texas Cancer Registry Bureau for Public Health Bureau of Epidemiology West Virginia Cancer Registry Texas Department of Health 350 Capitol Street 1100 West 49th Street Room 126 Austin, TX 78756 Charleston, WV 25301 (512) 458-7523 (304) 558-6421 http://www.tdh.state.tx.us/tcr http://www.wvdhhr.org/bph/oeh/sdc/cancerrep.htm

UTAH WISCONSIN Utah Cancer Registry Wisconsin Department of Health and Family 546 Chipeta Way, Suite 410 Services Salt Lake City, UT 84108 Bureau of Health Information (801) 581-8407 Division of Health Care Financing http://www.uuhsc.utah.edu/ucr P.O. Box 309 Appendix XV 285

Madison, WI 53701 6101 Yellowstone Road (608) 266-8926 Room 259A http://www.dhfs.state.wi.us/wcrs/index.htm Cheyenne, WY 82002 (307) 777-3477 WYOMING http://wdhfs.tate.wy.us/cancer Wyoming Cancer Surveillance Program Wyoming Central Tumor Registry APPENDIX XVI DIABETES RESEARCH AND TRAINING CENTERS AND ENDOCRINOLOGY RESEARCH CENTERS IN THE UNITED STATES

Note: These organizations are supported by the UNIVERSITY OF MICHIGAN DRTC National Institute on Diabetes and Digestive and Michigan Diabetes Research and Training Kidney Diseases (NIDDK). They perform important Center basic and clinical research and also provide infor- 1331 E. Ann St. Room 5111 mation on diabetes. University of Michigan Medical School Ann Arbor, MI 48109 DIABETES RESEARCH AND TRAINING (734) 763-5730 CENTERS (DRTCS) http://www.med.umich.edu/mdrtc

ALBERT EINSTEIN COLLEGE VANDERBILT UNIVERSITY DRTC OF MEDICINE DRTC Division of Diabetes, Endocrinology & Director, Prevention and Control Division Metabolism Diabetes Research and Training Center 715 PRB 701 Belfer Building 2220 Pierce Avenue Albert Einstein College of Medicine Nashville, TN 37232 1300 Morris Park Avenue (615) 936-1649 Bronx, NY 10461 http://medschool.mc.vanderbilt.edu/vdc/html/drtc (718) 430-2908 .htm

INDIANA UNIVERSITY DRTC WASHINGTON UNIVERSITY DRTC Indiana University School of Medicine The National Institute for Fitness and Sport Division of Health Behavior Research Room 122 Washington University 250 North University Boulevard 4444 Forest Park Avenue Indianapolis, IN 46202 St. Louis, MO 63108 (317) 278-0905 (314) 286-1900 http://medicine.wustl.edu/~drtc UNIVERSITY OF CHICAGO DRTC DIABETES ENDOCRINOLOGY AND RESEARCH Howard Hughes Medical Institute CENTERS (DERCS) University of Chicago 5841 South Maryland Avenue, MC 1028 Joslin Diabetes Center DERC Room N-216 Harvard Medical School Chicago, IL 60637 One Joslin Place (773) 702-1334 Boston, MA 02215 286 Appendix XVI 287

(617) 732-2635 Worcester, MA 01605 http://www.joslinresearch.org/HomeDir/home.htm (508) 856-3800 http://www.umass.edu/derc Massachusetts General DERC Diabetes Unit University of Pennsylvania DERC Department of Molecular Biology Division of Endocrinology, Diabetes and Wellman 8 Metabolism 50 Blossom Street 611 Clinical Research Building Boston, MA 02114 415 Curie Boulevard (617) 726-6909 Philadelphia, PA 19104 (215) 898-0198 University of Colorado DERC http://www.uphs.upenn.edu/pdc Barbara Davis Center for Childhood Diabetes 4200 East 9th Avenue University of Washington DERC Box B-140 Box 358285 Denver, CO 80262 DVA Puget Sound Health Care System (303) 315-8197 1660 S. Columbian Way http://www.uchsc.edu/misc/diabetes/bdc.html Seattle, WA 98108 University of Iowa DERC (206) 764-2688 Department of Internal Medicine Yale University School of Medicine DERC VA Medical Center Box 208020 Iowa City, IA 52246 333 Cedar Street (319) 338-0581, extension 7625 Fitikin 1 University of Massachusetts Medical School Section of Endocrinology DERC New Haven, CT 06520 373 Plantation Street, Suite 218 (203) 785-4183

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Boldface page numbers denote glucose blood levels 6, 7, and blood pressure 34 main entries. 127 McCune-Albright syn- and Graves’ disease 105 drome 158 A hypercalcemia 117 adrenal gland 8–15 Academy for Eating Disorders 75 hypotension 6, 132, 133, Addison’s disease. See Addi- acanthosis nigricans 1 176 son’s disease dwarfism 70 medical crisis 6–7, 10 adenoma 11 insulin resistance 1, 211 myxedema coma 165 adrenalectomy. See adrena- polycystic ovary syndrome postoperative 48 lectomy 1, 198 skin changes 2, 6, 211 androgen production 11, skin changes 1, 211 weight loss 6, 28 16, 26 achondroplasia and dwarfism adenoma Carney complex 43–44 69–70 adrenal 11 computerized tomography acquired immune deficiency syn- parathyroid 195 9, 11, 47 drome. See AIDS hypercalcemia 116, 117 congenital hyperplasia acromegaly 2–5, 106, 133 hyperparathyroidism 120 47–48, 123 acanthosis nigricans 1 pituitary 197 androgen excess 24, 182 amenorrhea 22 acromegaly 2–5 dwarfism and short stature bone disorders 3, 37 Carney complex 44 70 bromocriptine therapy 4, early puberty 73 early puberty 73, 74 38 hypopituitarism 131, 197 hirsutism 48, 111 cabergoline therapy 4, 39 prolactinoma 97, 197, infertility 140 Carney complex 44 204–205 polycystic ovary syndrome gigantism 2, 3, 102 adolescents 8 48, 198 hyperphosphatemia 123 anorexia nervosa 8, 28, 56 cortical cancer 8–9, 10, 24 hypertension 3, 34 Cushing’s syndrome 52–53 crisis 9–10, 50 McCune-Albright syn- delayed puberty 56–57 fatigue 10–11 drome 157, 158 diabetes mellitus 8, 28, feedback loops 94 skin changes 3, 211 157 hormones 11–12, 13, somatostatin therapy 4, obesity 171 17–18, 49 212 gastric surgery for weight hypothalamic-pituitary- ACTH 2. See also adrenocorti- loss 98 adrenal axis 13, 14, 133 cotropic hormone oral contraceptive use 175 insufficiency 2, 5–7, 10, acupuncture 18, 20 Tanner stages of sexual 12–13 Addison’s disease 2, 5–7, 11, 12 development 215 Addison’s disease 2, 5–7, AIDS 6, 15 adoption in infertility 141 10 cachexia 39 adrenalectomy 10 adrenoleukodystrophy 13, cortisol levels 2, 5–7, 10, 49 adrenal cortical cancer 9, 14 cortisone therapy 6, 7, 50 10 AIDS 6, 12, 15–16 differential diagnosis 6, 28 adrenal hyperplasia, con- hyponatremia 12–13, 129 glucocorticoid therapy 6, genital 48 hypopituitarism 12, 131, 7, 10, 103 aldosteronism 10, 11, 18 132

303 304 The Encyclopedia of Endocrine Diseases and Disorders adrenal gland (continued) pancreatic disorders 15, American Academy of Ophthal- macrocephaly 155 16, 193 mology 69, 87 leukodystrophy 13–15 pituitary disorders 16 American Association of Clinical pheochromocytoma. See thyroid disorders 15, 85 Endocrinologists 22–23, 81, pheochromocytoma Albright’s hereditary osteodystro- 232 adrenaline 11, 12 phy 205 American Cancer Society 43, clonidine suppression test albumin urine levels in diabetic 226 47 nephropathy 66 American Diabetes Association counterregulatory function alcohol use 23, 64, 100, 127, 175, 176, 202 50 hyperlipidemia, familial American Fertility Association glucose blood levels 11, 12 combined 90 142 pheochromocytoma 11, pancreatitis 192, 193 American Menopause Founda- 12, 195, 196 aldosterone 11, 17–18 tion 161 adrenocorticotropic hormone Addison’s disease 5, 7, 17 American Psychiatric Association (ACTH) 2 adrenal hyperplasia, con- 57 Addison’s disease 2, 7 genital 48 American Psychological Associa- adrenal hyperplasia, con- functions 11, 17 tion 57 genital 48 aldosteronism 17–18 American Society for Bariatric adrenal insufficiency 12, 13 adrenalectomy 10, 11, 18 Surgery 98 adrenoleukodystrophy 14 Conn’s syndrome 17 American Society for Reproduc- AIDS 15, 16 hypertension 17, 18, 34 tive Medicine 142 Cushing’s syndrome/dis- aldosteronoma 10, 17, 18 American Society of Bariatric ease 52, 53 alendronate 33, 181 Physicians 98 gastrinoma secretion 99 alprostadil in erectile dysfunction American Thyroid Association hypopituitarism 131, 197 83 23 pituitary synthesis and alternative medicine 18–21 amiodarone-induced thyroiditis secretion 2, 131, 197 medication interactions 229 adrenoleukodystrophy 13–15 19–20, 159 amylin 191 age menopause symptoms anabolic steroids 23–24, 27 bone age. See bone age 113, 115 Androgen Insensitivity Syn- children. See children amenorrhea 21–22 drome Support Group 26 delayed puberty 56–57 androgen excess 22, 24, 183 androgens 24–27 diabetes mellitus 60 androgen resistance 25 abuse 27 early puberty 73–74 anorexia nervosa 22, 28 adrenal production 11, 26 elderly 76–79. See also eld- anovulation 29–30 AIDS 16 erly Asherman’s syndrome 22, amenorrhea 22, 24, 25, fertility and infertility 94, 31 183 139, 140, 155–156 Cushing’s syndrome 52, 53 antiandrogens in cancer growth hormone levels eating disorders 22, 28, therapy 43 106, 107 75 excess 22, 24, 111 hyperparathyroidism 120 follicle-stimulating hor- ovarian overproduction metabolic rate 162 mone levels 95 182–183 testosterone levels 218 Graves’ disease 105 functions 26 AIDS 15–16 hyperthyroidism 123 gynecomastia 25, 26, 108 adrenal insufficiency 6, 12, thyrotoxicosis 233 hirsutism 24, 27, 111, 183 15–16 infertility 21–22, 140 ovarian overproduction cachexia 16, 39 POEMS syndrome 51 182–183 gonadal function 16 polycystic ovary syndrome polycystic ovary syndrome growth hormone therapy 22, 30, 198 24, 30, 182, 198, 199 16 prolactinoma 204 prostate cancer 24, 43 Index 305

resistance 24–26, 216 arteriosclerosis 31–32 hypotension. See hypoten- therapy 27 ascites in pancreatic cancer 192 sion anemia, androgen therapy in 27 Asherman’s syndrome 22, 31 insulin resistance syndrome angiotensin-converting enzyme aspirin in atherosclerosis 32 145 inhibitors in diabetic atherosclerosis 31–32, 90–92 blood sugar 35–36. See also glu- nephropathy 66 apolipoproteins 31 cose blood levels angiotensin receptor blockers in cholesterol levels 31–32, body mass index 36 diabetic nephropathy 66 44–45, 90–92 anorexia nervosa 27 anorexia 27 diabetes mellitus 32, 238 gastric surgery for weight AIDS 16 erectile dysfunction 81, 82 loss 97, 98 cachexia 39 homocysteine levels 111, obesity 36, 169 anorexia nervosa 27–29, 75 112 bone age 36–37 adolescent 8, 28, 56 obesity 32, 169, 170 adrenal hyperplasia, con- amenorrhea 22, 28 autoimmune disorders 80 genital 48 bone disorders 29, 181 adrenal insufficiency 6, 7, delayed puberty 36, 56 delayed puberty 56 12 early puberty 36, 73, 74 differential diagnosis 6, 28 antibodies 31 bone disorders 37 euthyroid sick syndrome diabetes mellitus 60, 80, acromegaly 3, 37 85 236 anorexia nervosa 29, 181 malnutrition 156 Graves’ disease 80, 104, bisphosphonate therapy anovulation 29–30, 94 227 33, 78, 177, 181, 190 hypothyroidism 29, 135 Hashimoto’s thyroiditis 31, calcitonin therapy 40, 78, polycystic ovary syndrome 80, 109, 134, 227 181, 182, 190 29, 30, 198–199 hypoparathyroidism 130 calcium balance 41, 116, antacids and milk-alkali syn- Klinefelter syndrome 150 179 drome 117, 163–164 painful subacute thyroiditis osteomalacia 180, 242 anti-thyroid peroxidase antibod- 228 osteoporosis 41, 116, 163, ies 223 postpartum thyroiditis 228 181 Hashimoto’s thyroiditis rickets 209 110, 223 B elderly 76–77, 78–79 hypothyroidism 136, 223 bariatric surgery (gastric bypass osteoporosis 76–77, antibodies 31 surgery) 36, 97–98, 101, 174 78–79, 95, 180–182 to thyroid peroxidase 110, basal body temperature 30 estrogen 84, 177 136, 223 basal-bolus insulin therapy 33 fractures. See fractures antidiuretic hormone binge eating disorder 75 hyperparathyroidism 37, diabetes insipidus 58, 59 bisphosphonates 33, 177 79, 121, 122, 177 hypopituitarism 131 hypercalcemia 33, 117 osteomalacia 121, 180 hypothalamus secretion osteomalacia from 179 osteoporosis 79, 121, 134 osteoporosis 33, 78, 181 180 inappropriate secretion 129 Paget’s disease of bone 33, Paget’s disease 190 aortic root disorders in Marfan’s 179, 190 Kallmann’s syndrome 149, syndrome 157 parathyroid cancer 150 apolipoproteins 31, 90 194 McCune-Albright syn- appetite blood pressure 33–35 drome 158, 159 AIDS 16 acromegaly 3 osteogenesis imperfecta anorexia 16, 27 aldosterone affecting 11, 17 70, 155, 177–179 cachexia 39–40 classification 34 osteomalacia 95, 121, ghrelin affecting 101 diabetes mellitus 34, 66 179–180, 209, 242 Prader-Willi syndrome 75, hypertension. See hyper- osteopenia 37, 57, 177, 101, 201, 202 tension 178, 180 306 The Encyclopedia of Endocrine Diseases and Disorders bone disorders (continued) cachexia 39–40 parathyroid cancer 194 osteoporosis 180–182. See AIDS 16, 39 pseudohypoparathyroidism also osteoporosis café au lait spots in neurofibro- 205, 206 Paget’s disease of bone matosis type 1 167 supplemental sources 41, 189–190. See also Paget’s calcitonin 40 42 disease of bone hypercalcemia 40, 117 hypocalcemia 126, 131 parathyroid cancer 194 osteoporosis 40, 78, 181, hypoparathyroidism 131 Prader-Willi syndrome 182 tetany 125, 130, 219 201, 202 Paget’s disease of bone 40, Trousseau’s sign 46, 126, prolactinoma 205 190 130, 219, 234 rickets 121, 155, 158, 209, pheochromocytoma 195 and vitamin D 41, 42, 117, 219, 242 thyroid cancer 224, 225 241, 242 thyroid disorders 76–77, calcitriol 41, 114, 241 hypocalcemia 125, 126, 79, 95 bone disorders 177 131 Turner syndrome 180, 235 and calcium 41, 42, 131 hypoparathyroidism 131 vitamin D 177, 179, 242, hypoparathyroidism 131, calcium carbonate 41, 42, 126, 243 241 163 osteoporosis 78, 180, 181, parathyroid cancer 194 calcium citrate 41, 42, 126 243 vitamin D resistance 243 calcium lactate 41, 42, 126 rickets 209, 242 calcium 41–42 calculi, renal bone marrow transplantation in absorption 41 hypercalcemia 116 adrenoleukodystrophy 14 balance 41–42, 194, 195 hyperoxaluria 119, 120 bone mass measurement 37 bone disorders 41, 116, hypocalcemia 130 DEXA scans 57–58. See also 179 Canadian Diabetes Association DEXA scans osteomalacia 180, 242 42–43 fractures 95 osteoporosis 41, 116, 163, cancer 43 hyperparathyroidism 37, 181 acanthosis nigricans 1 121 rickets 209 acromegaly 4 osteopenia 37, 57, 180 breast-feeding 37 ACTH production 2 osteoporosis 37, 57–58, and calcitonin 40, 117 adrenal cortex 8–9, 10, 24 78, 181 and calcitriol 41, 42, 131 alternative medicine 19 rickets 209 Chvostek’s sign 46, 126, androgen therapy 24 breast cancer and oral contracep- 130, 234 bisphosphonate therapy tive use 175 functions 125–126 33 breast-feeding 37–38 hypercalcemia 93, Carney complex 43, 44 diabetes mellitus 37–38, 101 115–117. See also hyper- euthyroid sick syndrome prolactin levels 37, 203 calcemia 85 bromocriptine 38, 39 hyperparathyroidism 41, humoral hypercalcemia of acromegaly 4, 38 116, 117, 120, 121, 122 malignancy 33, 40, 117 gigantism 102 familial hypocalciuric malnutrition 156 bulimia nervosa 75 hypercalcemia 93 melatonin therapy 160 Burnett’s syndrome 163 multiple endocrine neopla- multiple endocrine neopla- bypass surgery, gastric 36, sia type 1 164 sia. See multiple 97–98, 101, 174 parathyroid cancer 194 endocrine neoplasia hypocalcemia 125–126. ovarian 76, 161, 183–186, C See also hypocalcemia 187, 213 cabergoline 38, 39 hypoparathyroidism 41, pancreatic 76, 169, acromegaly 4, 39 125, 130–131, 195, 219 191–192 hyperprolactinemia 38, milk-alkali syndrome 117, parathyroid 194 39, 205 163–164 prostate 24, 43, 81, 83 Index 307

testicular 213, 216–218 hypothyroidism 48–49, clonidine suppression test 46–47 thymus gland 220 134, 135, 139. See also pheochromocytoma thyroid 223–226. See also hypothyroidism, children 46–47, 196 thyroid gland, cancer and adolescents coenzyme Q10 19 Carney complex 43–44 McCune-Albright syn- coma 47 gigantism 101–102 drome 157–159 Creutzfeldt-Jakob disease carpal tunnel syndrome in dia- melatonin deficiency 160 51 betic neuropathy 67 micropenis 163 dehydration 56 catecholamines neurofibromatosis 167, diabetic ketoacidosis 47, clonidine suppression test 168 64 46–47, 196 obesity 98, 171 myxedema 47, 79, 135, pheochromocytoma 195, osteogenesis imperfecta 165–166, 232 196 177–178 complementary medicine 18–21 Centers for Disease Control and osteomalacia 179 compliance with diabetes melli- Prevention 44 Paget’s disease of bone 189 tus therapy 62 cerebral vascular diseases 32, 44 phosphorus levels 123 computerized tomography 47 chemotherapy Prader-Willi syndrome acromegaly 3 adrenal cancer 9 201–202 adrenal gland 11, 47 ovarian cancer 186 rickets 209 cancer 9 pancreatic cancer 192 tall stature 102 aldosteronism 18 child abuse vitamin D resistance 243 bone mass measurement differentiated from osteo- cholesterol 44–45, 90–92 37 genesis imperfecta 178 apolipoproteins 31 Cushing’s syndrome/dis- and failure to thrive 89 atherosclerosis 31–32, ease 53 children 44–45, 90–92 gigantism 102 adolescent 8. See also ado- diabetes mellitus. See dia- insulinoma 144 lescents betes mellitus, cholesterol osteomalacia 179 adrenal hyperplasia, con- and lipoprotein levels osteopenia 180 genital 47–48 exercise 45, 86, 92, 93 pancreatic cancer 192 bone age 36–37 familial hypercholes- pancreatitis 193 breast-fed 37–38 terolemia 91–92, 99, 114 pheochromocytoma 196 Cushing’s syndrome 52–53 hyperlipidemia 90, 118. thyroid cancer 225 dehydration 55 See also hyperlipidemia thyroid nodules 230, 231 delayed puberty 56–57 hypertriglyceridemia congenital disorders diabetes insipidus 58 92–93, 124–125 adrenal hyperplasia. See diabetes mellitus 8, 28, 60, hypothyroidism 90, 118, adrenal gland, congenital 139, 148, 157, 236 136, 137 hyperplasia dwarfism 70, 71 insulin resistance syn- hypothyroidism 48–49, early puberty 73–74 drome 145 134, 139 endocrinologist specialty polycystic ovary syndrome Conn’s syndrome 17 80, 81 198 contraceptives, oral 174–175 failure to thrive 89 recommended levels 45 acanthosis nigricans 1 growth hormone levels xanthomas 91, 92, 245 adverse effects 175 106, 107 chromogranin A 46 amenorrhea 22 hermaphroditism 110–111 Chvostek’s sign 46 calcium absorption 41 hypercholesterolemia, hypocalcemia 46, 126, familial hypertriglyc- familial 91 130, 234 eridemia 93 hypernatremia 118 hypoparathyroidism 130 hirsutism therapy 111, hyperoxaluria 119 cinacalet in hyperparathyroidism 174 hypogonadism 128 122 hypertension 34 308 The Encyclopedia of Endocrine Diseases and Disorders contraceptives, oral (continued) Cushing’s disease 11, 52–53 depression 57 luteinizing hormone levels ACTH production 2 Cushing’s syndrome 52, 154, 175 adrenal cancer 9 57 ovarian androgen overpro- cortisol levels 49, 52 delayed puberty 57 duction therapy 183 fertility 94 hypothyroidism 57, painful menstruation ther- ovarian androgen overpro- 134–135 apy 161 duction 182 obesity 171 polycystic ovary syndrome skin changes 211 postpartum 200 therapy 175, 199 Cushing’s Support and Research desiccated thyroid hormone 57, thyroxine levels 222 Foundation, Inc. 53 153, 222 Cope’s syndrome 163 Cushing’s syndrome 11, 52–53 desmopressin acetate 59. See also coronary artery disease 32 acanthosis nigricans 1 antidiuretic hormone obesity 169, 170 adrenal cancer 9 DEXA scans 37, 57–58 cortisol 2, 11, 49 cachexia 39 hyperparathyroidism 121 Addison’s disease 2, 5–7, Carney complex 44 Kallmann’s syndrome 150 10, 49 depression 52, 57 osteopenia 180 adrenal crisis 9–10 drug-induced 52, 53, 103 osteoporosis 181 adrenal hyperplasia, con- hypernatremia 118 dexamethasone suppression test genital 47, 48 hypertension 34 in Cushing’s syndrome/disease adrenal insufficiency 13 McCune-Albright syn- 53 AIDS 15 drome 157, 158 diabetes insipidus 58–59 Cushing’s syndrome/dis- osteoporosis 52, 180 AIDS 16 ease 49, 52, 53 cyst dehydration 55 functions 11 hypothalamus 131, 133 hypernatremia 118 counterregulatory 49, 50 ovary 186, 187. See also hypotension 132 McCune-Albright syn- ovary, cyst hypothalamus function drome 158, 159 58, 59, 134 myxedema coma 165 D thirst and fluid intake 58, postpartum pituitary daily living activities in dwarfism 59, 219 necrosis 200 and short stature 70–71 Diabetes Insipidus Foundation, cortisone 50 DECODE study 176 Inc. 59 Addison’s disease 6, 7, 50 dehydration 55–56 diabetes mellitus 60–69, adrenal crisis 10, 50 diabetes insipidus 58 236–238 cosyntropin stimulation test diabetic ketoacidosis 56, acromegaly 2, 3, 4 Addison’s disease 7 64, 65 adolescent 8, 28, 157 adrenal hyperplasia, con- hypercalcemia 117 adrenal hormones 11 genital 48 hypotension 55, 132 alternative medicine 18 adrenal insufficiency 7, 13 delayed puberty 8, 56–57 amenorrhea 22 counterregulatory hormones 49, androgen therapy 27 American Diabetes Associa- 50 bone age 36, 56 tion 23 cranial nerve disorders in dia- Cushing’s syndrome 53 anorexia nervosa 28 betic neuropathy 67 Kallmann’s syndrome 56, atherosclerosis risk 32, creatinine levels in diabetic 149 238 nephropathy 65, 66 Klinefelter syndrome 56, autoimmune disorder 60, cretinism 49 150 80, 236 Creutzfeldt-Jakob disease 50–51 neurofibromatosis type 1 168 Canadian Diabetes Associa- Creutzfeldt-Jakob Disease Foun- Prader-Willi syndrome 56, tion 42–43 dation 51 201 cerebrovascular disorders crisis, adrenal/addisonian 6–7, Tanner stages of sexual 44 9–10, 50 development 215 cholesterol and lipoprotein Crow-Fukase syndrome 51–52 testicular changes 216 levels 44–45, 118, 238 Index 309 familial combined hyper- hypothyroidism 137 type 2 236–238. See also lipidemia 90 infants 139 type 2 diabetes mellitus familial dysbetalipopro- infertility 139 weight loss 28, 236 teinemia 91 insulin resistance 114, 144 of youth, maturity onset hypertriglyceridemia 92, syndrome 145 8, 157 93, 124 type 2 diabetes 114, 144, diet. See nutrition type 2 diabetes 44, 124, 236 Dietary Supplement and Health 238 insulin therapy. See insulin, Education Act 21 coma 47 diabetes mellitus therapy dietary supplements 18–21 compliance with therapy Joslin Diabetes Center menopause symptoms 62 147–148 113, 115 complications 63, 64–69 juvenile 148, 236 DiGeorge syndrome 220 costs 63 ketoacidosis. See ketoacido- dopamine levels in clonidine counterregulatory hor- sis, diabetic suppression test 47 mones 50 Klinefelter syndrome 151 Down syndrome and congenital dehydration 55, 56 medications 63–64, hypothyroidism 49 drug-induced 144 237–238 drug-induced disorders 159 eating disorders 28, 75 microcephaly 163 acanthosis nigricans 1 elderly 76, 77–78 nephropathy 34, 36, adrenal insufficiency 12 endocrinologist training 65–67, 236 in AIDS 15, 16 80, 81 neuropathy 36, 67–68, in aldosteronism 18 erectile dysfunction 67, 236, 237 amenorrhea 22 81, 82 obesity 144, 169, 170, Cushing’s syndrome 52, euthyroid sick syndrome 171, 236 53, 103 85 osteoporosis 180 dehydration 55 exercise. See exercise, dia- pancreatic endocrine func- diabetes mellitus 144 betes mellitus tions 191 elderly 77, 79 feedback loops 93–94 patient education 62, 237 erectile dysfunction 18, gastric surgery for weight physician specialty 22 81, 82 loss 97 POEMS syndrome 51–52 euthyroid sick syndrome genetic factors 66, 99, 100, polycystic ovary syndrome 85 157, 236 198 galactorrhea 97 gestational 60, 94, 99–101, Prader-Willi syndrome 201 gynecomastia 18, 108 203, 238 prediabetes 202–203. See herb interactions 19–20 glucose tolerance 100, also prediabetes hypercalcemia 117 101, 176 pregnancy and breast-feed- hyperglycemia 7, 103 glucagon levels 102 ing in 37–38, 101 hyperparathyroidism 121 glucose blood levels. See and hypothyroidism 137 hyperprolactinemia 204 glucose blood levels, dia- and postpartum thyroiditis hypertension 34 betes mellitus 228 infertility 156 glucose tolerance. See glu- prevalence 60–62 obesity 171 cose tolerance, diabetes prevention 64, 238 osteomalacia 179 mellitus retinopathy 36, 37–38, osteoporosis 79, 180 Graves’ disease 105 68–69, 86, 236, 237 thyroid Hashimoto’s thyroiditis risk factors 60, 210, 236 hypothyroidism 134 109 signs and symptoms 60, thyroiditis 229 hypertension 34, 66 210, 236–237 thyrotoxicosis 233 hypocalcemia in infants of skin changes 211 dry eye syndrome 86 mothers with 125 thirst 219, 236 dual-energy X-ray absorptiome- hypotension, orthostatic Turner syndrome 234 try scans 57–58. See also DEXA 176 type 1 60, 63, 64, 236 scans 310 The Encyclopedia of Endocrine Diseases and Disorders dwarfism 69–71, 106 sleep disorders 76, 160, 196 and follicle-stimulating acanthosis nigricans 70 testosterone levels 218 hormone 95 achondroplasia 69–70 thymus function 220 and luteinizing hormone 154 early puberty 70, 73, 74 thyroid disorders 76–77, menopause levels 84, 115 McCune-Albright syn- 79, 86, 95 ovarian production 187 drome 70, 157 goiter 104 polycystic ovary syndrome dysbetalipoproteinemia, familial hyperthyroidism 76, 77, 199 91 79, 124, 233 postpartum pituitary dysplasia, thanatophoric 70 hypothyroidism 76, 77, necrosis 200 79, 136 estrogen 84–85 E myxedema coma 79, 165 acromegaly 3 early puberty 8, 73–74 thyroid-stimulating hor- and androgen therapy 27 bone age 36, 73, 74 mone test 221 anovulation 30 Cushing’s syndrome 53 thyrotoxicosis 233 bone disorders 84, 177 gynecomastia 218 vitamin D resistance 243 calcium absorption 41 McCune-Albright syn- empty sella syndrome 80, 200 delayed puberty 56 drome 73, 74, 157–158, encephalopathy, transmissible hypogonadotropism 129 187 spongiform 51 Kallmann’s syndrome 149, melatonin deficiency 160 endocrine glands 80. See also spe- 150 neurofibromatosis type 1 cific glands levothyroxine therapy 85, 73, 168 The Endocrine Society 235 161 short stature 70, 73, 74 endocrinologist 80–81 and luteinizing hormone Tanner stages of sexual adrenal fatigue consulta- 153, 154 development 215 tion 11 menopause 84, 85, 113, testicular changes 216 American Association of 114, 115, 154, 161 eating disorders 75 Clinical Endocrinologists oral contraceptives amenorrhea 22, 28, 75 22–23, 81, 232 174–175. See also contra- anorexia nervosa. See anorexia nervosa treatment ceptives, oral anorexia nervosa 27 ovarian production 187 diabetes mellitus 28, 75 hypoparathyroidism treat- postpartum pituitary malnutrition 156 ment 131 necrosis 200 osteoporosis 75, 181 painful menstruation ther- prolactinoma 205 Prader-Willi syndrome 75, apy 161 replacement therapy 85, 101, 201, 202 pregnancy supervision 203 113, 114, 115, 154, 161 weight changes 6, 28, 75 thyroid blood tests 221 Turner syndrome 84, elderly 76–79 ephedra 19, 20 235 cachexia 39–40 epinephrine. See adrenaline euthyroid 85 cerebrovascular disorders erectile dysfunction 81–84 euthyroid sick syndrome 85–86, 44 acromegaly 3 131 dehydration 55 androgen deficiency 26 AIDS 15, 85 diabetes mellitus 76, diabetes mellitus 67, 81, 82 reverse T3 levels 209 77–78 drug-induced 18, 81, 82 thyroid-stimulating hor- fractures 76–77, 78, 79, hyperlipidemia 118 mone 85, 221 95 hypogonadism 82, 128 exercise 86 hypernatremia 118 infertility 139 atherosclerosis 32 medication interactions Kallmann’s syndrome 82, blood pressure 34, 35 159 149 cholesterol levels 45, 86, melatonin secretion 76, POEMS syndrome 51 92, 93 160, 196 estradiol 84–85 diabetes mellitus 60, osteoporosis 76–77, 78–79, anovulation 30 63–64, 86, 144 95, 180–182 delayed puberty 56 gestational 100 Index 311

insulin resistance 144 androgen resistance 25, 26 menopause 115 prediabetes 86, 144, 203 androgen therapy 27 ovarian androgen overpro- type 2 diabetes 237, 238 anovulation 29–30 duction 183 Marfan’s syndrome 156, female reproduction 94, pituitary secretion 95, 197 157 139, 140, 141. See also polycystic ovary syndrome obesity 86, 170, 171, 173 female reproduction 95, 199 eye disorders 86–87 gastric surgery for weight postpartum pituitary diabetic retinopathy 36, loss 97 necrosis 95, 200 68–69, 86, 236 hypogonadism 94, 128, pseudohypoparathyroidism breast-feeding affecting 140 206 37–38 hypothyroidism 94, 140 The Foundation for Prader-Willi type 2 diabetes 68, 69, in vitro fertilization 140 Research 202 237 Kallmann’s syndrome 140, fractures 95 Graves’ disease 86, 104, 149, 150, 156 calcitonin therapy for pain 105, 196, 207 Klinefelter syndrome 150 40 homocystinuria 111, 112 luteinizing hormone levels elderly 76–77, 78, 79, 95 140, 141, 154 from falls in hypotension F male reproduction 94, 132 failure to thrive 89 139, 140–141, 155–156. hyperthyroidism 76–77, diabetes insipidus 58 See also male reproduc- 79, 95 homocystinuria 111, 112 tion osteogenesis imperfecta McCune-Albright syn- polycystic ovary syndrome 177, 178 drome 158 30, 94, 198, 199 osteomalacia 95, 179 fatigue, adrenal 10–11 and pregnancy. See preg- osteoporosis 76–77, 78, fatty acids, very long chain, in nancy 95, 116, 181–182, 215 adrenoleukodystrophy 14 premature ovarian failure vitamin D resistance 243 feedback loops 93–94 186 fungal infections and adrenal counterregulatory hor- reproductive endocrinology insufficiency 6, 12 mones 50 208 hypothalamic-pituitary- testicular disorders 216 G adrenal axis 133 Turner syndrome 234 galactorrhea 97, 204 luteinizing hormone 154 varicocele 141, 156 gallstone pancreatitis 192, thyroid gland 94, 221 fibrate therapy in hypertriglyc- 193 female reproduction 94, 208 eridemia 125 gastric bypass surgery 36, amenorrhea 21–22 fight-or-flight response 11, 12 97–98, 101, 174 anovulation 29–30, 94 fluid balance gastrin 98–99 breast-feeding 37–38 dehydration 55–56 gastrinoma 46, 98–99 estrogen 84–85 hyponatremia 129–130 gender identity fertility and infertility 94, thirst 219 androgen resistance 25, 26 139–142 folic acid and homocysteine lev- hermaphroditism 110–111 Kallmann’s syndrome 149, els 112 micropenis 163 150 follicle-stimulating hormone 95 genetic factors 99, 210 oral contraceptives AIDS 16 achondroplasia 70 174–175 androgen resistance 26 adrenal hyperplasia 47, ovary 186–187 anovulation 30 48 pregnancy 203 hypogonadotropism 129 adrenal leukodystrophy reproductive endocrinology hypopituitarism 95, 131, 13 208 197 anorexia nervosa 28 feminization, testicular 25 infertility 140 diabetes mellitus 66, 99, fertility 94–95, 139–142, 208 Kallmann’s syndrome 149 100, 157 amenorrhea 21–22, 140 male 156 type 2 99, 236 312 The Encyclopedia of Endocrine Diseases and Disorders genetic factors (continued) obesity 101, 173 prediabetes 35, 202 dysbetalipoproteinemia, Prader-Willi syndrome 75, type 2 35, 237, 238 familial 91 101, 202 elderly 78 Graves’ disease 104 gigantism 101–102, 106, 133 and exercise 86 Hashimoto’s thyroiditis acromegaly 2, 3, 102 fasting 175 109 Carney complex 44 glucagonoma 102, 103 hermaphroditism 110 McCune-Albright syn- glucocorticoid excess hypercholesterolemia, drome 101, 158 affecting 7, 103 familial 91, 99 Gilda Radner Familial Ovarian hyperglycemia 118. See hyperlipidemia, familial Cancer Registry 186 also hyperglycemia combined 90, 99 glipizide in type 2 diabetes melli- hypoglycemia 127. See also hyperoxaluria 119 tus 237, 238 hypoglycemia hypothyroidism 136 glucagon 102–103 insulin actions 142, 143 infertility 140 counterregulatory function insulin resistance syn- Klinefelter syndrome 150 50 drome 145 Marfan’s syndrome 156 gastrinoma secretion 99 insulinoma 143–144 McCune-Albright syn- pancreas secretion 102, glucose suppression test in drome 157 191 gigantism 102 micropenis 163 glucagonoma 102–103 glucose tolerance 103, 139, multiple endocrine neopla- glucocorticoid therapy 103 175–176 sia 164 acanthosis nigricans from 1 acromegaly 3 neurofibromatosis 167 in Addison’s disease 6, 7, diabetes mellitus 35, 100, obesity 170–171 10, 103 101, 103, 139 osteogenesis imperfecta 178 in adrenal crisis 10 gestational 100, 101, 176 osteomalacia 179 in adrenal hyperplasia, oral test 175–176 ovarian cancer 183 congenital 48 prediabetes 139, 176, Paget’s disease of bone 189 in adrenal insufficiency 13 202–203 pancreatitis 193 adrenal insufficiency from type 2 175, 176, 237 Prader-Willi syndrome 201 12 impaired 103, 139, 176 pseudohypoparathyroidism bone disorders from 179 oral test 175–176 205 calcium absorption in 41 polycystic ovary syndrome rickets 209 cortisone in 50 103, 198 short stature 69, 70, 99 Cushing’s syndrome from Prader-Willi syndrome 201 tall stature 102 52, 53, 103 glyburide in type 2 diabetes mel- thyroid cancer 224 hyperglycemia from 7, 103 litus 237, 238 Turner syndrome 234, 235 osteoporosis from 79 goiter 77, 103–104, 109, 227 vitamin D resistance 243 ovarian androgen overpro- acromegaly 3 genitalia duction 183 Graves’ disease 104, 105 ambiguous 25, 48, weight gain from 171 Hashimoto’s thyroiditis 110–111 withdrawal syndrome 12 227 androgen resistance 25, 26 glucose blood levels 35–36, 139 hyperthyroidism 103, 123, hermaphroditism 110–111 Addison’s disease 6, 7, 127 124, 233 micropenis 25, 149, 150, and adrenaline levels 11, hypothyroidism 134 163, 216 12 levothyroxine therapy gestational diabetes mellitus 60, counterregulatory hor- 153 94, 99–101, 203, 238 mones 50 McCune-Albright syn- glucose tolerance 100, diabetes mellitus 35–36, drome 158 101, 176 60–69, 118, 175–176, multinodular 231 ghrelin 101 236 radioiodine therapy 207 gastric surgery for weight gestational 100, 101, 176 thyroid cancer risk 224 loss 98, 101 hypoglycemia 118, 127 thyrotoxicosis 233 Index 313 gonadal function early puberty 73–74 Klinefelter syndrome 108, acromegaly 3 failure to thrive 89 150 AIDS 16 genetic short stature 99 POEMS syndrome 51 androgen resistance 25, 26 gigantism 101–102, 106 testicular cancer 218 hypogonadism 128–129. growth hormone deficiency See also hypogonadism 107–108 H hypogonadotropism 129, Kallmann’s syndrome 149 Harvard Eating Disorders Center 149 Klinefelter syndrome 150, 75 gonadotropin 151 Hashimoto’s thyroiditis 31, deficiency 129 macrocephaly 155 109–110, 227–228 human chorionic 30 McCune-Albright syn- acromegaly 3 human menopausal 30 drome 157, 158 anti-thyroid peroxidase gonadotropin-releasing hormone microcephaly 163 antibodies 110, 223 Kallmann’s syndrome 149 Tanner stages 215 autoimmune disorder 31, stimulation test Turner syndrome 234–235 80, 109, 134, 227 early puberty 74 growth hormone 106–108 follicle-stimulating hor- hypogonadotropism 129 acanthosis nigricans 1 mone 95 granuloma and hypercalcemia acromegaly 2–5, 106, 133 goiter 227 117 AIDS therapy 16 hypothyroidism 31, Graves’ disease 104–106 bone age 36, 37 109–110, 134, 227–228 autoimmune disorder 80, counterregulatory function painful menstruation 161 104, 227 50 thyroid-stimulating hor- differential diagnosis 109, Creutzfeldt-Jakob disease mone 110, 228 228 51 thyrotoxicosis 233 eye problems 86, 104, deficiency 106, 107–108 thyroxine levels 110, 222 105, 196, 207 delayed puberty 8, 56 head size goiter 104, 105 dwarfism and short stature macrocephaly 155 Hashimoto’s thyroiditis 69, 70, 99, 106 microcephaly 163 109, 110 early puberty 73 neurofibromatosis type 1 hyperthyroidism 104–106, and ghrelin 101 163, 167 109, 123, 124, 227 gigantism 101–102, 106 head trauma hypothyroidism 136 hypopituitarism 131, 132, coma 47 physical examination 196 197 diabetes insipidus 58, postpartum 200 McCune-Albright syn- 59 pretibial myxedema drome 158, 159 hearing loss 165–166 micropenis 163 Paget’s disease of bone radioiodine diagnosis and osteogenesis imperfecta 189, 190 therapy 207 178 Turner syndrome 235 thyroid-stimulating osteoporosis 78, 182 heart disorders immunoglobulin test pituitary secretion 2, 106, Marfan’s syndrome 223 107, 197 156–157 thyroidectomy 105, 226 Prader-Willi syndrome Turner syndrome 234 thyrotoxicosis 104, 232, 201–202 hemoglobin A1c levels in dia- 233 Turner syndrome 235 betes mellitus 64, 236 triiodothyronine levels gynecomastia 108 hemorrhage, adrenal 11 234 androgen deficiency 26, herbal preparations 18–21 weight loss 28, 105 108 drug interactions 19–20, growth and development 106 androgen resistance 25 159 acromegaly 2–5, 106 drug-induced 18, 108 menopause symptoms delayed puberty 56–57 early puberty 218 113, 115 dwarfism 69–71, 106 hypogonadism 108, 128 regulations 20, 21 314 The Encyclopedia of Endocrine Diseases and Disorders hermaphroditism 22, 110–111, hyperaldosteronism 17–18. See hypernatremia 118–119 216 also aldosteronism hyperoxaluria 119–120 hirsutism 111, 211 hypercalcemia 41, 115–117, 126 hyperparathyroidism 120–122, acromegaly 3 bisphosphonate therapy 195 adrenal cancer 9 33, 117 bone disorders 37, 79, adrenal hyperplasia, con- calcitonin therapy 40, 117 121, 122, 177 genital 48, 111 in calcitriol therapy 41 osteomalacia 121, 180 androgen excess 24, 111, familial hypocalciuric 93, osteoporosis 79, 121, 180 183 116, 121 Paget’s disease 190 androgen therapy 27 humoral, of malignancy calcium balance 41, 116, Cushing’s syndrome 52 33, 40, 117 117, 120, 121, 122 oral contraceptives as ther- and hypernatremia 118 familial hypocalciuric apy 111, 174 hyperparathyroidism 41, hypercalcemia 93 polycystic ovary syndrome 93, 116, 117, 120, 121 multiple endocrine neopla- 30, 111, 198 parathyroid cancer 194 sia type 1 164 HIV infection 15. See also AIDS milk-alkali syndrome 117, parathyroid cancer 194 homocysteine (homocystine) 163–164 hypertension 34 111–112 multiple endocrine neopla- multiple endocrine neopla- homocystinuria 111, 112 sia type 1 164 sia type 1 164 differential diagnosis 112, pancreatitis 116, 193 parathyroid cancer 194 156 parathyroid cancer 194 hyperphagia 75 microcephaly 163 parathyroid hormone 195 hyperphosphatasia and macro- hormones 113–114. See also spe- hypercholesterolemia cephaly 155 cific hormones familial 91–92, 99, 114 hyperphosphatemia 122–123 adrenal 11–12, 13 hypothyroidism 136 acromegaly 123 adrenocorticotropic hor- xanthomas 91, 92, 245 pseudohypoparathyroidism mone 2 hyperglycemia 35, 118 205 aldosterone 17–18 AIDS 16 hyperplasia 123 androgens 24–27 Cushing’s syndrome 52 adrenal cortisol 49 diabetic ketoacidosis Carney complex 44 counterregulatory 49, 50 64–65 congenital. See adrenal estrogen 84–85, 113 gestational diabetes melli- gland, congenital hyper- growth hormone 106–108 tus 100 plasia insulin 142–145 glucagonoma 102, 103 parathyroid 120, 122 resistance 113–114, glucocorticoid excess 7, 103 prostatic benign 82 144–145 hypernatremia 118 hyperprolactinemia 38, 204–205 testosterone 218–219 impaired glucose tolerance cabergoline therapy 38, thyroid 220–223, 232, 139 39, 205 233–234 insulin levels 142 galactorrhea 97, 204 hot flashes hyperlipidemia 118 hypertension 33–35 hypogonadism 128 exercise in 86 acromegaly 3, 34 Kallmann’s syndrome 149 familial combined 90, 99 aldosteronism 17, 18, 34 menopause 84, 85, 113, glucose intolerance 103 atherosclerosis 32 114–115, 154, 161 hypothyroidism 90, 118, cerebrovascular disorders Human Growth Foundation 107 136, 137 44 humoral hypercalcemia of insulin resistance syn- cholesterol levels 45 malignancy 33, 40, 117 drome 145 diabetes mellitus 34, 66 hydrocortisone in adrenal crisis polycystic ovary syndrome insulin resistance syn- 10 198 drome 145 21-hydroxylase deficiency 47–48 xanthomas 91, 92, 245 obesity 169, 170 Index 315

pheochromocytoma 34, Chvostek’s sign 46, 126, pseudohypoparathyroidism 195, 196 130, 234 206 Turner syndrome 234, 235 hyperparathyroidism 121 teriparatide therapy 215 hyperthyroidism 123–124, 227 hyperphosphatemia 123 testosterone 128–129, 159, AIDS 15 hypoparathyroidism 218, 219 amenorrhea 123, 233 130–131, 195, 219 hypogonadotropism 129 apathetic 77, 124 pregnancy and breast-feed- Kallmann’s syndrome 129, breast-feeding 38 ing 37 149 cachexia 39 pseudohypoparathyroidism hypokalemia in aldosteronism dietary supplements caus- 205 17, 18 ing 20 tetany 125, 130, 219 hypomagnesemia and hypocal- differential diagnosis 143 Trousseau’s sign 46, 126, cemia 125, 126 drug-induced 229 130, 219, 234 hyponatremia 129–130 elderly 76, 77, 79, 124, hypocalciuric hypercalcemia, adrenal crisis 10 233 familial 93, 116, 121 adrenal insufficiency fractures 76–77, 79, 95 hypochondroplasia 70 12–13, 129 goiter 103, 123, 124, 233 hypocortisolism AIDS 16 Graves’ disease 104–106, Addison’s disease 2, 5–7, hypothyroidism 129, 135 109, 123, 124, 227 10 myxedema coma 165 hypercalcemia 117 adrenal crisis 9–10 hypoparathyroidism 130–131, hypertension 34 hypoglycemia 35, 127 195 McCune-Albright syn- ACTH levels 2 calcitriol therapy 41, 241 drome 157, 158, 159 Addison’s disease 6, 7, 127 calcium balance 41, 125, metabolic rate 162 AIDS 15 130–131, 195 osteoporosis 180 counterregulatory hor- tetany 219 physical examination mones 50 hyperphosphatemia 123 196 diabetes mellitus 118, 127 POEMS syndrome 52 skin changes 124, 211 elderly 78 pseudohypoparathyroidism subclinical 212–213 hypothyroidism 135 205–206 tall stature 102 insulin levels 142, 143 thyroidectomy 226 testicular cancer 218 insulinoma 143 vitamin D 41, 131, 241 thyroid nodules 231 myxedema coma 165 hypophosphatasia and osteoma- thyroid-stimulating hor- unawareness 50 lacia 179 mone test 221, 232 hypogonadism 128–129 hypophosphatemia 122 thyroiditis 227 acromegaly 3 rickets 209 thyrotoxicosis and thyroid AIDS 16 hypopituitarism 131–132, 197 storm 232–233 androgen therapy 27 adenoma of pituitary 131, thyroxine levels 124, 222 erectile dysfunction 82, 128 197 triiodothyronine levels fertility 94, 128, 140 adrenal insufficiency 12, 124, 222, 234 gynecomastia 108, 128 131, 132 hypertriglyceridemia 124–125 hypopituitarism 131, 132 follicle-stimulating hor- familial 92–93, 124 Kallmann’s syndrome 128, mone 95, 131, 197 pancreatitis 92, 192–193 149 hypothalamic cyst or hypervitaminosis vitamin D 242 Klinefelter syndrome 128, tumor 131, 133 hypoaldosteronism 17 150 postpartum 199, 200 hypocalcemia 41, 125–126 luteinizing hormone levels hypotension 132–133 AIDS 16 154 Addison’s disease 6, 132, calcitriol therapy 41, 42 osteoporosis 128, 132 133, 176 calcium supplements 41, Prader-Willi syndrome adrenal hyperplasia, con- 42 201, 202 genital 48 316 The Encyclopedia of Endocrine Diseases and Disorders hypotension (continued) elderly 76, 77, 79, 136 immunoglobulins 31 dehydration 55, 132 estrogen replacement ther- thyroid-stimulating 223 orthostatic 132, 176, 195 apy 85 impaired glucose tolerance 103, postpartum pituitary fertility and infertility 94, 139 necrosis 199, 200 140 incidentalomas 197 hypothalamic-pituitary-adrenal galactorrhea 97 infants 139 axis 13, 14, 133 goiter 103, 104 diabetes mellitus 139 hypothalamus 133–134 hyperlipidemia 90, 118, failure to thrive 89, 111, adrenal insufficiency 12, 136, 137 112 13 hypertriglyceridemia, homocystinuria 111, 112 computerized tomography familial 92, 93 hypothyroidism, congenital 47 hyponatremia 129, 135 48–49, 134, 139 cyst or tumor 131, 133 hypopituitarism 131, 132 macrocephaly 155 diabetes insipidus 58, 59, Klinefelter syndrome 151 microcephaly 163 134 Lugol’s solution 153 micropenis 163 feedback loops 94, 133 metabolic rate 162 infertility 139–142. See also fer- follicle-stimulating hor- myxedema coma 165 tility mone 95 orthostatic hypotension in vitro fertilization 140 gigantism 101, 102, 133 176 insulin 114, 142–145 hypothalamic-pituitary- POEMS syndrome 52 diabetes mellitus therapy adrenal axis 13, 14, 133 postpartum 137 60, 63, 142–143, 159, hypothyroidism, secondary and pregnancy 136–137, 191, 236 134, 211 203 basal-bolus 33 Kallmann’s syndrome 133, prolactin levels 204 gestational 100 149 pseudohypoparathyroidism type 2 diabetes 142, 238 magnetic resonance imag- 206 functions 191 ing 155 radioiodine-induced 207 gastrinoma secretion 99 prolactin 203–204, 205 secondary 134, 211 glucagonoma secretion hypothyroidism 134–137, 227 skin changes 134, 211 102 acanthosis nigricans 1 subclinical 212–213 pancreas secretion 114, acromegaly 3 tertiary 211 142, 143, 144, 191 AIDS 15 thyroid nodules 231 preparations available 142, alternative medicine treat- thyroid-stimulating hor- 143 ment 18 mone 134, 136, 137, 211 resistance 114, 144–145 anovulation 29, 135 blood test 220, 221, 232 acanthosis nigricans 1, anti-thyroid peroxidase thyroiditis 227 211 antibodies 136, 223 Hashimoto’s 31, 109–110, AIDS 16 children and adolescents 134, 227–228 anovulation 29 48–49, 134, 135, 139 thyroxine levels 134, 136, exercise 86 bone age 36 137, 211, 222, 234 hypertriglyceridemia, delayed puberty 56 thyroxine therapy 18, 135, familial 92 early puberty 73, 74 136, 137, 153, 159, 161 obesity 145, 169 failure to thrive 89 triiodothyronine levels ovarian androgen overpro- coma 47 136, 137, 222 duction 183 congenital 48–49, 134, Turner syndrome 234, 235 polycystic ovary syndrome 139 weight 170 144, 187, 198, 199 depression 57, 134–135 syndrome 145 drug-induced 229 I Turner syndrome 234 dysbetalipoproteinemia, immune deficiency syndrome, type 2 diabetes mellitus familial 91 acquired. See AIDS 114, 144, 236 Index 317

shock in hypoglycemia keratoconjunctivitis sicca 86 lipids 44–45, 90–92 127 ketoacidosis, diabetic 64–65 hyperlipidemia 90, 118. tolerance test coma 47, 64 See also hyperlipidemia Addison’s disease 7 dehydration 56, 64, 65 polycystic ovary syndrome growth hormone defi- euthyroid sick syndrome 198 ciency 107 85 xanthomas 91, 92, 245 insulin-like growth factor 1 hypoglycemia 127 lipoproteins 44–45, 90–92 acromegaly 3, 4, 5 17-ketosteroid reductase defi- apolipoproteins 31, 90 gigantism 102 ciency 48 diabetes mellitus. See dia- growth hormone deficiency kidney disorders betes mellitus, cholesterol 107 calculi. See calculi, renal and lipoprotein levels osteoporosis 182 diabetic nephropathy 34, dysbetalipoproteinemia, postpartum pituitary 36, 65–66, 236 familial 91 necrosis 200 hyperparathyroidism 120 and exercise 45, 86 insulinoma 142, 143–144 hyperphosphatemia 123 hypercholesterolemia. See interferon-induced thyroiditis hypoparathyroidism 130 hypercholesterolemia 229 Klinefelter syndrome 150–151 hyperlipidemia. See hyper- interleukin-induced thyroiditis delayed puberty 56, 150 lipidemia 229 early puberty 73 hypertriglyceridemia iodine erectile dysfunction 82 92–93, 124–125, 192–193 deficiency 104, 109, 134, gynecomastia 108, 150 insulin resistance syn- 224 hypogonadism 128, 150 drome 145 Lugol’s solution 153 osteoporosis 180 polycystic ovary syndrome radioactive 207–208. See 198 also radioactive iodine L xanthomas 91, 92, 245 thyrotoxicosis from 145 La Leche League International lithiasis, renal. See calculi, renal 38 lithium-induced thyroid disor- J lanreotide in acromegaly 4 ders 229, 233 jaundice in pancreatic cancer laparoscopic adrenalectomy 10 Little People of America, Inc. 71 192 laser therapy in diabetic Lorenzo’s oil 14 Joslin Diabetes Center 147–148 retinopathy 69 Lugol’s solution 153 juvenile diabetes mellitus 148, lead blood levels in delayed luteinizing hormone 153–154 236 puberty 56 AIDS 16 Juvenile Diabetes Research leukodystrophy, adrenal 13–15 androgen resistance 26 Foundation International 128 levothyroxine 114, 153, 159, anovulation 29, 30 222 and follicle-stimulating K desiccated preparations 57, hormone levels 95 Kallmann’s syndrome 149–150 153, 222 hypogonadotropism 129 delayed puberty 56, 149 elderly 77 hypopituitarism 131, erectile dysfunction 82, 149 estrogen replacement ther- 197 hypogonadism 128, 149 apy 85, 161 infertility 140, 141, 154 hypogonadotropism 129, Hashimoto’s thyroiditis Kallmann’s syndrome 149, 149 110 154 hypopituitarism 132 hypopituitarism 197 micropenis 163 hypothalamus disorders hypothyroidism 18, 135, oral contraceptives affect- 133, 149 136, 137, 153, 234 ing 154, 175 infertility 140, 149, 150, secondary 211 ovarian androgen overpro- 156 liotrix tablets 233 duction 183 luteinizing hormone levels Light of Life Foundation 226 pituitary secretion 153, 149, 154 liotrix tablets 233 154, 197 318 The Encyclopedia of Endocrine Diseases and Disorders luteinizing hormone (continued) massage therapy 18, 20 basal rate 162 polycystic ovary syndrome maturity onset diabetes of youth cachexia 39 154, 199 8, 157 insulin resistance syn- pseudohypoparathyroidism McCune-Albright syndrome drome 145 206 157–159 thyroid functions 226 luteinizing hormone-releasing dwarfism and short stature metaiodobenzylguanide scan hormone agonists 43, 74 70, 157 162, 196 early puberty 73, 74, metformin M 157–158, 187 diabetes mellitus 63, 237, macrocephaly 155, 167 gigantism 101, 158 238 mad cow disease 51 infertility 140 polycystic ovary syndrome MAGIC Foundation 159 ovarian cysts 158, 159, 187 30, 199 magnesium and calcium levels megacolon, myxedema 165 prediabetes 203 125, 126 megestrol acetate therapy MIBG scan 162, 196 magnetic resonance imaging 47, AIDS 16 microcephaly 163 155 cachexia 39 micropenis 25, 163, 216 acromegaly 3 melanin and acanthosis nigricans Kallmann’s syndrome 149 adrenal gland 11 1 Klinefelter syndrome 150 cancer 9 melatonin 159–160 mifepristone 175 adrenoleukodystrophy 14 pineal gland secretion 76, milk-alkali syndrome 117, aldosteronism 18 159–160, 196 163–164 Cushing’s syndrome/dis- sleep disorders of elderly mineralocorticoids 103 ease 53 76, 160, 196 aldosterone. See aldos- diabetes insipidus 58 menarche 8 terone gigantism 102 and amenorrhea 21, 22 multiple endocrine neoplasia hypogonadism 128 menopause 161, 208 164–165 insulinoma 144 anovulation 29 Carney complex 43 Kallmann’s syndrome 150 estrogen levels and therapy gastrinoma 99 osteomalacia 179 84, 85, 113, 114, 115, pheochromocytoma 196 thyroid cancer 225 154, 161 type 1 164 thyroid nodules 230 eye problems 86 adrenal cancer 8 ma huang 19, 20 follicle-stimulating hor- follicle-stimulating hor- male reproduction 155–156, 208 mone levels 115 mone levels 95 erectile dysfunction 81–84 hot flashes 84, 85, 113, gigantism 102 fertility and infertility 94, 114–115, 154, 161 glucagonoma 102 139–142 luteinizing hormone levels insulinoma 143 hypogonadism 128–129 154 parathyroid cancer 194 Kallmann’s syndrome 149, osteoporosis 182 type 2 164–165 150 surgically-induced 161 thyroid cancer 164–165, Klinefelter syndrome menorrhagia 161–162 224 150–151 menstruation VIPoma 241 reproductive endocrinology amenorrhea 21–22 The Myelin Project 15 208 early puberty 74 myxedema testis 215–216 onset in adolescence 8, 21, coma 47, 79, 135, testosterone 155, 156, 22 165–166, 232 218, 219 painful 161–162 megacolon 165 malnutrition 156 metabolic syndrome 145 pretibial 165–166 Marfan’s syndrome 156–157 metabolism 162 differential diagnosis 112, adrenal functions 11 N 156 alternative medicine treat- National Adrenal Disease Foun- osteoporosis 180 ment 18 dation 7 Index 319

National Arthritis and Muscu- type 1 167–168 acanthosis nigricans 1 loskeletal and Skin Diseases early puberty 73, 168 atherosclerosis 32, 169, Information Clearinghouse head circumference 163, 170 159 167 body mass index 36, 169 National Association of Anorexia type 2 168 causes 170 Nervosa and Associated Disor- Neurofibromatosis, Inc. 168 children and adolescents ders 29 neurologic disorders 98, 171 National Cancer Institute 43, Creutzfeldt-Jakob disease Cushing’s syndrome 52 226 50–51 depression 171 National Diabetes Information diabetic neuropathy 36, diabetes mellitus 169, 170, Clearinghouse 64 67–68, 236, 237 171 National Eating Disorders Associ- orthostatic hypotension prediabetes 144 ation 75 176 type 2 169, 170, 171, 236 National Eye Health Education POEMS syndrome 51 diet 171, 173 Program 69 neuropathy dysbetalipoproteinemia, National Graves’ Disease Foun- diabetic 36, 67–68, 236, familial 91 dation 106 237 eating disorder 75 National Heart, Lung, and Blood POEMS syndrome 51 exercise 86, 170, 171, 173 Institute 45 niacin in hypertriglyceridemia gastric bypass surgery 36, National Institute of Child 125 97–98, 174 Health and Human Develop- nodules, thyroid 230–232. See genetic factors 170–171 ment 159 also thyroid gland, nodules ghrelin levels 101, 173 National Institute of Neurologi- norepinephrine in clonidine sup- glucose intolerance 103 cal Disorders 15 pression test 47 hyperlipidemia, familial National Institute on Drug Abuse nutraceuticals in alternative combined 90 24 medicine 18–21 hypertriglyceridemia, National Institutes of Health 95, nutrition familial 92 167, 182, 202, 204 alternative medicine sup- insulin resistance 145, 169 National Kidney and Urologic plements 18–21 pancreatitis 193 Diseases Information Clearing- and blood pressure 34, 35 polycystic ovary syndrome house 59 breast milk 37 198, 199 National Neurofibromatosis cachexia 39–40 Prader-Willi syndrome 75, Foundation 168 cholesterol levels 45, 90, 170, 201 National Organization for Rare 91, 92, 93, 118 statistical data 169–170 Disorders 15, 51 delayed puberty 56 octreotide 212, 241 National Osteoporosis Founda- diabetes mellitus 60, 63, oligomenorrhea 22, 30 tion 182 64 oral contraceptives 174–175. See National Ovarian Cancer Coali- gestational 100 also contraceptives, oral tion, Inc. 186 prediabetes 203 oral glucose tolerance test necrosis, postpartum pituitary type 2 237, 238 175–176 94, 131–132, 197, 199–200 eating disorders 75 orthophosphate therapy in nephrogenic diabetes insipidus failure to thrive 89 hyperoxaluria 119 58, 59 hyperoxaluria 119, 120 orthostatic hypotension 132, Nephrogenic Diabetes Insipidus hypothyroidism 134 176, 195 Foundation 59 malnutrition 156 osteitis nephropathy, diabetic 34, 36, obesity 171, 173 deformans 189. See also 65–66, 236 vitamin D 241 Paget’s disease of bone neurofibromatosis 167–168 fibrosa disseminate 157. gigantism 102 O See also McCune-Albright pheochromocytoma 167, obesity 169–174 syndrome 168, 196 abdominal 170 osteoblasts 176–177 320 The Encyclopedia of Endocrine Diseases and Disorders osteoclasts 37, 176, 177 hyperparathyroidism 79, Paget’s disease of bone 37, bisphosphonate therapy 121, 180 189–190 33 hypogonadism 128, 132 bisphosphonate therapy Paget’s disease of bone hypopituitarism 132 33, 179, 190 177, 189 Kallmann’s syndrome 149, calcitonin therapy 40, 190 parathyroid hormone 177, 150 hypercalcemia 117 195 Klinefelter syndrome 151 osteoclast activity 177, 189 osteodystrophy, Albright’s hered- Paget’s disease of bone 190 pain itary 205 physician specialty 22 diabetic neuropathy 67–68 osteogenesis imperfecta Prader-Willi syndrome menstrual cycle 161–162 177–179 201, 202 Paget’s disease of bone macrocephaly 155 prolactinoma 205 189, 190 short stature 70, 178 teriparatide therapy thyroiditis 228 Osteogenesis Imperfecta Founda- 181–182, 195, 215 pamidronate in osteogenesis tion 179 Turner syndrome 180, imperfecta 178 osteomalacia 179–180, 209 235 pancreas 191–193 fractures 95, 179 vitamin D 78, 180, 181, AIDS 15, 16, 193 hyperparathyroidism 121, 243 cancer 191–192 180 ovary 182–187 elderly 76 vitamin D deficiency 242 androgen overproduction obesity 169 osteopenia 177, 180 182–183 functions 191 bone mass measurement cancer 183–186, 187 glucagon secretion 102, 191 37, 57, 180 elderly 76 insulin secretion 114, 142, osteogenesis imperfecta surgery 161, 184, 213 143, 144, 191 178 cyst 186, 187 insulinoma 142, 143–144 osteoporosis 37, 177, 180–182 follicle-stimulating hor- vasoactive intestinal peptide acromegaly 3 mone levels 95 producing tumor 241 AIDS 16 McCune-Albright syn- pancreatitis 191, 192–193 alternative medicine treat- drome 158, 159, 187 AIDS 15, 193 ment 19 polycystic syndrome. See hypercalcemia 116, 193 androgen deficiency 26 polycystic ovary syn- hypertriglyceridemia 92, bisphosphonate therapy drome 192–193 33, 78, 181 surgically-induced papaverine in erectile dysfunc- bone mass measurement menopause 161 tion 83 37, 57–58, 78, 181 premature failure 186 parathyroid gland 194–195 calcitonin therapy 40, 78, overweight 36 adenoma 195 181, 182 ovulation 186–187 hypercalcemia 116, 117 calcium balance 41, 116, anovulation 29–30, 94 hyperparathyroidism 120 163, 181 basal body temperature 30 and calcium balance 41, Cushing’s syndrome 52, drugs inducing 30 93, 116, 117, 194, 195 180 luteinizing hormone levels hyperparathyroidism 41, eating disorders 75, 181 154 116, 117, 120, 121, 122, elderly 76–77, 78–79, 95, oxalate levels in urine 119– 195 180–182 120 hypocalcemia 125–126, estrogen 84, 177 Oxalosis and Hyperoxaluria 130–131, 195, 219 fractures 76–77, 78, 95, Foundation 120 hypoparathyroidism 41, 116, 181–182, 215 125, 130–131, 195, 219 vitamin D resistance 243 P multiple endocrine neopla- growth hormone 78, 182 Paget Foundation for Paget’s Dis- sia type 1 164 homocysteine levels 111, ease of Bone and Related Dis- parathyroid cancer 194 112 orders 190 cancer 194 Index 321

hyperparathyroidism hypertension 34, 195, 196 luteinizing hormone secre- 120–122. See also hyper- metaiodobenzylguanide tion 153, 154, 197 parathyroidism scan 162, 196 magnetic resonance imag- hyperplasia 120, 122 neurofibromatosis 167, ing 155 hypoparathyroidism 168, 196 male infertility 156 130–131. See also phosphodiesterase inhibitors in postpartum necrosis 95, hypoparathyroidism erectile dysfunction 83 131–132, 197, 199–200 pseudohypoparathyroidism phosphorus prolactin secretion 197, 123, 205–206 hyperphosphatemia 203, 204 parathyroid hormone 194, 195 122–123, 205 thyroid-stimulating hor- and calcium balance 41, hypophosphatemia 122, mone secretion 197, 232 93, 116, 194, 195 209 tumors 197 hypocalcemia 125–126, photocoagulation in diabetic acromegaly 2–5, 106 130–131 retinopathy 69 Carney complex 44 functions 195 physical examination 196 early puberty 73 hyperparathyroidism skin changes 211–212 gigantism 101, 102, 106 120–122, 195 testis 216 growth hormone secretion hypoparathyroidism thyroid 227, 230 2, 106 130–131, 195 pigmentation changes hypopituitarism 131, 197 osteoblast activity 177 acanthosis nigricans 1 prolactinoma 97, 197, osteoclast activity 177, Addison’s disease 2, 6 204–205 195 adrenal insufficiency 12–13 Pituitary Network Association 5, osteomalacia 180 neurofibromatosis 167 53, 205 osteoporosis 181–182 pineal gland 196, 220 POEMS syndrome 51–52 pseudohypoparathyroidism early puberty 160 Polycystic Ovarian Syndrome 205 melatonin production 76, Association 199 teriparatide preparation 159–160, 196 polycystic ovary syndrome 187, 177, 181–182, 195, 215 pituitary gland 197–198 198–199 and vitamin D 195, 241 ACTH synthesis and secre- acanthosis nigricans 1, 198 pegvisomant in acromegaly 4–5 tion 2, 131, 197 adrenal hyperplasia, con- penis AIDS 16 genital 48, 198 androgen resistance 25, 26 computerized tomography amenorrhea 22, 30, 198 erectile dysfunction 81–84 47 androgen excess 24, 30, micropenis 25, 149, 150, diabetes insipidus 58, 59 182, 198, 199 163, 216 dwarfism 70, 106 anovulation 29, 30, pergolide empty sella syndrome 80, 198–199 acromegaly 4 200 fertility 30, 94, 198, 199 hyperprolactinemia 38, 39 failure 197 follicle-stimulating hor- perimenopause 161 feedback loops 94 mone levels 95, 199 peroneal nerve disorders in dia- follicle-stimulating hor- glucose tolerance 103, 198 betic neuropathy 67 mone 95, 197 hirsutism 30, 111, 198 Peyronie’s disease 82 functions 197 insulin resistance 144, phentermine in obesity 173 growth hormone secretion 187, 198, 199 pheochromocytoma 8, 195–196 106, 107, 197 luteinizing hormone levels adrenalectomy 10 hypopituitarism 131–132. 154, 199 adrenaline levels 11, 12, See also hypopituitarism metformin therapy 30, 195, 196 hypotension 132 199 chromogranin A 46 hypothalamic-pituitary- oral contraceptives as ther- clonidine suppression test adrenal axis 13, 14, 133 apy 175, 199 46–47, 196 hypothyroidism, secondary pregnancy 199, 203, 208 hypercalcemia 117 134, 211 skin changes 198, 211 322 The Encyclopedia of Endocrine Diseases and Disorders postpartum pituitary necrosis progesterone neurofibromatosis type 1 95, 131–132, 197, 199–200 estrogen replacement ther- 73, 168 postpartum thyroid disorders apy 85, 113, 115, 161 Tanner stages of sexual 137, 200 ovarian production 187 development 215 thyroiditis 137, 200, 228, prolactin 37, 197, 203–205 testosterone levels 218 233 breast-feeding 37, 203 pyridoxine thyrotoxicosis 233 galactorrhea 97, 204 and homocysteine levels potassium levels in aldostero- hyperprolactinemia 38, 39, 112 nism 17, 18 97, 204–205 hyperoxaluria 119 Prader-Willi syndrome 201–202 hypopituitarism 131, 197 appetite 75, 101, 201, 202 infertility 141 R delayed puberty 56, 201 pituitary secretion 197, radiation exposure ghrelin levels 75, 101, 202 203, 204 and thyroid cancer risk obesity 75, 170, 201 postpartum pituitary necro- 224 precocious puberty. See early sis 200 and thyroiditis 229–230 puberty pregnancy levels 203 radiation therapy prediabetes 144, 202–203, 238 prolactinoma 197, 204–205 acromegaly 5 exercise 86, 144, 203 erectile dysfunction 82 ovarian cancer 184 glucose blood levels 35, 202 galactorrhea 97, 204 pancreatic cancer 192 glucose tolerance 139, McCune-Albright syn- parathyroid cancer 194 176, 202–203 drome 157 radiculopathy, diabetic 67 pregnancy 94, 203 prostate radioactive iodine 207–208, 227 amenorrhea 21, 22 benign hyperplasia 82 hyperthyroidism 124 breast-feeding 37–38 cancer 43 thyroid cancer 208, diabetes insipidus 58, 59 androgens 24, 43 225–226 in diabetes mellitus 37–38, erectile dysfunction 81, 83 thyroiditis 229–230 101, 137 prostate-specific antigen levels in raloxifene in osteoporosis 78, 181 diabetes mellitus in, gesta- erectile dysfunction 82 5-alpha reductase tional 60, 94, 99–101, prostatitis and erectile dysfunc- deficiency 24, 25, 26 203, 238 tion 82 excessive activity in hir- glucose tolerance 100, prosthesis, penile 83–84 sutism 111 101, 176 proteinuria in diabetic nephropa- refeeding syndrome in anorexia gastric surgery for weight thy 65–66 nervosa 29 loss 97 pseudogynecomastia 108 Reifenstein’s syndrome 25 Graves’ disease 105–106 pseudohyperphosphatemia 123 reproductive endocrinology 208 hypothyroidism 136–137, pseudohypoparathyroidism 123, amenorrhea 21–22 203 205–206 anovulation 29–30 infertility 139–142 pseudopseudohypoparathy- female 94, 208 polycystic ovary syndrome roidism 205 fertility and infertility 94, 199, 203, 208 puberty 8 139–142 postpartum pituitary necro- androgen resistance 25 follicle-stimulating hor- sis 95, 131–132, 197, delayed 56–57. See also mone 95 199–200 delayed puberty in vitro fertilization 140 postpartum thyroid disor- early 73–74. See also early luteinizing hormone ders 137, 200, 228, puberty 153–154 233 Klinefelter syndrome 56, male 155–156, 208 prolactin levels 203 73, 150 RESOLVE: The National Infertil- reproductive endocrinology McCune-Albright syn- ity Association 142 208 drome 157–158 retinopathy, diabetic 36, 68–69, prehypertension 34 menstruation onset 8, 21, 22 86, 236 Index 323

breast-feeding affecting hypothyroidism 134, 211 sun exposure and vitamin D 37–38 McCune-Albright syn- 241, 242 type 2 diabetes 68, 69, 237 drome 158 surgery 213 rickets 121, 209 neurofibromatosis type 1 adrenal cancer 9 macrocephaly 155 167 adrenalectomy 10. See also McCune-Albright syn- polycystic ovary syndrome adrenalectomy drome 158 198, 211 gastric bypass 36, 97–98, tetany 219 sleep disorders 101, 174 vitamin D 209, 242 elderly 76, 160, 196 ovarian cancer 161, 184, risedronate 33, 78, 181 melatonin secretion 76, 213 risk factors 210 159–160, 196 pancreatic cancer 192 genetic 99, 210. See also smoking parathyroid cancer 194 genetic factors autoimmune thyroid disor- pheochromocytoma 196 rosiglitazone in type 2 diabetes ders 80 testicular cancer 213, 218 mellitus 237, 238 hypertension 34, 35 thyroid cancer 213, 225, RU486 175 sodium 226 hypernatremia 118–119 thyroidectomy 226. See S hyponatremia 129–130. also thyroidectomy Saint John’s wort 19 See also hyponatremia syndrome X 145 screening for gestational diabetes somatostatin 212 mellitus 100 acromegaly 4, 212 T semen analysis 156 gigantism 101 T-score on bone mass 37 Sheehan’s syndrome 95, sperm 156 tadalafil in erectile dysfunction 131–132, 197, 199–200 infertility 140–141, 156 83 short stature intracytoplasmic injection Tanner stages 215 dwarfism 69–71 140, 141, 156 tarsal tunnel syndrome in dia- genetic factors 69, 70, 99 Klinefelter syndrome 150 betic neuropathy 67 growth hormone deficiency spine teriparatide 195, 215 107–108 fractures in osteoporosis osteoblast activity 177 neurofibromatosis type 1 78, 181–182 osteoporosis therapy 168 Paget’s disease 190 181–182, 195, 215 osteogenesis imperfecta spironolactone in aldosteronism testis 215–218 70, 178 18 androgen resistance 25, 26 Prader-Willi syndrome 201 Stein-Leventhal syndrome 198 cancer 216–218 Turner syndrome 70, 234, steroids, anabolic 23–24, 27 surgery 213, 218 235 stomach bypass surgery for testosterone production sibutramine in obesity 173 weight loss 36, 97–98, 101, 215–216, 218 sildenafil in erectile dysfunction 174 testosterone 26–27, 218–219 83 strontium ranelate in osteoporo- acromegaly 3 skeletal maturity and bone age sis 182 adrenal hyperplasia, con- 36–37 subclinical thyroid disorders genital 48 skin changes 211–212 212–213 adrenal production 11, acanthosis nigricans 1, substance abuse 216 211 alcohol anabolic effects 24 acromegaly 3, 211 familial combined hyper- androgen resistance Addison’s disease 2, 6, 211 lipidemia 90 24–25, 26 adrenal insufficiency pancreatitis 192, 193 bone disorders 177 12–13 anabolic steroids 24, deficiency 208, 218–219 hirsutism. See hirsutism 27 delayed puberty 56 hyperthyroidism 124, 211 and anorexia nervosa 28 erectile dysfunction 82 324 The Encyclopedia of Endocrine Diseases and Disorders testosterone (continued) anti-thyroid peroxidase nodules 123, 124, 153, functions 216, 218 antibodies 110, 136, 223 227, 230–232 hypogonadism 128–129, bone disorders 76–77, 79, biopsy 231 159, 218, 219 95 cancer risk 225, 230–231 hypogonadotropism 129 breast-feeding 38 diagnosis and treatment infertility 141 calcitonin 40 230, 231–232 Kallmann’s syndrome 149, cancer 40, 46, 223–226 McCune-Albright syn- 150 anti-thyroid peroxidase drome 158 Klinefelter syndrome 151 antibodies 223 ultrasonography 230, 231, and luteinizing hormone chromogranin A levels 46 239 153, 154 diagnosis 225 as physician specialty 22 male reproduction 155, levothyroxine therapy postpartum disorders 137, 156, 218, 219 153 200, 228, 233 micropenis 163 multiple endocrine neopla- subclinical disorders ovarian overproduction sia type 2 164–165, 224 212–213 182–183 and nodules 225, 230–231 thyroiditis 227–230. See polycystic ovary syndrome radioiodine therapy 208, also thyroiditis 198 225–226 Turner syndrome 109, prostate cancer 43 risk factors 224 234, 235 replacement therapy 27, surgery 213, 225, 226 thyroid-stimulating hormone 114, 129, 219 symptoms 224 232 testicular production thyroid-stimulating hor- AIDS 15 215–216, 218 mone 208, 225–226 blood test 220, 221, 232 tetany 125, 130, 219 types 223–224 breast-fed infants 38 tetrahydrogestrinone 24 dietary supplements affect- elderly 76, 77, 79, 221 thanatophoric dysplasia 70 ing 20 euthyroid sick syndrome thirst 219, 236 elderly. See elderly, thyroid 85, 221 thromboembolism and homocys- disorders goiter 104 teine levels 112 euthyroid sick syndrome Graves’ disease 105 thymoma 220 85–86. See also euthyroid Hashimoto’s thyroiditis thymus gland 219–220 sick syndrome 110, 228 cancer 220 feedback loops 94, 221 hyperthyroidism 124 functions 219–220 goiter 103–104. See also blood test 221, 232 thyrogen 208, 225–226 goiter hypopituitarism 131, 132, thyroglobulin 225, 227 Graves’ disease 104–106. 197 thyroid-binding globulin 15, See also Graves’ disease hypothyroidism 134, 136, 233 Hashimoto’s thyroiditis. See 137 Thyroid Cancer Survivors Asso- Hashimoto’s thyroiditis blood test 220, 221, ciation 226 hormones 232, 233–234 232 thyroid gland 220–234 blood tests 220–223 secondary 211 acromegaly 3 desiccated preparations McCune-Albright syn- AIDS 15, 85 57, 153, 222 drome 158 alternative medicine treat- hyperthyroidism 123–124. pituitary secretion 197, ment 18 See also hyperthyroidism 232 amenorrhea 22, 233 hypothyroidism 48–49, postpartum pituitary American Thyroid Associa- 134–137. See also necrosis 200 tion 23 hypothyroidism pseudohypoparathyroidism anatomy and functions McCune-Albright syn- 206 226–227 drome 157, 158, 159 recombinant preparation anovulation 29 metabolic rate 162 208, 225–226 Index 325

subclinical thyroid disor- thyroid storm 232–233 liotrix tablets 233 ders 212 triiodothyronine levels 234 reverse T3 208–209 thyroid cancer 208, thyrotropin-releasing hormone subclinical disorders 212 225–226 221, 232 Trousseau-von Bonsdorff test thyroid-stimulating thyroxine 114, 227, 233–234 234 immunoglobulin 223 blood test 220, 222–223, Trousseau’s sign 46, 234 thyroid storm 232–233 233–234 hypocalcemia 46, 126, thyroidectomy 213, 226 desiccated preparations 57, 130, 219, 234 Graves’ disease 105, 226 153, 222 hypoparathyroidism 130 hyperthyroidism 124 euthyroid sick syndrome tetany 219 hypocalcemia after 125, 85 tuberculosis, adrenal insuffi- 219 Hashimoto’s thyroiditis ciency in 6, 12 hypoparathyroidism after 110, 222 Turner syndrome 234–235 226 hyperthyroidism 124, 222 amenorrhea 22 radioiodine therapy after hypothyroidism 134, 136, delayed puberty 56 208, 225 137, 222, 234 estrogen 84, 235 tetany after 219 secondary 211 follicle-stimulating hor- thyroid cancer 213, 225, therapy 18, 135, 136, 137, mone 95 226 153, 159, 161 menopause symptoms 114 thyroid-stimulating hor- levothyroxine formulation osteoporosis 180, 235 mone 208 153. See also levothyrox- short stature 70, 234, 235 thyroiditis 227–230 ine thyroid disorders 109, 234, differential diagnosis 105 liotrix tablets 233 235 drug-induced 229 postpartum pituitary Turner Syndrome Society 235 fibrous 230 necrosis 200 type 1 diabetes mellitus 236. See goiter 104 reverse T3 208–209 also diabetes mellitus Hashimoto’s 109–110. See subclinical disorders 212 type 2 diabetes mellitus 60, also Hashimoto’s thyroidi- topiramate in obesity 174 63–64, 236–238 tis triglycerides 92–93, 124–125 acanthosis nigricans 1 hyperthyroidism 123, 124 dysbetalipoproteinemia, aldosterone levels 17 painful subacute 228 familial 91 cholesterol levels 44, 124, painless lymphocytic or hyperlipidemia, familial 238 sporadic 228, 233 combined 90 elderly 76, 77–78 palpation-induced 230 hypertriglyceridemia gastric surgery for weight postpartum 137, 200, 228, 124–125, 192–193 loss 97 233 familial 92–93, 124 genetic factors 99, 236 radioiodine uptake test 207 insulin resistance syn- and gestational diabetes suppurative 229 drome 145 100, 101, 238 Thyrolar (liotrix tablets) 233 pancreatitis 92, 192–193 glucose blood levels 35, thyrotoxicosis 233 polycystic ovary syndrome 237, 238 amiodarone-induced 229 198 glucose tolerance test 175, apathetic 77, 124 triiodothyronine 227, 233, 234 176, 237 elderly 77, 79, 124 blood test 220, 221–222 hypertriglyceridemia 124 Graves’ disease 104, 232, desiccated preparations 57, infertility 139 233 222 insulin resistance 114, hyperphosphatemia 123 euthyroid sick syndrome 85 144, 236 iodine-induced 145 hyperthyroidism 124, 222, insulin therapy 142, 238 osteoporosis 79 234 Klinefelter syndrome 151 postpartum thyroiditis hypothyroidism 136, 137, medications 63–64, 228, 233 222 237–238 326 The Encyclopedia of Endocrine Diseases and Disorders type 2 diabetes mellitus vitamin B6 W (continued) and homocysteine levels water deprivation test in dia- obesity 169, 170, 171, 236 112 betes insipidus 59 polycystic ovary syndrome hyperoxaluria therapy 119 weight 198 vitamin B12 and homocysteine Addison’s disease 6, 28 retinopathy 68, 69, 237 levels 112 anorexia nervosa 6, 28 risk factors 210, 236 vitamin D 241–243 body mass index. See body of youth, maturity onset bone disorders 177, 179, mass index 8, 157 242, 243 cachexia 39–40 osteoporosis 78, 180, 181, and cholesterol levels 45 U 243 Cushing’s syndrome 52 ultrasonography 239 rickets 209, 242 diabetes mellitus 63 Asherman’s syndrome 31 calcitriol. See calcitriol prediabetes 144 pancreatitis 193 and calcium balance 41, type 2 169, 170, 171, 236, thyroid cancer 225 42, 117, 131, 241, 242 237, 238 thyroid nodules 230, 231, hypocalcemia 125, 126, eating disorders 6, 28, 75 239 131 and exercise 86, 170, 171, United Leukodystrophy Founda- hypoparathyroidism 131 173 tion 15 deficiency 241–242 failure to thrive 89 functions 241 gastric surgery for weight V hyperparathyroidism 122 loss 36, 97–98, 101, 174 vacuum constriction device in hypoparathyroidism 41, Graves’ disease 28, 105 erectile dysfunction 83 131, 241 hypothyroidism 170 vardenafil in erectile dysfunction milk-alkali syndrome 117, insulin resistance 145, 169 83 163 obesity 169–174. See also varicocele 141, 156 parathyroid cancer 194 obesity vasoactive intestinal peptide and parathyroid hormone Prader-Willi syndrome 75, producing tumor 212, 241 195, 241 170, 201, 202 vasopressin. See antidiuretic hor- pseudohypoparathyroidism Wermer’s syndrome 164. See mone 206 also multiple endocrine neo- vertebral column resistance 243 plasia, type 1 fractures in osteoporosis supplements 242, 243 78, 181–182 toxic levels 242 X Paget’s disease 190 vitamin supplements in alterna- xanthomas 91, 92, 245 VIPoma 212, 241 tive medicine 18–19 virilization vitrectomy in diabetic retinopa- Z adrenal cortical cancer 9 thy 69 Z-score on bone mass 37 adrenal hyperplasia, con- von Recklinghausen’s disease Zollinger-Ellison syndrome 98 genital 48 73, 163, 167–168 androgen excess 24 vision disorders acromegaly 3–4 diabetes mellitus 63, 68–69