ODESA NATIONAL MEDICAL UNIVERSITY Department of Internal Medicine № 1 with the course of cardiovascular diseases

METHODIC RECOMMENDATIONS FOR PRACTICAL CLASSES

Topic "Disease of the hypothalamic-pituitary system. Diseases of the gonads "

Course IV Faculty: international Specialty :222 -"Medicine"

The lecture was discussed on the methodical meeting of the department 27.08.2020 Protocol № 1 Head of the department Prof, Yu.I. Karpenko

Odesa I. Actuality of the topic. Acromegalyis a syndrome that results when the produces excess growth hormone (hGH) after epiphyseal plate closure at puberty. A number of disorders may increase the pituitary's GH output, although most commonly it involves a GH producing tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs). Acromegaly most commonly affects adults in middle age, and can result in severe disfigurement, serious complicating conditions, and premature death if unchecked. Because of its insidious pathogenesis and slow progression, the disease is hard to diagnose in the early stages and is frequently missed for many years, until changes in external features, especially of the face, become noticeable. Acromegaly is often also associated with gigantism. Diseases of the sexual glands are a consequence of chromosomal abnormalities, detected when other endocrine glands are affected. In diseases associated with violations of sexual differentiation, sex may be incorrectly defined, which requires its change in the future.

II. The purpose of the lecture: 1. To study the method of determination of etiologic and pathogenic factors of diseases of the hypothalamic-pituitary system (HPS). 2. To familiarize students with classifications of diseases of HPS. 3. Determination of variants of clinical picture of HPS diseases. 4. Familiarization with the atypical clinical variants of diseases of HPS. 5. Familiarization of students with possible complications of diseases of HPS. 6. Working off the methodology of determination of basic diagnostic criteria of HPS diseases. 7. Planning of patients examination with the diseases of HPS. 8. Analyzing of results of laboratory and instrumental investigations that are used for diagnostics of HPS diseases. 9. Tactic of conducting differential diagnostics of HPS diseases. 10. Technology of grounding and formulation of diagnosis for HPS diseases. 11. Planning of treatment of patients with the HPS diseases. 12. Deontological and psychological features of curation of patients with the disease of HPS. 13. Spread diseases of the sexual glands among population in Ukraine and other countries 14. To be able to carry out a clinical examination of a patient with diseases of the sexual glands

To realize the goal of study, basic knowledge is necessary: 1. Determination of concept of HPS diseases. 2. Epidemiology of HPS diseases. 3. Risk factors of HPS diseases. 4. Mechanism of hormonal and metabolic disorders at the diseases of HPS. 5. Etiology and pathogenesis of HPS diseases. 6. Classification of HPS diseases. 7. Clinical picture of HPS diseases. 8. Polyorganic complications of HPS diseases. 9. Diagnostic criteria of HPS diseases. 10. Choice of method of treatment of HPS diseases. 11. Etiology and pathogenesis of diseases of the sexual glands 12. To know clinical manifestations of diseases of the sexual glands 13. Laboratory methods of diagnostics in patients with diseases of the sexual glands 14. to know medical treatment of patients with diseases of the sexual glands

This discipline needs basic knowledge: 1. Peculiarities of anatomy and physiology of 2. Anamnesis of endocrine patients 3. Objective investigation 4. Methods of instrumental and laboratory diagnosis 5. Differential diagnosis of acromegaly 6. Treatment of acromegaly

III. A task for the self-preparation of a student for a lesson Information for raising the level of basic knowledge can be found in the following textbooks: Training: . Davidson’s “Principles of Practice of Medicine” 22th edition, 2014. 2. Harrison’s “Principles of internal medicine”, 19th edition, 2015 Additional:

 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly - © 2011

 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Growth Hormone Use in Growth Hormone-deficient Adults and Transition Patients – 2009 Update  AACE Medical Guidelines for Clinical Practice for Diagnosis and Treatment of Menopause © 2011  AACE Medical Guidelines for the Clinical Practice for Evaluation and Treatment of Male Sexual Dysfunction: A Couple's Problem- 2013 Update  AACE Medical Guidelines for Clinical Practice for Evaluation and Treatment of Hypogonadism in Adult Male Patients- 2012 Update  AACE Medical Guidelines for Clinical Practice for Diagnosis and Treatment of Hyperandrogenic Disorders © 2011

IV. Questions: 1. Etiology of acromegaly 2. Clinical diagnosis of acromegaly 3. Laboratory and instrumental diagnosis of acromegaly 4. Treatment of acromegaly 5. Etiology and pathogenesis of different types of diseases of the sexual glands 6. Classification of diseases of the sexual glands 7. Clinical manifestations of different types of diseases of the sexual glands 8. Laboratory diagnosis of different types of diseases of the sexual glands 9. Diff. diagnosis of different types of diseases of the sexual glands 10. Treatment of diseases of the sexual glands

V. Plan of self-study: # Consequence of actions Indications 1 Diagnosis of acromegaly Plan of patient examination 2 Basic clinical and instrumental laboratory data of Criterions of acromegaly acromegaly diagnosis, tests 3 Practical actions in clinics Clinical diagnosis, prescribe medicine 4 Know the diagnostic capabilities for detecting diseases Draw up a plan for examining of the sexual glands the patient 5 Know the basic clinical and instrumental and Write the criteria for diagnosis laboratory data for diseases of the sexual glands of diseases of the sexual glands. Solution of test tasks of final control 6 Be able to apply the knowledge acquired in a clinical Record the clinical diagnosis situation of the examined patient. Write prescriptions.

Task for self-study: References, tables, schemes of treatment

Acromegaly is a syndrome that results when the pituitary gland produces excess growth hormone (hGH) after epiphyseal plate closure at puberty. A number of disorders may increase the pituitary's GH output, although most commonly it involves a GH producing tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs). Acromegaly most commonly affects adults in middle age, and can result in severe disfigurement, serious complicating conditions, and premature death if unchecked. Because of its insidious pathogenesis and slow progression, the disease is hard to diagnose in the early stages and is frequently missed for many years, until changes in external features, especially of the face, become noticeable. Acromegaly is often also associated with gigantism. Signs and symptoms Features that result from high level of GH or expanding tumor include: - Soft tissue swelling visibly resulting in enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin. In particular the appearance of the hands can indicate to a knowledgeable person that a stranger may be developing acromegaly; there are documented instances of physicians warning strangers that they had acromegaly. - Soft tissue swelling of internal organs, notably the heart with attendant weakening of its muscularity, and the kidneys, also the vocal cords resulting in a characteristic thick, deep voice and slowing of speech - Generalized expansion of the skull at the fontanelle - Pronounced brow protrusion, often with ocular distension - Pronounced lower jaw protrusion with attendant macroglossia (enlargement of the tongue) and teeth gapping - Hypertrichosis, hyperpigmentation, and hyperhidrosis may occur in these patients. Causes Pituitary adenoma In over 90 percent of acromegaly patients, the overproduction of growth hormones is caused by a benign tumor of the pituitary gland, called an adenoma. These tumors produce excess growth hormones and, as they expand, compress surrounding brain tissues, such as the optic nerves. This expansion causes the headaches and visual disturbances that often accompany acromegaly. In addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men because of reduced testosterone production. There is a marked variation in rates of GH production and the aggressiveness of the tumor. Some adenomas grow slowly and symptoms of growth hormone excess are often not noticed for many years. Other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary. In general, younger patients tend to have more aggressive tumors. Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from a genetic alteration in a single pituitary cell which leads to increased cell division and tumor formation. This genetic change, or mutation, is not present at birth, but is acquired during life. The mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells; it permanently switches on the signal that tells the cell to divide and secrete growth hormones. The events within the cell that cause disordered pituitary cell growth and growth hormone oversecretion currently are the subject of intensive research. Other tumors In a few patients, acromegaly is caused not by pituitary tumors but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH (Growth Hormone Releasing Hormone), the hormone that stimulates the pituitary to make GH. In these patients, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. When these non-pituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve. In patients with GHRH-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Therefore, it is important that physicians carefully analyze all "pituitary tumors" removed from patients with acromegaly in order not to overlook the possibility that a tumor elsewhere in the body is causing the disorder. Pituitary gigantism This condition of growth hormone excess is rare in children and is referred to as pituitary gigantism, because the excessive growth hormone produces excessive growth of bones and the child can achieve excessive height; from 2.1 to 2.7 m (6'11" to 8'11") in stature by adulthood if left untreated. As an affected child becomes an adult, many of the adult problems can gradually develop. The distinction between gigantism (occurring in children) and acromegaly (occurring in adults) can be made by the occurrence of the adenoma in relation to the closure of the epiphyses. If elevated growth hormone levels occur before the closure of the epiphyses (i.e. in prepubertal children), then gigantism ensues. If it occurs after the closure of the epiphyses (i.e., in adults) then acromegaly ensues. Diagnosis Frequent blood sampling with serum GH measurement shows that in normal subjects (left panel) GH can fluctuate between undetectable levels (most of the time) and peaks of up to 30 μg/l (90 mIU/l), owing to the episodic nature of GH secretion, while in patients with acromegaly (an example is given on right panel), GH hypersecretion is continuous and GH never returns to undetectable levels. Magnetic resonance image of a pituitary macroadenoma that caused acromegaly with compression of the optic chiasm. Site of action of the different therapeutic tools in acromegaly. Surgery, radiotherapy, somatostatin analogues and dopamine agonists act at the level of the pituitary adenoma, while GH-receptor antagonists act in periphery by blocking the growth hormone receptor and thus impairing the effects of GH on the different tissues. If acromegaly is suspected, medical imaging and medical laboratory investigations are generally used together to confirm or rule out the presence of this condition. IGF1 provides the most sensitive and useful lab test for the diagnosis of acromegaly. A single value of the Growth hormone (GH) is not useful in view of its pulsatality (levels in the blood vary greatly even in healthy individuals). GH levels taken 2 hours after a 75 or 100 gram glucose tolerance test are helpful in the diagnosis: GH levels are suppressed below 1 μg/L in normal people, and levels higher than this cutoff are confirmatory of acromegaly. Other pituitary hormones have to be assessed to address the secretory effects of the tumor as well as the mass effect of the tumor on the normal pituitary gland. They include TSH ( stimulating hormone), gonadotropic hormones (FSH,LH), ACTH (adrenocorticotropic hormone), prolactin. An MRI of the brain focusing on the sella turcica after gadolinium administration allows for clear delineation of the pituitary and the hypothalamus and the location of the tumor. Treatment The goals of treatment are to reduce GH production to normal levels, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, to preserve normal pituitary function, and to reverse or ameliorate the symptoms of acromegaly. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary. Surgery is a rapid and effective treatment, of which there are two alternative methods. The first method, a procedure known as Endonasal Transphenoidal surgery, involves the surgeon reaching the pituitary through an incision in the nasal cavity wall. The wall is reached by passing through the nostrils with microsurgical instruments. The second method is during which an incision is made into the gum beneath the upper lip. Further incisions are made to cut through the septum to reach the nasal cavity, where the pituitary is located. Endonasal Transphenoidal surgery is a less invasive procedure with a shorter recovery time than the older method of Transphenoidal surgery, and the likelihood of removing the entire tumor is greater with reduced side-effects. Consequently, Endonasal Transphenoidal surgery is often used as a first option, with Transphenoidal and other treatments, such as, medicinal therapy or radiostatic neurosurgery being used to reduce the remaining adverse effects of the remaining tumor. These procedures normally relieve the pressure on the surrounding brain regions and lead to a lowering of GH levels. If the surgery is successful, facial appearance and soft tissue swelling improve within a few days. Surgery is most successful in patients with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter. Success depends on the skill and experience of the surgeon. The success rate also depends on what level of GH is defined as a cure. The best measure of surgical success is normalization of GH and IGF-1 levels. Ideally, GH should be less than 2 ng/ml after an oral glucose load. A review of GH levels in 1,360 patients worldwide immediately after surgery revealed that 60 percent had random GH levels below 5 ng/ml. Complications of surgery may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement. Even when surgery is successful and hormone levels return to normal, patients must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These patients may then require additional treatment, usually with medications. The primary current medical treatment of acromegaly is to use somatostatin analogues -- octreotide (Sandostatin) or lanreotide (Somatuline). These somatostatin analogues are synthetic forms of a brain hormone, somatostatin, which stops GH production. The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most patients with acromegaly respond to this medication. In many patients, GH levels fall within one hour and headaches improve within minutes after the injection. Several studies have shown that octreotide and lanreotide are effective for long-term treatment. Octreotide and lanreotide have also been used successfully to treat patients with acromegaly caused by non-pituitary tumors. Somatostatin analogues are also sometimes used to shrink large tumors before surgery. Because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of patients. In addition, approximately 25 percent of patients develop gallstones, which are usually asymptomatic. In rare cases, octreotide treatment can cause diabetes. On the other hand, scientists have found that in some acromegaly patients who already have diabetes, octreotide can reduce the need for insulin and improve blood sugar control. For those who are unresponsive to somatostatin analogues, or for whom they are otherwise contraindicated, it is possible to treat using one of the dopamine agonists, Bromocriptine (Parlodel) or Cabergoline. These have the advantage of being tablets rather than injections, and cost considerably less. These drugs can also be used as an adjunct to somatostatin analogue therapy. They are most effective in those whose pituitary tumours cosecrete prolactin. Side effects of these dopamine agonists include gastrointestinal upset, nausea, vomiting, light-headedness when standing, and nasal congestion. These side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose. However, bromocriptine lowers GH and IGF-1 levels and reduces tumor size in fewer than half of patients with acromegaly. Some patients report improvement in their symptoms although their GH and IGF-1 levels still are elevated. The latest development in the medical treatment of acromegaly is the use of growth hormone receptor antagonists. The only available member of this family is pegvisomant (Somavert). By blocking the action of the endogenous growth hormone molecules, this compound is able to control disease activity of acromegaly in virtually all patients. Pegvisomant has to be administered subcutaneously by daily injections. Combinations of long-acting somatostatin analogues and weekly injections of pegvisomant seem to be equally effective as daily injections of pegvisomant. Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for patients who have tumor remaining after surgery. These patients often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. Patients monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments. No single treatment is effective for all patients. Treatment should be individualized depending on patient characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice. After surgery, a patient must be monitored for a long time for increasing GH levels. If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The current first choice is generally octreotide or lanreotide. However, bromocriptine or cabergoline are much cheaper and easier to administer. With both types of medication, long-term therapy is necessary because their withdrawal can lead to rising GH levels and tumor re-expansion. Radiation therapy is generally used for patients whose tumors are not completely removed by surgery; for patients who are not good candidates for surgery because of other health problems; and for patients who do not respond adequately to surgery and medication. Complications - Severe headache - Arthritis and carpal tunnel syndrome - Enlarged heart - Hypertension - Diabetes mellitus - Heart failure - Kidney failure - Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia) - Increased palmar sweating and sebum production over the face (seborrhea) are clinical indicators of active growth hormone (GH) producing pituitary tumors. These symptoms can also be used to monitor the activity of the tumor after surgery although biochemical monitoring is confirmatory. Pseudoacromegaly Pseudoacromegaly is a condition with the usual acromegaloid features but without an increase in growth hormone. Cases have been reported due to minoxidil at an unusually high dose.

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of most pituitary hormones, the term panhypopituitarism (pan meaning "all") is used. The signs and symptoms of vary, depending on which hormones are undersecreted and on the underlying cause of the abnormality. The diagnosis of hypopituitarism is made by blood tests, but often specific scans and other investigations are needed to find the underlying cause, such as tumors of the pituitary, and the ideal treatment. Most hormones controlled by the secretions of the pituitary can be replaced by tablets or injections. Hypopituitarism is a rare disease, but may be significantly underdiagnosed in people with previous traumatic brain injury. The first description of the condition was made in 1914 by the German physician Dr Morris Simmonds. Signs and symptoms The hormones of the pituitary have different actions in the body, and the symptoms of hypopituitarism therefore depend on which hormone is deficient. The symptoms may be subtle and are often initially attributed to other causes. In most of the cases, three or more hormones are deficient. The most common problem is insufficiency of follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) leading to sex hormone abnormalities. Growth hormone deficiency is more common in people with an underlying tumor than those with other causes. Sometimes, there are additional symptoms that arise from the underlying cause; for instance, if the hypopituitarism is due to a growth hormone-producing tumor, there may be symptoms of acromegaly (enlargement of the hands and feet, coarse facial features), and if the tumor extends to the optic nerve or optic chiasm, there may be visual field defects. Headachesmay also accompany pituitary tumors, as well as pituitary apoplexy (stroke of the pituitary gland) and lymphocytic hypophysitis (autoimmune inflammation of the pituitary). Pituitary failure results in many changes in the skin, hair and nails as a result of the absence of pituitary hormone action on these sites. Anterior pituitary The major endocrine glands of the body. Pituitary hormones control the function of the adrenal gland, thyroid gland and the gonads (testes and ovaries). Deficiency of all anterior pituitary hormones is more common than individual hormone deficiency. Deficiency of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), together referred to as the gonadotropins, leads to different symptoms in men and women. Women experience oligo- or amenorrhea (infrequent/light or absent menstrual periods respectively) and infertility. Men lose facial, scrotal and trunk hair, as well as suffering decreased muscle mass and anemia. Both sexes may experience a decrease in libido and loss of sexual function, and have an increased risk of osteoporosis (bone fragility). Lack of LH/FSH in children is associated with delayed puberty. Growth hormone (GH) deficiency leads to a decrease in muscle mass, central obesity (increase in body fat around the waist) and impaired attention and memory. Children experience growth retardation and short stature. Adrenocorticotropic hormone (ACTH) deficiency leads to adrenal insufficiency, a lack of production of glucocorticoids such as cortisol by the adrenal gland. If the problem is chronic, symptoms consist of fatigue, weight loss, failure to thrive (in children), delayed puberty (in adolescents), hypoglycemia (low blood sugar levels), anemia and hyponatremia (low sodium levels). If the onset is abrupt, collapse, shock and vomiting may occur. ACTH deficiency is highly similar to Addison's disease, which is cortisol deficiency as the result of direct damage to the adrenal glands; the latter form, however, often leads to hyperpigmentation of the skin, which does not occur in ACTH deficiency. Thyroid-stimulating hormone (TSH) deficiency leads to hypothyroidism (lack of production of thyroxine(T4) and triiodothyronine (T3) in the thyroid). Typical symptoms are tiredness, intolerance to cold, constipation, weight gain, hair loss and slowed thinking, as well as a slowed heart rate and low blood pressure. In children, hypothyroidism leads to delayed growth and in extreme inborn forms to a syndrome called cretinism. Prolactin plays a role in breastfeeding, and inability to breastfeed may point at abnormally low prolactin levels. Posterior pituitary Antidiuretic hormone (ADH) deficiency leads to the syndrome of (unrelated to diabetes mellitus): inability to concentrate the urine, leading to polyuria (production of large amounts of clear urine) that is low in solutes, dehydration and—in compensation—extreme thirst and constant need to drink (polydipsia), as well as hypernatremia (high sodium levels in the blood). ADH deficiency may be masked if there is ACTH deficiency, with symptoms only appearing when cortisol has been replaced. Oxytocin deficiency generally causes few symptoms, as it is only required at the time of childbirth and breastfeeding. Diagnosis CT scan of the brain showing a craniopharyngioma (white structure in the center of the image). This tumor may cause hypopituitarism and requires surgical removal. The diagnosis of hypopituitarism is made on blood tests. Two types of blood tests are used to confirm the presence of a hormone deficiency: basal levels, where blood samples are taken–usually in the morning–without any form of stimulation, and dynamic tests, where blood tests are taken after the injection of a stimulating substance. Measurement of ACTH and growth hormone usually requires dynamic testing, whereas the other hormones (LH/FSH, prolactin, TSH) can typically be tested with basal levels. There is no adequate direct test for ADH levels, but ADH deficiency can be confirmed indirectly; oxytocin levels are not routinely measured. Generally, the finding of a combination of a low pituitary hormone together with a low hormone from the effector gland is indicative of hypopituitarism. Occasionally, the pituitary hormone may be normal but the effector gland hormone decreased; in this case, the pituitary is not responding appropriately, and the combination of findings is still suggestive of hypopituitarism. Basal tests Levels of LH/FSH may be suppressed by a raised prolactin level, and are therefore not interpretable unless prolactin is low or normal. In men, the combination of low LH and FSH in combination with a low testosterone confirms LH/FSH deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor). In women, the diagnosis of LH/FSH deficiency depends on whether the woman has been through the menopause. Before the menopause, abnormal menstrual periods together with low estradiol and LH/FSH levels confirm a pituitary problem; after the menopause (when LH/FSH levels are normally elevated and the ovaries produce less estradiol), inappropriately low LH/FSH alone is sufficient. Stimulation tests with GnRH are possible, but their use is not encouraged. For TSH, basal measurements are usually sufficient, as well as measurements of thyroxine to ensure that the pituitary is not simply suppressing TSH production in response to hyperthyroidism (an overactive thyroid gland). A stimulation test with thyrotropin-releasing hormone (TRH) is not regarded as useful. Prolactin can be measured by basal level, and is required for the interpretation of LH and FSH results in addition to the confirmation of hypopituitarism or diagnosis of a prolactin-secreting tumor. Stimulation tests Growth hormone deficiency is almost certain if all other pituitary tests are also abnormal, and insulin-like growth factor 1 (IGF-1) levels are decreased. If this is not the case, IGF-1 levels are poorly predictive of the presence of GH deficiency; stimulation testing with the insulin tolerance test is then required. This is performed by administering insulin to lower the blood sugar to a level below 2.2 mmol/l. Once this occurs, growth hormone levels are measured. If they are low despite the stimulatory effect of the low blood sugars, growth hormone deficiency is confirmed. The test is not without risks, especially in those prone to seizures or are known to have heart disease, and causes the unpleasant symptoms of hypoglycemia. Alternative tests (such as the growth hormone releasing hormone stimulation test) are less useful, although a stimulation test with arginine may be used for diagnosis, especially in situations where an insulin tolerance test is thought to be too dangerous. If GH deficiency is suspected, and all other pituitary hormones are normal, two different stimulation tests are needed for confirmation. If morning cortisol levels are over 500 nmol/l, ACTH deficiency is unlikely, whereas a level less than 100 is indicative. Levels between 100-500 require a stimulation test. This, too, is done with the insulin tolerance test. A cortisol level above 500 after achieving a low blood sugar rules out ACTH deficiency, while lower levels confirm the diagnosis. A similar stimulation test using corticotropin- releasing hormone (CRH) is not sensitive enough for the purposes of the investigation. If the insulin tolerance test yields an abnormal result, a further test measuring the response of the adrenal glands to synthetic ACTH (the ACTH stimulation test) can be performed to confirm the diagnosis. Stimulation testing with metyrapone is an alternative. Some suggest that an ACTH stimulation test is sufficient as first-line investigation, and that an insulin torlerance test is only needed if the ACTH test is equivocal. The insulin tolerance test is discouraged in children. None of the tests for ACTH deficiency are perfect, and further tests after a period of time may be needed if initial results are not conclusive. Symptoms of diabetes insipidus should prompt a formal fluid deprivation test to assess the body's response to dehydration, which normally causes concentration of the urine and increasing osmolarity of the blood. If these parameters are unchanged, desmopressin (an ADH analogue) is administered. If the urine then becomes concentrated and the blood osmolarity falls, there is a lack of ADH due to lack of pituitary function ("cranial diabetes insipidus"). In contrast, there is no change if the kidneys are unresponsive to ADH due to a different problem ("nephrogenic diabetes insipidus"). Further investigations If one of these tests shows a deficiency of hormones produced by the pituitary, magnetic resonance imaging (MRI) scan of the pituitary is the first step in identifying an underlying cause. MRI may show various tumors and may assist in delineating other causes. Tumors smaller than 1 cm are referred to as microadenomas, and larger lesions are called macroadenomas. Computed tomography with radiocontrast may be used if MRI is not available. Formal visual field testing by perimetry is recommended, as this would show evidence of optic nerve compression by a tumor. Other tests that may assist in the diagnosis of hypopituitarism, especially if no tumor is found on the MRI scan, are ferritin (elevated in hemochromatosis), angiotensin converting enzyme (ACE) levels (often elevated in sarcoidosis), and human chorionic gonadotropin (often elevated in tumor of germ cell origin). If a genetic cause is suspected, genetic testing may be performed. Pathophysiology The pituitary gland is located at the base of the brain, and intimately connected with the hypothalamus. It consists of two lobes: the posterior pituitary, which consists of nervous tissue branching out of the hypothalamus, and the anterior pituitary, which consists of hormone-producing epithelium. The posterior pituitary secretes antidiuretic hormone, which regulates osmolarity of the blood, and oxytocin, which causes contractions of the uterus in childbirth and participates in breastfeeding. The pituitary develops in the third week of embryogenesis from interactions between the diencephalon part of the brain and the nasal cavity. The brain cells secrete FGF-8, Wnt5a and BMP-4, and the nasal cavity BMP-2. Together, these cellular signals stimulate a group of cells from the nasal cavity to form Rathke's pouch, which becomes independent of the nasal cavity and develops into the anterior pituitary; this process includes the suppression of production of a protein called Sonic hedgehog by the cells of Rathke's pouch. The cells then differentiate further into the various hormone-producing cells of the pituitary. This requires particular transcription factors that induce the expression of particular genes. Some of these transcription factors have been found to be deficient in some forms of rare combined pituitary hormone deficiencies (CPHD) in childhood. These are HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. Each transcription factor acts in particular groups of cells. Therefore, various genetic mutations are associated with specific hormone deficiencies. For instance, POU1F1 (also known as Pit-1) mutations cause specific deficiencies in growth hormone, prolactin and TSH. In addition to the pituitary, some of the transcription factors are also required for the development of other organs; some of these mutations are therefore also associated with specific birth defects. Most of the hormones in the anterior pituitary are each part of an axis that is regulated by the hypothalamus. The hypothalamus secretes a number of releasing hormones, often according to a circadian rhythm, into blood vessels that supply the anterior pituitary; most of these are stimulatory (thyrotropin- releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone and growth hormone-releasing hormone), apart from dopamine, which suppresses prolactin production. In response to the releasing hormone rate, the anterior pituitary produces its hormones (TSH, ACTH, LH, FSH, GH) that stimulate effector hormone glands in the body, although prolactin acts directly on the breast gland. Once the effector glands produce sufficient hormones (thyroxine, cortisol, estradiol or testosterone and IGF-1), both the hypothalamus and the pituitary cells sense their abundance and reduce their secretion of stimulating hormones. The hormones of the posterior pituitary are produced in the hypothalamus and are carried by nerve endings to the posterior lobe; their feedback system is therefore located in the hypothalamus, but damage to the nerve endings would still lead to a deficiency in hormone release. Unless the pituitary damage is being caused by a tumor that overproduces a particular hormone, it is the lack of pituitary hormones that leads to the symptoms described above, and an excess of a particular hormone would indicate the presence of a tumor. The exception to this rule is prolactin: if a tumor compresses the pituitary stalk, a decreased blood supply means that the lactotrope cells, which produce prolactin, are not receiving dopamine and therefore produce excess prolactin. Hence, mild elevations in prolactin are attributed to stalk compression. Very high prolactin levels, though, point more strongly towards a prolactinoma (prolactin-secreting tumor). Treatment Treatment of hypopituitarism is threefold: removing the underlying cause, treating the hormone deficiencies, and addressing any other repercussions that arise from the hormone deficiencies. Underlying cause Pituitary tumors require treatment when they are causing specific symptoms, such as headaches, visual field defects or excessive hormone secretion. Transsphenoidal surgery (removal of the tumor by an operation through the nose and the sphenoidal sinuses) may, apart from addressing symptoms related to the tumor, also improve pituitary function, although the gland is sometimes damaged further as a result of the surgery. When the tumor is removed by craniotomy (opening the skull), recovery is less likely–but sometimes this is the only suitable way to approach the tumor. After surgery, it may take some time for hormone levels to change significantly. Retesting the pituitary hormone levels is therefore performed 2 to 3 months later. Prolactinomas may respond to dopamine agonist treatment–medication that mimics the action of dopamine on the lactrotrope cells, usually bromocriptine or cabergoline. This approach may improve pituitary hormone secretion in more than half the cases, and obviate the need for supplementary treatment. Other specific underlying causes are treated as normally. For example, hemochromatosis is treated by venesection, the regular removal of a fixed amount of blood. Eventually, this decreases the iron levels in the body and improves the function of the organs in which iron has accumulated. Hormone replacement Most pituitary hormones can be replaced indirectly by administering the products of the effector glands: hydrocortisone (cortisol) for adrenal insufficiency, levothyroxine for hypothyroidism, testosterone for male hypogonadism, and estradiol for female hypogonadism (usually with a progestagen to inhibit unwanted effects on the uterus). Growth hormone is available in synthetic form, but needs to be administered parenterally (by injection). Antidiuretic hormone can be replaced by desmopressin (DDAVP) tablets or nose spray. Generally, the lowest dose of the replacement medication is used to restore wellbeing and correct the deranged results, as excessive doses would cause side-effects or complications. Those requiring hydrocortisone are usually instructed to increase their dose in physically stressful events such as injury, hospitalization and dental work as these are times when the normal supplementary dose may be inadequate, putting the patient at risk of adrenal crisis. Long-term follow up by specialists in endocrinology is generally needed for people with known hypopituitarism. Apart from ensuring the right treatment is being used and at the right doses, this also provides an opportunity to deal with new symptoms and to address complications of treatment. Difficult situations arise in deficiencies of the hypothalamus-pituitary-gonadal axis in people (both men and women) who experience infertility; infertility in hypopituitarism may be treated with subcutaneous infusions of FSH, human chorionic gonadotropin–which mimics the action of LH–and occasionally GnRH. Complications Several hormone deficiencies associated with hypopituitarism may lead to secondary diseases. For instance, growth hormone deficiency is associated with obesity, raised cholesterol and the metabolic syndrome, and estradiol deficiency may lead to osteoporosis. While effective treatment of the underlying hormone deficiencies may improve these risks, it is often necessary to treat them directly.

Hyperprolactinaemia (HP), or hyperprolactinemia in the United States (U.S.), is the presence of abnormally-high levels of prolactin in the blood. Normal levels are less than 580 mIU/L for women, and less than 450 mIU/L for men. Prolactin is a peptide hormone produced by the anterior pituitary gland primarily associated with lactation and plays a vital role in breast development during pregnancy. Hyperprolactinaemia may cause production and spontaneous flow of breast milk and disruptions in the normal menstrual period in women and hypogonadism, infertility and erectile dysfunction in men. Hyperprolactinaemia can be a part of normal body changes during pregnancy and breastfeeding. It can also be caused by diseases affecting the hypothalamus and pituitary gland. It can also be caused by disruption of the normal regulation of prolactin levels by drugs, medicinal herbs and heavy metals. Hyperprolactinaemia may also be the result of disease of other organs such as the liver, kidneys, ovaries and thyroid. Causes Hyperprolactinaemia may be caused by either disinhibition (e.g., compression of the pituitary stalk or reduced dopamine levels) or excess production from a prolactinoma (a pituitary gland adenoma tumour). A blood serum prolactin level of 1000–5000 mIU/L could be from either mechanism, but >5000 mIU/L is likely due to the activity of an adenoma with macroadenomas (large tumours over 10 mm diameter) whose levels of prolactin are up to 100,000 mIU/L. Hyperprolactinemia inhibits gonadotropin- releasing hormone (GnRH) by increasing the release of dopamine from the arcuate nucleus of the hypothalamus (dopamine inhibits GnRH secretion), thus inhibiting gonadal steroidogenesis, which is the cause of many of the symptoms described below. There is a suspicion that Minoxidil, a potassium channel agonist, may be related to the development of this disease. A two-year test with Minoxidil, under normal dosing parameters, was carried out on rats, which caused pheochromocytomas in both males and females, and preputial gland adenomas in males. Physiological causes Physiological causes (i.e., as result of normal body functioning): pregnancy, breastfeeding, mental stress, sleep, hypothyroidism. Prescription drugs Use of prescription drugs is the most common cause of hyperprolactinaemia. Prolactin secretion in the pituitary is normally suppressed by the brain chemical dopamine. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin. These drugs include the major tranquilizers (phenothiazines), trifluoperazine (Stelazine), and haloperidol (Haldol); antipsychotic medications in general; metoclopramide (Reglan), domperidone, cisapride used to treat gastroesophageal reflux and medication induced nausea(such as cancer drugs); and, less often, alpha-methyldopa and reserpine, used to control hypertension; and oestrogens and TRH. The sleep drug ramelteon (Rozerem) also increases the risk of hyperprolactinemia. In particular, the dopamine antagonists metoclopramide and domperidone are both powerful prolactin stimulators and have been used to stimulate breastmilk secretion for decades. However since prolactin is antagonized by dopamine and the body depends on the two being in balance, the risk of prolactin stimulation is generally present with all drugs that deplete dopamine, either directly or as a rebound effect. Diseases Prolactinoma or other tumors arising in or near the pituitary — such as those that cause acromegaly or Cushing's disease — may block the flow of dopamine from the brain to the prolactin- secreting cells, likewise, division of the pituitary stalk or hypothalamic disease. Other causes include chronic renal failure, hypothyroidism, and sarcoidosis. Some women with polycystic ovary syndrome may have mildly-elevated prolactin levels. Apart from diagnosing hyperprolactinaemia and hypopituitarism, prolactin levels are often determined by physicians in patients that have suffered a seizure, when there is doubt as to whether this was an epileptic seizure or a non-epileptic seizure. Shortly after epileptic seizures, prolactin levels often rise, whereas they are normal in non-epileptic seizures. Idiopathic In many patients, elevated levels remain unexplained and may represent a form of hypothalamic- pituitary dysregulation. Symptoms In women, a high blood level of prolactin often causes hypoestrogenism with anovulatory infertility and a decrease in menstruation. In some women, menstruation may disappear altogether (amenorrhea). In others, menstruation may become irregular or menstrual flow may change. Women who are not pregnant or nursing may begin producing breast milk. Some women may experience a loss of libido (interest in sex). Intercourse may become painful because of vaginal dryness. In men, the most common symptoms of hyperprolactinemia are decreased libido, erectile dysfunction, and infertility. Because men have no reliable indicator such as menstruation to signal a problem, many men with hyperprolactinemia being caused by an adenoma may delay going to the doctor until they have headaches or eye problems caused by the enlarged pituitary pressing against nearby optic nerves. They may not recognize a gradual loss of sexual function or libido. Only after treatment do some men realize they had a problem with sexual function. Because of hypoestrogenism, hyperprolactinaemia can lead to osteoporosis. Diagnosis A doctor will test for prolactin blood levels in women with unexplained milk secretion (galactorrhea) or irregular menses or infertility, and in men with impaired sexual function and, in rare cases, milk secretion. If prolactin is high, a doctor will test thyroid function and ask first about other conditions and medications known to raise prolactin secretion. While a plain X-ray of the bones surrounding the pituitary may reveal the presence of a large macro-adenoma, the small micro-adenoma will not be apparent. Magnetic resonance imaging (MRI) is the most sensitive test for detecting pituitary tumors and determining their size. MRI scans may be repeated periodically to assess tumor progression and the effects of therapy. Computed Tomography (CT scan) also gives an image of the pituitary, but it is less sensitive than the MRI. In addition to assessing the size of the pituitary tumor, doctors also look for damage to surrounding tissues, and perform tests to assess whether production of other pituitary hormones is normal. Depending on the size of the tumor, the doctor may request an eye exam with measurement of visual fields. The hormone prolactin is downregulated by dopamine and is upregulated by estrogen. A falsely- high measurement may occur due to the presence of the biologically-inactive macroprolactin in the serum. This can show up as high prolactin in some types of tests, but is asymptomatic. Treatment Two drugs that have been used are the dopamine agonists cabergoline and bromocriptine. A new drug in use is norprolac with the active ingredient quinagolide. Herbal supplement Rhodiola rosea helps to optimize the levels of dopamine in the body.

Itsenko-Cushings disease Etiology and Prevalence

Pituitary corticotrope adenomas account for 70% of patients with endogenous causes of Cushing's disease. However, it should be emphasized that iatrogenic hypercortisolism is the most common cause of cushingoid features. Ectopic tumor ACTH production, cortisol-producing adrenal adenomas, adrenal carcinoma, and adrenal hyperplasia account for the other causes; rarely, ectopic tumor CRH production is encountered.

ACTH-producing adenomas account for about 10–15% of all pituitary tumors. Because the clinical features of Cushing's disease often lead to early diagnosis, most ACTH-producing pituitary tumors are relatively small microadenomas. However, macroadenomas are also seen, and some ACTH-secreting adenomas are clinically silent. Cushing's disease is 5–10 times more common in women than in men. These pituitary adenomas exhibit unrestrained ACTH secretion, with resultant hypercortisolemia. However, they retain partial suppressibility in the presence of high doses of administered glucocorticoids, providing the basis for dynamic testing to distinguish pituitary and nonpituitary causes of Cushing's syndrome.

Presentation and Diagnosis

The diagnosis of Cushing's disease presents two great challenges: (1) to distinguish patients with pathologic cortisol excess from those with physiologic or other disturbances of cortisol production; and (2) to determine the etiology of cortisol excess.

Typical features of chronic cortisol excess include thin, fragile skin, central obesity, hypertension, plethoric moon facies, purple striae and easy bruisability, glucose intolerance or diabetes mellitus, gonadal dysfunction, osteoporosis, proximal muscle weakness, signs of hyperandrogenism (acne, hirsutism), and psychological disturbances (depression, mania, and psychoses). Hematopoietic features of hypercortisolism include leukocytosis, lymphopenia, and eosinopenia. Immune suppression includes delayed hypersensitivity. The protean manifestations of hypercortisolism make it challenging to decide which patients mandate formal laboratory evaluation. Certain features make pathologic causes of hypercortisolism more likely—these include characteristic central redistribution of fat, thin skin with striae and bruising, and proximal muscle weakness. In children and in young females, early osteoporosis may be particularly prominent. The primary cause of death is cardiovascular disease, but infections and risk of suicide are also increased.

Rapid development of features of hypercortisolism associated with skin hyperpigmentation and severe myopathy suggests an ectopic source of ACTH. Hypertension, hypokalemic alkalosis, glucose intolerance, and edema are also more pronounced in these patients. Serum potassium levels <3.3 mmol/L are evident in ~70% of patients with ectopic ACTH secretion but are seen in <10% of patients with pituitary-dependent Cushing's syndrome.

Laboratory Investigation

The diagnosis of Cushing's disease is based on laboratory documentation of endogenous hypercortisolism. Measurements of 24-h urine free cortisol (UFC) is a precise and cost-effective screening test. Alternatively, the failure to suppress plasma cortisol after an overnight 1-mg dexamethasone suppression test can be used to identify patients with hypercortisolism. As nadir levels of cortisol occur at night, elevated midnight samples of cortisol are suggestive of Cushing's disease. Basal plasma ACTH levels often distinguish patients with ACTH-independent (adrenal or exogenous glucocorticoid) from those with ACTH-dependent (pituitary, ectopic ACTH) Cushing's syndrome. Mean basal ACTH levels are about eightfold higher in patients with ectopic ACTH secretion compared to those with pituitary ACTH-secreting adenomas. However, extensive overlap of ACTH levels in these two disorders precludes using ACTH to make the distinction. Instead, dynamic testing, based on differential sensitivity to glucocorticoid feedback, or ACTH stimulation in response to corticotropin releasing hormone (CRH) or cortisol reduction is used to discriminate ectopic versus pituitary sources of excess ACTH. Very rarely, circulating CRH levels are elevated, reflecting ectopic tumor-derived secretion of CRH and often ACTH.

Most ACTH-secreting pituitary tumors are <5 mm in diameter, and about half are undetectable by sensitive MRI. The high prevalence of incidental pituitary microadenomas diminishes the ability to distinguish ACTH-secreting pituitary tumors accurately by MRI. Inferior Petrosal Venous Sampling

Because pituitary MRI with gadolinium enhancement is insufficiently sensitive to detect small (<2 mm) pituitary ACTH-secreting adenomas, bilateral inferior petrosal sinus ACTH sampling before and after CRH administration may be required to distinguish these lesions from ectopic ACTH-secreting tumors that may have similar clinical and biochemical characteristics. Simultaneous assessment of ACTH concentrations in each inferior petrosal vein and in the peripheral circulation provides a strategy for confirming and localizing pituitary ACTH production. Sampling is performed at baseline and 2,5, and 10 min after intravenous ovine CRH (1 g/kg) injection. An increased ratio (>2) of inferior petrosal: peripheral vein ACTH confirms pituitary Cushing's syndrome. After CRH injection, peak petrosal:peripheral ACTH ratios of 3 confirm the presence of a pituitary ACTH-secreting tumor. The sensitivity of this test is >95%, with very rare false-positive results. False-negative results may be encountered in patients with aberrant venous drainage. Petrosal sinus catheterizations are technically difficult, and about 0.05% of patients develop neurovascular complications. The procedure should not be performed in patients with hypertension or in the presence of a well-visualized pituitary adenoma on MRI.

Treatment

Selective transsphenoidal resection is the treatment of choice for Cushing's disease. The remission rate for this procedure is ~80% for microadenomas but <50% for macroadenomas. After successful tumor resection, most patients experience a postoperative period of symptomatic ACTH deficiency that lasts for up to 12 months. This usually requires low-dose cortisol replacement, as patients experience steroid withdrawal symptoms as well as having a suppressed HPA axis. Biochemical recurrence occurs in approximately 5% of patients in whom surgery was initially successful.

When initial surgery is unsuccessful, repeat surgery is sometimes indicated, particularly when a pituitary source for ACTH is well documented. In older patients, in whom issues of growth and fertility are less important, hemi- or total may be necessary if a discrete adenoma is not recognized. Pituitary irradiation may be used after unsuccessful surgery, but it cures only about 15% of patients. Because radiation is slow and only partially effective in adults, steroidogenic inhibitors are used in combination with pituitary irradiation to block the adrenal effects of persistently high ACTH levels.

Ketoconazole, an imidazole derivative antimycotic agent, inhibits several P450 enzymes and effectively lowers cortisol in most patients with Cushing's disease when administered twice daily (600–1200 mg/d). Elevated hepatic transaminases, gynecomastia, impotence, gastrointestinal upset, and edema are common side effects. Metyrapone (2–4 g/d) inhibits 11-hydroxylase activity and normalizes plasma cortisol in up to 75% of patients. Side effects include nausea and vomiting, rash, and exacerbation of acne or hirsutism. Mitotane (o, p'-DDD; 3–6 g/d orally in four divided doses) suppresses cortisol hypersecretion by inhibiting 11-hydroxylase and cholesterol side-chain cleavage enzymes and by destroying adrenocortical cells. Side effects of mitotane include gastrointestinal symptoms, dizziness, gynecomastia, hyperlipidemia, skin rash, and hepatic enzyme elevation. It may also lead to hypoaldosteronism. Other agents include aminoglutethimide (250 mg tid), trilostane (200–1000 mg/d), cyproheptadine (24 mg/d), and IV etomidate (0.3 mg/kg per hour). Glucocorticoid insufficiency is a potential side effect of agents used to block steroidogenesis.

The use of steroidogenic inhibitors has decreased the need for bilateral . Removal of both adrenal glands corrects hypercortisolism but may be associated with significant morbidity and necessitates permanent glucocorticoid and mineralocorticoid replacement. Adrenalectomy in the setting of residual corticotrope adenoma tissue predisposes to the development of Nelson's syndrome, a disorder characterized by rapid pituitary tumor enlargement and increased pigmentation secondary to high ACTH levels. Radiation therapy may be indicated to prevent the development of Nelson's syndrome after adrenalectomy. Diabetes insipidus Diabetes insipidus (DI) is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the latter. There are several different types of DI, each with a different cause. The most common type in humans is central DI, caused by a deficiency of arginine (AVP), also known as antidiuretic hormone (ADH). The second common type of DI is nephrogenic diabetes insipidus, which is caused by an insensitivity of the kidneys to ADH. It can also be an iatrogenic artifact of drug use. Signs and symptoms Excessive urination and extreme thirst (especially for cold water and sometimes ice or ice water) are typical for DI. Symptoms of diabetes insipidus are quite similar to those of untreated diabetes mellitus, with the distinction that the urine is not sweet as it does not contain glucose and there is no hyperglycemia (elevated blood glucose). Blurred vision is a rarity. Signs of dehydration may also appear in some individuals since the body cannot conserve much (if any) of the water it takes in. The extreme urination continues throughout the day and the night. In children, DI can interfere with appetite, eating, weight gain, and growth as well. They may present with fever, vomiting, or diarrhea. Adults with untreated DI may remain healthy for decades as long as enough water is consumed to offset the urinary losses. However, there is a continuous risk of dehydration and loss of potassium. Diagnosis In order to distinguish DI from other causes of excess urination, blood glucose levels, bicarbonate levels, and calcium levels need to be tested. Measurement of blood electrolytes can reveal a high sodium level (hypernatremia as dehydration develops). Urinalysis demonstrates a dilute urine with a low specific gravity. Urine osmolarity and electrolyte levels are typically low. A fluid deprivation test helps determine whether DI is caused by: - excessive intake of fluid - a defect in ADH production - a defect in the kidneys' response to ADH This test measures changes in body weight, urine output, and urine composition when fluids are withheld and as dehydration occurs. The body's normal response to dehydration is to concentrate urine and conserve water, so urine becomes more concentrated and urination becomes less frequent. Those with DI continue to urinate large amounts of dilute urine in spite of not drinking any fluids. Sometimes measuring blood levels of ADH during this test is also necessary. To distinguish between the main forms, desmopressin stimulation is also used; desmopressin can be taken by injection, a nasal spray, or a tablet. While taking desmopressin, a patient should drink fluids or water only when thirsty and not at other times, as this can lead to sudden fluid accumulation in the central nervous system. If desmopressin reduces urine output and increases osmolarity, the pituitary production of ADH is deficient, and the kidney responds normally. If the DI is due to renal pathology, desmopressin does not change either urine output or osmolarity. If central DI is suspected, testing of other hormones of the pituitary, as well as magnetic resonance imaging (MRI), is necessary to discover if a disease process (such as a prolactinoma, or histiocytosis, syphilis, tuberculosis or other tumor or granuloma) is affecting pituitary function. Most people with this form have either experienced past head trauma or have stopped ADH production for an unknown reason. Habit drinking (in its severest form termed psychogenic polydipsia) is the most common imitator of diabetes insipidus at all ages. While many adult cases in the medical literature are associated with mental disorders, most patients with habit polydipsia have no other detectable disease. The distinction is made during the water deprivation test, as some degree of urinary concentration above isosmolar is usually obtained before the patient becomes dehydrated. Pathophysiology Electrolyte and volume homeostasis is a complex mechanism that balances the body's requirements for blood pressure and the main electrolytes sodium and potassium. In general, electrolyte regulation precedes volume regulation. When the volume is severely depleted, however, the body will retain water at the expense of deranging electrolyte levels. The regulation of urine production occurs in the hypothalamus, which produces ADH in the supraoptic and paraventricular nuclei. After synthesis, the hormone is transported in neurosecretory granules down the axon of the hypothalamic neuron to the posterior lobe of the pituitary gland where it is stored for later release. In addition, the hypothalamus regulates the sensation of thirst in the ventromedial nucleus by sensing increases in serum osmolarity and relaying this information to the cortex. The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts and distal convoluted tubule, specifically it acts on proteins called aquaporins which open to allow water into the collecting duct cells. This increase in permeability allows for reabsorption of water into the bloodstream, thus concentrating the urine. Classification There are several forms of DI: Neurogenic Neurogenic diabetes insipidus, more commonly known as central diabetes insipidus, is due to a lack of vasopressin production in the brain. Nephrogenic Nephrogenic diabetes insipidus is due to the inability of the kidney to respond normally to ADH. Dipsogenic Dipsogenic DI is due to a defect or damage to the thirst mechanism, which is located in the hypothalamus. This defect results in an abnormal increase in thirst and fluid intake that suppresses ADH secretion and increases urine output. Desmopressin is ineffective, and can lead to fluid overload as the thirst remains. Gestational Gestational DI only occurs during pregnancy. While all pregnant women produce vasopressinase in the placenta, which breaks down ADH, this can assume extreme forms in GDI. Most cases of gestational DI can be treated with desmopressin. In rare cases, however, an abnormality in the thirst mechanism causes gestational DI, and desmopressin should not be used. Diabetes insipidus is also associated with some serious diseases of pregnancy. These are pre- eclampsia, HELLP Syndrome and Acute fatty liver of pregnancy. These cause diabetes insipidus by activating hepatic vasopressinase. It is important to consider these if a woman presents with diabetes insipidus in pregnancy, because the treatment of these diseases requires delivery of the baby before the disease will improve. Failure to treat these diseases promptly can lead to maternal or perinatal mortality. Treatment Central DI and gestational DI respond to desmopressin. Carbamazepine, an anti-convulsive medication, has also had some success in this type of DI. Also gestational DI tends to abate on its own 4 to 6 weeks following labour, though some women may develop it again in subsequent pregnancies. In dipsogenic DI, desmopressin is not usually an option. Desmopressin will be ineffective in nephrogenic DI. Instead, the diuretic hydrochlorothiazide (a thiazide diuretic) or indomethacin can improve nephrogenic diabetes insipidus. Thiazide diuretics are sometimes combined with amiloride to prevent hypokalemia. It seems paradoxical to treat an extreme diuresis with a diuretic but the thiazide diuretics will decrease distal convoluted tubule reabsorption of sodium and water and decrease the osmolarity of the fluid to the distal nephron thereby decreasing excretion rates. Again, adequate hydration is important for patients with DI, as they may become dehydrated easily. Lithium-induced nephrogenic DI may be effectively managed with the administration of amiloride, a potassium-sparing diuretic often used in conjunction with thiazide or loop diuretics. Clinicians have been aware of lithium toxicity for many years and traditionally have administered thiazide diuretics for lithium-induced polyuria and nephrogenic diabetes insipidus. However, recently amiloride has been shown to be a successful treatment for this condition.

Nanism is more commonly referred to as dwarfism and is a condition in which a person experiences abnormal growth and has a shorter stature than the average person. It can be due to genetics, but can also occur in people who have parents of average height. People with the condition are typically not mentally disabled and can learn to live and function comfortably. The most common symptom of nanism is an adult who is done growing and never reaches the height comparable to other adults. A person is usually considered to be of short stature if he or she is under 4 feet10 inches (147 cm) tall. His or her limbs may be shorter and more rigid in proportion to the rest of the body. Nanism can be the result of an inherited gene that makes a person more likely to never reach an average height range. It can also occur if a gene in a sperm cell or egg becomes altered before a embryo is formed. The gene alteration randomly occurs and has no reason for changing; therefore, it cannot be prevented. The condition can also be a result of problems that delay development after a child is born, such as kidney disease, pituitary gland disorders, or any other disorders that prevent a child’s body from taking in nutrients from food that are essential for growth. A short stature can contribute to a variety of possible health effects; however, most of the effects are not fatal. Children with nanism may be more likely to have sleep apnea, in which their breathing temporarily halts while they are asleep, due to abnormally developed or constricted airways. They may also have more difficulty learning to sit up on their own or walk because their spines or joints are not as flexible. Although nanism cannot be cured, it can be treated surgically if it causes other health complications or discomfort. Many structural deficiencies in the joints can be treated by adding prosthetics to the areas to help alleviate pain and make movement easier. Maintaining a healthy weight can aid in reducing stress on joints that are already stiff, so a healthy diet can help make those with nanism more comfortable. Since the condition can make physical activity difficult or even dangerous, it is typically recommended to only be performed under a doctor’s supervision. A person’s lifespan is not usually shortened due to having the condition. Although his or her size is smaller than average, it does not typically have a negative affect on mental ability. People with the condition can also conceive children who end up growing up to be average sized.

Gigantism, also known as giantism (from Greek gigas, gigantas "giant"), is a condition characterized by excessive growth and height significantly above average. This condition is caused by an over production of human growth hormone. Terminology The term is typically applied to those whose height is not just in the upper 1% of the population but several standard deviations above mean for persons of the same sex, age, and ethnic ancestry. The term is seldom applied to those who are simply "tall" or "above average" whose heights appear to be the healthy result of normal genetics and nutrition. It is usually caused by a tumor on the pituitary gland on the brain. It causes growth of the hands, face, and feet. Other names somewhat obsolete for this pathology are hypersomia (Greek: hyper over the normal level; soma body) and somatomegaly (Greek; soma body, object pronoun somatos of the body; megas, megalos great). In the past, while many of them were social outcasts because of their height, some (usually unintentionally) found employment in Friedrich Wilhelm I's famous Potsdam Giants regiment. Many of those who have been identified with gigantism have suffered from multiple health problems involving their circulatory or skeletal system.

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines people as overweight (pre-obese) when their BMI is between 25 kg/m2 and 30 kg/m2, and obese when it is greater than 30 kg/m2. Obesity increases the likelihood of various diseases, particularly heart disease, type 2 diabetes, breathing difficulties during sleep, certain types of cancer, and osteoarthritis. Obesity is most commonly caused by a combination of excessive dietary calories, lack of physical activity, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. Evidence to support the view that some obese people eat little yet gain weight due to a slow metabolism is limited; on average obese people have a greater energy expenditure than their thin counterparts due to the energy required to maintain an increased body mass. The primary treatment for obesity is dieting and physical exercise. To supplement this, or in case of failure, anti-obesity drugsmay be taken to reduce appetite or inhibit fat absorption. In severe cases, surgery is performed or an intragastric balloon is placed to reduce stomach volume and/or bowel length, leading to earlier satiation and reduced ability to absorb nutrients from food. Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, and authorities view it as one of the most serious public health problems of the 21st century. Obesity is stigmatized in the modern Western world, though it has been perceived as a symbol of wealth and fertility at other times in history, and still is in many parts of Africa. Classification Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health. It is defined by body mass index (BMI) and further evaluated in terms of fat distribution via the waist–hip ratio and total cardiovascular risk factors. BMI is closely related to both percentage body fat and total body fat. An obese male with a body mass index of 46 kg/m2: weight 146 kg (322 lb), height 177 cm (5 ft10 in) In children a healthy weight varies with age and sex. Obesity in children and adolescents is defined not as an absolute number but in relation to a historical normal group, such that obesity is a BMI greater than the 95th percentile. The reference data that these percentiles are based on are from 1963 to 1994, and thus have not been affected by the recent increases in weight.

BMI Classification < 18.5 underweight 18.5–24.9 normal weight 25.0–29.9 overweight 30.0–34.9 class I obesity 35.0–39.9 class II obesity ≥ 40.0 class III obesity BMI is calculated by dividing the subject's mass by the square of his or her height, typically expressed either in metric or US "customary" units: Metric: BMI = kilograms / meters2 The most commonly used definitions, established by the World Health Organization (WHO) in 1997 and published in 2000, provide the values listed in the table at right. Some modifications to the WHO definitions have been made by particular bodies. The surgical literature breaks down "class III" obesity into further categories whose exact values are still disputed. Any BMI ≥ 35 or 40 is severe obesity A BMI of ≥ 35 or 40–44.9 or 49.9 is morbid obesity A BMI of ≥ 45 or 50 is super obese As Asian populations develop negative health consequences at a lower BMI than Caucasians, some nations have redefined obesity; the Japanese have defined obesity as any BMI greater than 25 while China uses a BMI of greater than 28.

Causes At an individual level, a combination of excessive caloric intake and a lack of physical activity is thought to explain most cases of obesity. A limited number of cases are due primarily to genetics, medical reasons, or psychiatric illness. In contrast, increasing rates of obesity at a societal level are felt to be due to an easily accessible and palatable diet, increased reliance on cars, and mechanized manufacturing. A 2006 review identified ten other possible contributors to the recent increase of obesity: (1) insufficient sleep, (2) endocrine disruptors (environmental pollutants that interfere with lipid metabolism), (3) decreased variability in ambient temperature, (4) decreased rates of smoking, because smoking suppresses appetite, (5) increased use of medications that can cause weight gain (e.g., atypical antipsychotics), (6) proportional increases in ethnic and age groups that tend to be heavier, (7) pregnancy at a later age (which may cause susceptibility to obesity in children), (8) epigenetic risk factors passed on generationally, (9) natural selection for higher BMI, and (10) assortative mating leading to increased concentration of obesity risk factors (this would not necessarily increase the number of obese people, but would increase the average population weight). While there is substantial evidence supporting the influence of these mechanisms on the increased prevalence of obesity, the evidence is still inconclusive, and the authors state that these are probably less influential than the ones discussed in the previous paragraph. Diet The per capita dietary energy supply varies markedly between different regions and countries. It has also changed significantly over time. From the early 1970s to the late 1990s the average calories available per person per day (the amount of food bought) has increased in all parts of the world except Eastern Europe. The United States had the highest availability with 3,654 calories per person in 1996. This increased further in 2003 to 3,754. During the late 1990s Europeans had 3,394 calories per person, in the developing areas of Asia there were 2,648 calories per person, and in sub-Saharan Africa people had 2,176 calories per person. Total calorie consumption has been found to be related to obesity. The widespread availability of nutritional guidelines has done little to address the problems of overeating and poor dietary choice. From 1971 to 2000, obesity rates in the United States increased from 14.5% to 30.9%. During the same period, an increase occurred in the average amount of calories consumed. For women, the average increase was 335 calories per day (1,542 calories in 1971 and 1,877 calories in 2004), while for men the average increase was 168 calories per day (2,450 calories in 1971 and 2,618 calories in 2004). Most of these extra calories came from an increase in carbohydrate consumption rather than fat consumption. The primary source of these extra carbohydrates are sweetened beverages, which now account for almost 25 percent of daily calories in young adults in America. Consumption of sweetened drinks is believed to be contributing to the rising rates of obesity. As societies become increasingly reliant on energy-dense, big-portion, fast-food meals, the association between fast-food consumption and obesity becomes more concerning. In the United States consumption of fast-food meals tripled and calorie intake from these meals quadrupled between 1977 and 1995. Agricultural policy and techniques in the United States and Europe have led to lower food prices. In the United States, subsidization of corn, soy, wheat, and rice through the U.S. farm bill has made the main sources of processed food cheap compared to fruits and vegetables. Obese people consistently under-report their food consumption as compared to people of normal weight. This is supported both by test of people carried out in a calorimeter rooms and by direct observation. Sedentary lifestyle A sedentary lifestyleplays a significant role in obesity. Worldwide there has been a large shift towards less physically demanding work, and currently at least 60% of the world's population gets insufficient exercise. This is primarily due to increasing use of mechanized transportation and a greater prevalence of labor-saving technology in the home. In children there appears to be declines in levels of physical activity due to less walking and physical education. World trends in active leisure time physical activity are less clear. The World Health Organization indicates that people worldwide are taking up less active recreational pursuits, while a study from Finland found an increase and a study from the United States found leisure-time physical activity has not changed significantly. In both children and adults there is an association between television viewing time and the risk of obesity. A 2008 meta-analysis found that 63 of 73 studies (86%) showed an increased rate of childhood obesity with increased media exposure, with rates increasing proportionally to time spent watching television. Genetics A 1680 painting by Juan Carreno de Miranda of a girl presumed to have Prader-Willi syndrome. Like many other medical conditions, obesity is the result of an interplay between genetic and environmental factors. Polymorphisms in various genes controlling appetite and metabolism predispose to obesity when sufficient calories are present. As of 2006 more than 41 of these sites have been linked to the development of obesity when a favorable environment is present. The percentage of obesity that can be attributed to genetics varies, depending on the population examined, from 6% to 85%. Obesity is a major feature in several syndromes, such as Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, and MOMO syndrome. (The term "non-syndromic obesity" is sometimes used to exclude these conditions.) In people with early-onset severe obesity (defined by an onset before 10 years of age and body mass index over three standard deviations above normal), 7% harbor a single point DNA mutation. Studies that have focused upon inheritance patterns rather than upon specific genes have found that 80% of the offspring of two obese parents were obese, in contrast to less than 10% of the offspring of two parents who were of normal weight. The thrifty gene hypothesis postulates that certain ethnic groups may be more prone to obesity in an equivalent environment. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would be more likely survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies. This is the presumed reason that Pima Indians, who evolved in a desert ecosystem, developed some of the highest rates of obesity when exposed to a Western lifestyle. Medical and psychiatric illness Certain physical and mental illnesses and the pharmaceutical substances used to treat them can increase risk of obesity. Medical illnesses that increase obesity risk include several rare genetic syndromes (listed above) as well as some congenital or acquired conditions: hypothyroidism, Cushing's syndrome, growth hormone deficiency, and the eating disorders: binge eating disorder and night eating syndrome. However, obesity is not regarded as a psychiatric disorder, and therefore is not listed in the DSM-IVR as a psychiatric illness. The risk of overweight and obesity is higher in patients with psychiatric disorders than in persons without psychiatric disorders. Certain medications may cause weight gain or changes in body composition; these include insulin, sulfonylureas, thiazolidinediones, atypical antipsychotics, antidepressants, steroids, certain anticonvulsants (phenytoin and valproate), pizotifen, and some forms of hormonal contraception. Social determinants While genetic influences are important to understanding obesity, they cannot explain the current dramatic increase seen within specific countries or globally. Though it is accepted that calorie consumption in excess of calorie expenditure leads to obesity on an individual basis, the cause of the shifts in these two factors on the societal scale is much debated. There are a number of theories as to the cause but most believe it is a combination of various factors. The correlation between social class and BMI varies globally. A review in 1989 found that in developed countries women of a high social class were less likely to be obese. No significant differences were seen among men of different social classes. In the developing world, women, men, and children from high social classes had greater rates of obesity. An update of this review carried out in 2007 found the same relationships, but they were weaker. The decrease in strength of correlation was felt to be due to the effects of globalization. Among developed countries, levels of adult obesity, and percentage of teenage children who are overweight, are correlated with income inequality. A similar relationship is seen between US states: more adults, even in higher social classes, are obese in more unequal states. Many explanations have been put forth for associations between BMI and social class. It is thought that in developed countries, the wealthy are able to afford more nutritious food, they are under greater social pressure to remain slim, and have more opportunities along with greater expectations for physical fitness. In undeveloped countries the ability to afford food, high energy expenditure with physical labor, and cultural values favoring a larger body size are believed to contribute to the observed patterns. Attitudes toward body mass held by people in one's life may also play a role in obesity. A correlation in BMI changes over time has been found between friends, siblings, and spouses. Stress and perceived low social status appear to increase risk of obesity. Smoking has a significant effect on an individual's weight. Those who quit smoking gain an average of 4.4 kilograms (9.7 lb) for men and 5.0 kilograms (11.0 lb) for women over ten years. However, changing rates of smoking have had little effect on the overall rates of obesity. In the United States the number of children a person has is related to their risk of obesity. A woman's risk increases by 7% per child, while a man's risk increases by 4% per child. This could be partly explained by the fact that having dependent children decreases physical activity in Western parents. In the developing world urbanization is playing a role in increasing rate of obesity. In China overall rates of obesity are below 5%; however, in some cities rates of obesity are greater than 20%. Malnutrition in early life is believed to play a role in the rising rates of obesity in the developing world. Endocrine changes that occur during periods of malnutrition may promote the storage of fat once more calories become available. Infectious agents The study of the effect of infectious agents on metabolism is still in its early stages. Gut flora has been shown to differ between lean and obese humans. There is an indication that gut flora in obese and lean individuals can affect the metabolic potential. This apparent alteration of the metabolic potential is believed to confer a greater capacity to harvest energy contributing to obesity. Whether these differences are the direct cause or the result of obesity has yet to be determined unequivocally. An association between viruses and obesity has been found in humans and several different animal species. The amount that these associations may have contributed to the rising rate of obesity is yet to be determined. Pathophysiology Flier summarizes the many possible pathophysiological mechanisms involved in the development and maintenance of obesity. This field of research had been almost unapproached until leptin was discovered in 1994. Since this discovery, many other hormonal mechanisms have been elucidated that participate in the regulation of appetite and food intake, storage patterns of adipose tissue, and development of insulin resistance. Since leptin's discovery, ghrelin, insulin, orexin, PYY 3-36, cholecystokinin, adiponectin, as well as many other mediators have been studied. The adipokines are mediators produced by adipose tissue; their action is thought to modify many obesity-related diseases. Leptin and ghrelin are considered to be complementary in their influence on appetite, with ghrelin produced by the stomach modulating short-term appetitive control (i.e. to eat when the stomach is empty and to stop when the stomach is stretched). Leptin is produced by adipose tissue to signal fat storage reserves in the body, and mediates long-term appetitive controls (i.e. to eat more when fat storages are low and less when fat storages are high). Although administration of leptin may be effective in a small subset of obese individuals who are leptin deficient, most obese individuals are thought to be leptin resistant and have been found to have high levels of leptin. This resistance is thought to explain in part why administration of leptin has not been shown to be effective in suppressing appetite in most obese people. While leptin and ghrelin are produced peripherally, they control appetite through their actions on the central nervous system. In particular, they and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite, the melanocortin pathway being the most well understood. The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively. The arcuate nucleus contains two distinct groups of neurons. The first group coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity. Management The main treatment for obesity consists of dieting and physical exercise. Diet programs may produce weight loss over the short term, but keeping this weight off can be a problem and often requires making exercise and a lower calorie diet a permanent part of a person's lifestyle. Success rates of long- term weight loss maintenance are low and range from 2–20%. In a more structured setting, however, 67% of people who lost greater than 10% of their body mass maintained or continued to lose weight one year later. An average maintained weight loss of more than 3 kg (6.6 lb) or 3% of total body mass could be sustained for five years. Some studies have found significant benefits in mortality in certain populations with weight loss. In a prospective study of obese women with weight related diseases, intentional weight loss of any amount was associated with a 20% reduction in mortality. In obese women without obesity related illnesses a weight loss of greater than 9 kg (20 lb) was associated with a 25% reduction in mortality. A recent review concluded that certain subgroups such as those with type 2 diabetes and women show long term benefits in all cause mortality, while outcomes for men do not seem to be improved with weight loss. A subsequent study has found benefits in mortality from intentional weight loss in those who have severe obesity. The most effective treatment for obesity is bariatric surgery; however, due to its cost and the risk of complications, researchers are searching for other effective yet less invasive treatments.

Turner syndrome or Ullrich-Turner syndrome (also known as "Gonadal dysgenesis") encompasses several conditions, of which monosomy X (absence of an entire sex chromosome) is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent (unaffected humans have 46 chromosomes, of which two are sex chromosomes). Typical females have two X chromosomes, but in Turner syndrome, one of those sex chromosomes is missing or has other abnormalities. In some cases, the chromosome is missing in some cells but not others, a condition referred to as mosaicism or 'Turner mosaicism'. Occurring in 1 out of every 2500 girls, the syndrome manifests itself in a number of ways. There are characteristic physical abnormalities, such as short stature, swelling, broad chest, low hairline, low-set ears, and webbed necks. Girls with Turner syndrome typically experience gonadal dysfunction (non- working ovaries), which results in amenorrhea (absence of menstrual cycle) and sterility. Concurrent health concerns are also frequently present, including congenital heart disease, hypothyroidism (reduced hormonesecretion by the thyroid), diabetes, vision problems, hearing concerns, and many autoimmune diseases. Finally, a specific pattern of cognitive deficits is often observed, with particular difficulties in visuospatial, mathematical, and memory areas.

Klinefelter's syndrome, 47, XXY, or XXY syndrome is a condition in which males have an extra (an aneuploidy) X sex chromosome . While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome. Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males". Klinefelter's syndrome is the most common sex chromosome disorder and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 1,000 males. One in every 500 males has an extra X chromosome but does not have the syndrome. The principal effects are development of small testicles and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms. Massachusetts General Hospital in Boston, Massachusetts and first described it in the same year.

True hermaphroditism is a medical term for an intersex condition in which an individual is born with ovarian and testicular tissue. There may be an ovary on one side and a testis on the other, but more commonly one or both gonads is an ovotestis containing both types of tissue. It is rare — so far undocumented — for both types of gonadal tissue to function. Encountered karyotypes are 47XXY, 46XX/46XY, or 46XX/47XXY. Although similar in some ways to mixed gonadal dysgenesis, the conditions can be distinguished histologically. Presentation External genitalia are often ambiguous, the degree depending mainly on the amount of testosterone produced by the testicular tissue between 8 and 16 weeks of gestation. Causes This condition is very rare. There are several ways in which this may occur. It can be caused by the division of one ovum, followed by fertilization of each haploid ovum and fusion of the two zygotes early in development. Alternately, an ovum can be fertilized by two sperm followed by trisomic rescue in one or more daughter cells. Two ova fertilized by two sperm will occasionally fuse to form a tetragametic chimera. If one male zygote and one female zygote fuse, a hermaphroditic individual may result. It can be associated with mutation in the SRY gene.

Cryptorchidism is the absence of one or both testes from the scrotum. This usually represents failure of the testis to move, or "descend," during fetal development from an abdominal position, through the inguinal canal, into the ipsilateral scrotum. About 3% of full-term and 30% of premature infant boys are born with at least one undescended testis, making cryptorchidism the most common birth defect of male genitalia. However, about 80% of cryptorchid testes descend by the first year of life (the majority within three months), making the true incidence of cryptorchidism around 1% overall. A testis absent from the normal scrotal position can be: - ound anywhere along the "path of descent" from high in the posterior (retroperitoneal) abdomen, just below the kidney, to the inguinal ring; - found in the inguinal canal; - ectopic, that is, found to have "wandered" from that path, usually outside the inguinal canal and sometimes even under the skin of the thigh, the perineum, the opposite scrotum, and femoral canal; - found to be undeveloped (hypoplastic) or severely abnormal (dysgenetic); - found to have vanished (also see Anorchia). About two thirds of cases without other abnormalities are unilateral; 1/3 involve both testes. In 90% of cases an undescended testis can be palpated (felt) in the inguinal canal; in a minority the testis or testes are in the abdomen or nonexistent (truly "hidden"). Undescended testes are associated with reduced fertility, increased risk of testicular germ cell tumors and psychological problems when the boy is grown. Undescended testes are also more susceptible to testicular torsion and infarction and inguinal hernias. To reduce these risks, undescended testes are usually brought into the scrotum in infancy by a surgical procedure called an Orchiopexy. Although cryptorchidism nearly always refers to congenital absence or maldescent, a testis observed in the scrotum in early infancy can occasionally "reascend" (move back up) into the inguinal canal. A testis which can readily move or be moved between the scrotum and canal is referred to as retractile.

Hypogonadism is a medical term for decreased functional activity of the gonads. The gonads (ovaries or testes) produce hormones (testosterone, estradiol, antimullerian hormone, progesterone, inhibin B, activin) and gametes (eggs or sperm). Late-onset hypogonadism (LOH), Andropause or Androgen Decline in the Aging Male (ADAM), is a syndrome caused by a decline in gonadal production of testosterone in males that occurs with aging. This "male menopause" can also cause hypogonadism. However, it occurs for certain men and not for the others. Symptoms In men Effects of low testosterone in men may include: (not all are present in any single individual) and Poor libido (Low sexual desire), Fatigue (medical) always tired, Muscle loss/atrophy, Erectile Dysfunction, Increasing abdominal fat, Glucose intolerance (early diabetes), High Cholesterol/Lipid, Poor sleep, Difficulty concentrating, Memory Loss-difficulty in choosing words in language, Depression, Anxiety, Psychological and relationship problems, Increase size of chest, Hot flashes, Decrease in growth of, or loss of, beard and body hair, Loss of bone mass (osteoporosis), Irritability, Infertility, Shrinking of the testicles, Decrease in firmness of testicles, Frequent urination (polyuria) without infection/waking at night to urinate, Achy muscles, Night sweats, Dry skin and/or cracking nails, In women Effects of low estrogen levels in women may include: (not all are present in any individual) and Hot flashes, Irritability, Poor libido, Infertility, Loss of, or failure to develop, Menstruation, Loss of body hair, Loss of bone mass (osteoporosis), Heart disease, Sleep disturbances, Symptoms of urinary bladder discomfort like frequency, urgency, frequent infections, lack of lubrication, discharge, Shrinking of breasts, loss of or nonexistent sense of smell Diagnosis In men Low Testosterone can be identified through a simple blood test performed by a laboratory, ordered by a physician. This test is typically ordered in the morning hours, when levels are highest, but even in men over 60 levels can drop by as much as 13% during the day. Normal total testosterone levels range from 300 - 1000ng/dl Treatment is often prescribed for total testosterone levels below 350 ng/dl If the serum total testosterone level is between 230 and 350 ng/dl, repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful. However, there are no widely accepted diagnoses or reference ranges for Free Testosterone or Bioavailable Testosterone due to large discrepancies in the reference ranges for these tests between different testing labs. Blood testing A position statement by The Endocrine Society has expressed dissatisfaction with the manner in which most assays for TT (Total Testosterone) and FT (Free Testosterone) are currently performed. In particular, research has questioned the validity of commonly administered assays of FT by RIA. The FAI (Free Androgen Index) has been found to be the worst predictor of Free Testosterone. In women Similar to men, the LH and FSH will be used, particularly in women who believe they are in menopause. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels. Hypogonadism is often discovered during evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women. Treatment Male hypogonadism is most often treated with testosterone replacement therapy (TRT). Commonly-used testosterone replacement therapies include transdermal (through the skin) using a patch or gel, injections, or pellets. Oral testosterone is no longer used in the U.S. because it is broken down in the liver and rendered inactive. Like many hormonal therapies, changes take place over time. It may take as long as 2-3 months at optimum level to reduce the symptoms, particularly the wordfinding and cognitive dysfunction. Testosterone levels in the blood should be evaluated to ensure the increase is adequate. Levels between 500-700 ng/l are considered adequate for young, healthy men from 20 to 40 years of age, but the lower edge of the normal range is poorly defined and single testosterone levels alone cannot be used to make the diagnosis. Modern treatment may start with 200mg intramuscular testosterone, repeated every 10-14 days. Getting a blood level of testosterone on the 13th day will give a "trough" level, assisting the physician in deciding whether the correct dose is being given. Recently some have reported using Arimidex, an aromatase inhibitor used in women for breast cancer, to decrease conversion of testosterone to estrogen in men, and increase serum testosterone levels. While historically men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth. Other side effects can include an elevation of the hematocrit to levels that require blood to be withdrawn (phlebotomy) to prevent complications from it being "too thick". Another is that a man may have some growth in the size of the breasts (gynecomastia), though this is relatively rare. Finally, some physicians worry that Obstructive Sleep Apnea may worsen with testosterone therapy, and should be monitored. Another feasible treatment alternative is human chorionic gonadotropin (hCG). For both men and women, an alternative to testosterone replacement is Clomifenetreatment which can stimulate the body to naturally increase hormone levels while avoiding infertility and other side effects as a consequence of direct hormone replacement therapy. For women, estradiol and progesterone are replaced. Some types of fertility defects can be treated, others cannot. Some physicians will also give testosterone to women, mainly to increase libido. Classification Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. The term hypogonadism is usually applied to permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or without fertility defects. The term is less commonly used for infertility without hormone deficiency. There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective.Physicians measure gonadotropins (LH and FSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles, whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain. Affected system Hypogonadism resulting from defects of the gonads is traditionally referred to as primary hypogonadism. Examples include Klinefelter syndrome and Turner syndrome. Mumps is known to cause testicular failure, and in recent years has been immunized against in the US. A varicocele can reduce hormonal production as well. Hypogonadism resulting from hypothalamic or pituitary defects are termed secondary hypogonadism or central hypogonadism (referring to the central nervous system). Examples of Hypothalamic defects include Kallmann syndrome. Examples of Pituitary defects include hypopituitarism. An example of a hypogonadism resulting from the lack of hormone response is androgen insensitivity syndrome, where there are inadequate receptors to bind the testosterone, resulting in a female appearance despite XY chromosomes. Primary or secondary Primary - defect is inherent within the gonad: eg. Noonan syndrome, Turner syndrome (45X,0), Klinefelter syndrome (47XXY), XX males with SRY gene Secondary - defect lies outside of the gonad: eg. Kallmann syndrome and Polycystic ovary syndrome, also called hypogonadotropic hypogonadism. Hemochromatosis and diabetes mellitus can be causes of this as well. Congenital vs. acquired An example of congenital hypogonadism (present at birth) in females is Turner syndrome, and in males is Klinefelter syndrome. It is also one of the signs of CHARGE syndrome. An example of acquired hypogonadism is the Anabolic Steroids Induced Hypogonadism (ASIH), and childhood mumps. Additionally, there is some evidence men whose mothers ingested the endocrine disruptor diethylstilbestrol for potential miscarriage may have hypogonadism. Hormones vs. fertility Hypogonadism can involve just hormone production or just fertility, but most commonly involves both. Examples of hypogonadism that affect hormone production more than fertility are hypopituitarism and Kallmann syndrome; in both cases, fertility is reduced until hormones are replaced but can be achieved solely with hormone replacement. Examples of hypogonadism that affect fertility more than hormone production are Klinefelter syndrome and Kartagener syndrome. Testosterone Testosterone is a key steroid hormone produced in the body, which plays an important role in many fundamental physical processes. Hormones are essentially chemical signaling molecules, that activate certain processes in the body, through a receptor mechanism. A signaling molecule like testosterone, binds with the various chemical receptors in the body, to trigger various bodily processes. A steroid is a particular chemical type of hormone called terpenoid lipid. It is the hormone that initiates most of the sexual developmental processes in a male and also contributes to other vital processes. Hence it is also called the male sex hormone as it manifests all the typical male qualities and physical processes. The testosterone secretion timing and amount is regulated by the hypothalamus and the pituitary gland in the brain through a complex signaling mechanism. It is also produced in the female body but in comparatively very lesser amounts. The female equivalent of testosterone is estrogen, the female sex hormone. Testosterone is synthesized from cholesterol by mostly the Leydig cells in the male testicles. In females, it is synthesized in the ovaries by Thecal cells in very small quantities. In males, testosterone plays the very important role of initiating sperm production in the sertoli cells of the male testes. Drop in the levels of testosterone causes problems in cognitive processes, depression, sleep disorders, fatigue, decrease in libido and erectile dysfunction. It is also known to cause excessive fat accumulation. Hypogonadism may be induced after the chronic use of anabolic/androgenic steroids (AAS). The negative-feedback system of the hypothalamic-pituitary-gonadal axis (HPTA) shuts down pituitary production of gonadotropins after extended exposure to AAS. Coping Hypogonadism can have many psychological effects, especially in younger patients due to infertility and appearance. A supportive family that understands the condition is paramount, as well as psychological treatment. Possible treatments include the use of regular injections or the application of gels or ointments. Testosterone and longevity A longitudinal (18 year) study published by The Endocrine Society and funded by the National Institute on Aging and the American Heart Association stated: Men over 50 may not live as long if they have low testosterone. The study looked at death from any cause in nearly 800 men ages 50 to 91 years who were living in a southern California community and who participated in the Rancho Bernardo Study in the 1980s. At the beginning of the study, almost one-third of these men had suboptimal blood testosterone levels for men their age. The men with low testosterone levels had a 33 percent greater risk of death during the next 18 years than the men with higher testosterone. This difference was not explained by smoking, alcohol intake and level of physical activity or by pre-existing diseases such as diabetes or heart disease. The new study is the second report linking the deficiency of this sex hormone with increased death from all causes over time, said study author Gail Laughlin, PhD.

Andropause or male menopause is a name that has been given to a menopause-like condition in aging men. This relates to the slow but steady reduction of the production of the hormones testosterone and dehydroepiandrosterone in middle-aged men, and the consequences of that reduction, which is associated with a decrease in Leydig cells. Unlike women, middle-aged men do not experience a complete and permanent physiological shutting down of the reproductive system as a normal event. A steady decline in testosterone levels with age (in both men and women) is well documented. Unlike "menopause", the word "andropause" is not currently recognized by the World Health Organization and its ICD-10 medical classification. This is likely because "Andropause" is term of convenience describing the stage of life when symptoms in aging appear in men. While the words are sometimes used interchangeably, hypogonadism a deficiency state in which the hormone testosterone goes below the normal range for even an aging male. As a "state" The impact of low levels of testosterone has been previously reported. In 1944, Heller and Myers[5] identified symptoms of what they labeled the "male climacteric" including loss of libido and potency, nervousness, depression, impaired memory, the inability to concentrate, fatigue, insomnia, hot flushes, and sweating. Heller and Myers found that their subjects had lower than normal levels of testosterone, and that symptoms improved dramatically when patients were given replacement doses of testosterone. Andropause has been observed in association with Alzheimer's disease. In one study, 98.0% of primary care physicians believed that andropause and osteoporosis risk were related. The term "symptomatic late onset hypogonadism" (or "SLOH") is sometimes considered to refer to the same condition as the word "andropause". Some researchers prefer the term "androgen deficiency of the aging male" ("ADAM"), to more accurately reflect the fact that the loss of testosterone production is gradual and asymptotic (in contrast to the more abrupt change associated with menopause) The "D" is sometimes given as "decline" instead of "deficiency". In some contexts, the term "partial androgen deficiency in aging males" ("PADAM") is used instead. As a disorder Proponents Proponents of andropause as a distinct condition claim that it is a biological change experienced by men during mid-life, and often compare it to female menopause. Menopause, however, is a complete cessation of reproductive ability caused by the shutting down of the female reproductive system. Andropause is a decline in the male hormone testosterone. This drop in testosterone levels is considered to lead in some cases to loss of energy and concentration, depression, and mood swings. While andropause does not cause a man's reproductive system to stop working altogether, many will experience bouts of impotence. Andropause is usually caused by a very gradual testosterone deficiency and an increase in sex hormone-binding globulin (SHBG) that occurs from age 35 onwards. By contrast, women have a sudden onset of menopause around age 51. Testosterone declines 10% every decade after age 30 (1% per year). workplace exposure to estrogen. Men who work in the pharmaceutical industry, plastics factories, near incinerators, and on farms that use pesticides are high-risk for early andropause. About 30% of men in their 50’s experience andropause. About 5 million American men do not produce adequate testosterone, which leads to early andropause. In Australia, about 1 in every 200 men under the age of 60 and about 1 in every 10 men over 60 have low testosterone. Regardless of location, the most likely males to develop early andropause are those with diabetes, hypertension, and genetic disorders that produce hypogonadism, including Klinefelter's, Wilson-Turner, and Androgen insensitivity syndromes. Some of the current popular interest in the concept of andropause has been fueled by the book Male Menopause, written by Jed Diamond, a lay person. According to Diamond's view, andropause is a change of life in middle-aged men, which has hormonal, physical, psychological, interpersonal, social, sexual, and spiritual aspects. Diamond claims that this change occurs in all men, generally between the ages of 40 and 55, though it can occur as early as 35 or as late as 65. The term "male menopause" may be a misnomer, as unlike women, men's reproductive systems do not cease to work completely in mid-life; some men continue to father children late into their lives (at age 90 or older[13]). But Diamond claims that, in terms of other life impacts, women’s and men’s experience are somewhat similar phenomena. The concept of andropause is perhaps more widely accepted in Australia and some parts of Europe than it is in the United States. Opponents Many clinicians believe that andropause is not a valid concept, because men can continue to reproduce into old age. Their reproductive systems do not stop working completely, and therefore they do not exhibit the sudden and dramatic drops in hormone levels characteristic of women undergoing menopause. It should be noted that in some men before the age of 60 there is a complete loss of libido, erectile function, and orgasmic ability. Others feel that andropause is simply synonymous with hypogonadism or low testosterone levels. There is opposition to the concept of andropause in Europe as well as the U.S. Some clinicians argue that many of the cited symptoms are not specific enough to warrant describing a new condition. For example, people who are overweight may be misguided into treating a new illness rather than addressing the lifestyle that led to their being overweight. Similarly, energy levels vary from person to person, and for people who are generally inactive, energy levels will automatically be lower overall. While it is true that active and otherwise healthy men could in theory develop andropause-like symptoms, how common and widespread the phenomenon is, and whether genetics, lifestyle, environment, or a combination of factors are responsible, is not yet known. Suggestions for treatment Although there is disagreement over whether or not andropause is a condition to be "diagnosed" and "treated", those who support that position have made several proposals to address andropause and mitigate some of its effects. Morley emphasizes the importance of response to treatment, as well as testosterone level and identifiable symptoms. Mintz, Dotson, & Mukai include an emphasis on hormones other than testosterone. They also focus upon diet, and exercise. Diamond (a lay person) believes that depression is one of the most common problems of middle- aged men, and feels it is greatly under-diagnosed, sometimes with serious consequences.

Menopause is the permanent cessation of ovarian function occurring some time before the end of the natural lifespan. In human females, menopause usually happens more or less in midlife, signaling the end of the fertile phase of a woman's life. The word "menopause" literally means the "end of monthly cycles" from the Greek words pausis (cessation) and the word root men from mensis meaning (month), because the word menopause was created to describe this change (from reproductive to non-reproductive) in human females, where the end of fertility is traditionally indicated by the permanent stopping of monthly menstruation or menses. However menopause also exists in some other animals, many of which do not have monthly menstruation. The date of menopause in human females is formally medically defined as the time of the last menstrual period (or menstrual flow of any amount however small), in a woman who has not had a hysterectomy. Signs and symptoms During the menopause transition years, as the body responds to the rapidly fluctuating and dropping levels of natural hormones, a number of effects may appear. Not every woman experiences bothersome levels of these effects; the range of effects and the degree to which they appear is very variable from person to person. Effects that are due to low estrogen levels (for example vaginal atrophy and skin drying) will continue after the menopause transition years are over; however, many effects that are caused by the extreme fluctuations in hormone levels (for example hot flashes and mood changes) usually disappear or improve significantly once the perimenopause transition is completely over. All the various possible perimenopause effects are caused by an overall drop, as well as dramatic but erratic fluctuations, in the absolute levels and relative levels of estrogens and progesterone. Some of the effects, such as formication (crawling, itching, or tingling skin sensations), may be associated directly with hormone withdrawal. Both users and non-users of hormone replacement therapy identify lack of energy as the most frequent and distressing effect. Other effects can include vasomotor symptoms such as hot flashes and palpitations, psychological effects such as depression, anxiety, irritability, mood swings, memory problems and lack of concentration, and atrophic effects such as vaginal dryness and urgency of urination. The average woman also has increasingly erratic menstrual periods, due to skipped ovulations. Typically, the timing of the flow becomes unpredictable. In addition the duration of the flow may be considerably shorter or longer than normal, and the flow itself may be significantly heavier or lighter than was previously the case, including sometimes long episodes of spotting. Early in the process it is not uncommon to have some 2-week cycles. Further into the process it is common to skip periods for months at a time, and these skipped periods may be followed by a heavier period. The number of skipped periods in a row often increases as the time of last period approaches. At the point when a woman of menopausal age has had no periods or spotting for 12 months she is considered to be one year into post-menopause. Vascular instability - Hot flashes or hot flushes, including night sweats and, in a few people, cold flashes; Possible but contentious increased risk of atherosclerosis; Migraine; Rapid heartbeat Urogenital atrophy, also known as vaginal atrophy - Thinning of the membranes of the vulva, the vagina, the cervix, and also the outer urinary tract, along with considerable shrinking and loss in elasticity of all of the outer and inner genital areas; Itching; Dryness; Bleeding; Watery discharge; Urinary frequency; Urinary incontinence; Urinary urgency; Increased susceptibility to inflammation and infection, for example vaginal candidiasis, and urinary tract infections Skeletal - Back pain; Joint pain, Muscle pain; Osteopenia and the risk of osteoporosis gradually developing over time; Skin, soft tissue - Breast atrophy breast tenderness +/- swelling; Decreased elasticity of the skin Formication (itching, tingling, burning, pins and needles, or sensation of ants crawling on or under the skin); Skin thinning and becoming drier Psychological - Depression and/or anxiety; Fatigue; Irritability; Memory loss, and problems with concentration; Mood disturbance; Sleep disturbance, poor quality sleep, light sleep, insomnia; Sexual - Dyspareunia or painful intercourse; Decreased libido; Problems reaching orgasm; Vaginal dryness and vaginal atrophy Cohort studies have reached mixed conclusions about medical conditions associated with the menopause. For example, a 2007 study found that menopause was associated with hot flashes; joint pain and muscle pain; and depressed mood. In the same study, it appeared that menopause was not associated with poor sleep, decreased libido, and vaginal dryness. However, in contrast to this, a 2008 study did find an association with poor sleep quality.

Turner syndrome or Ullrich-Turner syndrome (also known as "Gonadal dysgenesis") encompasses several conditions, of which monosomy X (absence of an entire sex chromosome) is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent (unaffected humans have 46 chromosomes, of which two are sex chromosomes). Typical females have two X chromosomes, but in Turner syndrome, one of those sex chromosomes is missing or has other abnormalities. In some cases, the chromosome is missing in some cells but not others, a condition referred to as mosaicism or 'Turner mosaicism'. Occurring in 1 out of every 2500 girls, the syndrome manifests itself in a number of ways. There are characteristic physical abnormalities, such as short stature, swelling, broad chest, low hairline, low-set ears, and webbed necks. Girls with Turner syndrome typically experience gonadal dysfunction (non- working ovaries), which results in amenorrhea (absence of menstrual cycle) and sterility. Concurrent health concerns are also frequently present, including congenital heart disease, hypothyroidism (reduced hormone secretion by the thyroid), diabetes, vision problems, hearing concerns, and many autoimmune diseases. Finally, a specific pattern of cognitive deficits is often observed, with particular difficulties in visuospatial, mathematical, and memory areas.

Klinefelter's syndrome, 47, XXY, or XXY syndrome is a condition in which males have an extra (an aneuploidy) X sex chromosome . While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome. Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males". Klinefelter's syndrome is the most common sex chromosome disorder and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 1,000 males. One in every 500 males has an extra X chromosome but does not have the syndrome. The principal effects are development of small testicles and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms. Massachusetts General Hospital in Boston, Massachusetts and first described it in the same year.

True hermaphroditism is a medical term for an intersex condition in which an individual is born with ovarian and testicular tissue. There may be an ovary on one side and a testis on the other, but more commonly one or both gonads is an ovotestis containing both types of tissue. It is rare — so far undocumented — for both types of gonadal tissue to function. Encountered karyotypes are 47XXY, 46XX/46XY, or 46XX/47XXY. Although similar in some ways to mixed gonadal dysgenesis, the conditions can be distinguished histologically. Presentation External genitalia are often ambiguous, the degree depending mainly on the amount of testosterone produced by the testicular tissue between 8 and 16 weeks of gestation. Causes This condition is very rare. There are several ways in which this may occur. It can be caused by the division of one ovum, followed by fertilization of each haploid ovum and fusion of the two zygotes early in development. Alternately, an ovum can be fertilized by two sperm followed by trisomic rescue in one or more daughter cells. Two ova fertilized by two sperm will occasionally fuse to form a tetragametic chimera. If one male zygote and one female zygote fuse, a hermaphroditic individual may result. It can be associated with mutation in the SRY gene.

Cryptorchidism is the absence of one or both testes from the scrotum. This usually represents failure of the testis to move, or "descend," during fetal development from an abdominal position, through the inguinal canal, into the ipsilateral scrotum. About 3% of full-term and 30% of premature infant boys are born with at least one undescended testis, making cryptorchidism the most common birth defect of male genitalia. However, about 80% of cryptorchid testes descend by the first year of life (the majority within three months), making the true incidence of cryptorchidism around 1% overall. A testis absent from the normal scrotal position can be: - ound anywhere along the "path of descent" from high in the posterior (retroperitoneal) abdomen, just below the kidney, to the inguinal ring; - found in the inguinal canal; - ectopic, that is, found to have "wandered" from that path, usually outside the inguinal canal and sometimes even under the skin of the thigh, the perineum, the opposite scrotum, and femoral canal; - found to be undeveloped (hypoplastic) or severely abnormal (dysgenetic); - found to have vanished (also see Anorchia). About two thirds of cases without other abnormalities are unilateral; 1/3 involve both testes. In 90% of cases an undescended testis can be palpated (felt) in the inguinal canal; in a minority the testis or testes are in the abdomen or nonexistent (truly "hidden"). Undescended testes are associated with reduced fertility, increased risk of testicular germ cell tumors and psychological problems when the boy is grown. Undescended testes are also more susceptible to testicular torsion and infarction and inguinal hernias. To reduce these risks, undescended testes are usually brought into the scrotum in infancy by a surgical procedure called an Orchiopexy. Although cryptorchidism nearly always refers to congenital absence or maldescent, a testis observed in the scrotum in early infancy can occasionally "reascend" (move back up) into the inguinal canal. A testis which can readily move or be moved between the scrotum and canal is referred to as retractile.

Hypogonadism is a medical term for decreased functional activity of the gonads. The gonads (ovaries or testes) produce hormones (testosterone, estradiol, antimullerian hormone, progesterone, inhibin B, activin) and gametes (eggs or sperm). Late-onset hypogonadism (LOH), Andropause or Androgen Decline in the Aging Male (ADAM), is a syndrome caused by a decline in gonadal production of testosterone in males that occurs with aging. This "male menopause" can also cause hypogonadism. However, it occurs for certain men and not for the others. Symptoms In men Effects of low testosterone in men may include: (not all are present in any single individual) and Poor libido (Low sexual desire), Fatigue (medical) always tired, Muscle loss/atrophy, Erectile Dysfunction, Increasing abdominal fat, Glucose intolerance (early diabetes), High Cholesterol/Lipid, Poor sleep, Difficulty concentrating, Memory Loss-difficulty in choosing words in language, Depression, Anxiety, Psychological and relationship problems, Increase size of chest, Hot flashes, Decrease in growth of, or loss of, beard and body hair, Loss of bone mass (osteoporosis), Irritability, Infertility, Shrinking of the testicles, Decrease in firmness of testicles, Frequent urination (polyuria) without infection/waking at night to urinate, Achy muscles, Night sweats, Dry skin and/or cracking nails, In women Effects of low estrogen levels in women may include: (not all are present in any individual) and Hot flashes, Irritability, Poor libido, Infertility, Loss of, or failure to develop, Menstruation, Loss of body hair, Loss of bone mass (osteoporosis), Heart disease, Sleep disturbances, Symptoms of urinary bladder discomfort like frequency, urgency, frequent infections, lack of lubrication, discharge, Shrinking of breasts, loss of or nonexistent sense of smell Diagnosis In men Low Testosterone can be identified through a simple blood test performed by a laboratory, ordered by a physician. This test is typically ordered in the morning hours, when levels are highest, but even in men over 60 levels can drop by as much as 13% during the day. Normal total testosterone levels range from 300 - 1000ng/dl Treatment is often prescribed for total testosterone levels below 350 ng/dl If the serum total testosterone level is between 230 and 350 ng/dl, repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful. However, there are no widely accepted diagnoses or reference ranges for Free Testosterone or Bioavailable Testosterone due to large discrepancies in the reference ranges for these tests between different testing labs. Blood testing A position statement by The Endocrine Society has expressed dissatisfaction with the manner in which most assays for TT (Total Testosterone) and FT (Free Testosterone) are currently performed. In particular, research has questioned the validity of commonly administered assays of FT by RIA. The FAI (Free Androgen Index) has been found to be the worst predictor of Free Testosterone. In women Similar to men, the LH and FSH will be used, particularly in women who believe they are in menopause. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels. Hypogonadism is often discovered during evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women. Treatment Male hypogonadism is most often treated with testosterone replacement therapy (TRT). Commonly-used testosterone replacement therapies include transdermal (through the skin) using a patch or gel, injections, or pellets. Oral testosterone is no longer used in the U.S. because it is broken down in the liver and rendered inactive. Like many hormonal therapies, changes take place over time. It may take as long as 2-3 months at optimum level to reduce the symptoms, particularly the wordfinding and cognitive dysfunction. Testosterone levels in the blood should be evaluated to ensure the increase is adequate. Levels between 500-700 ng/l are considered adequate for young, healthy men from 20 to 40 years of age, but the lower edge of the normal range is poorly defined and single testosterone levels alone cannot be used to make the diagnosis. Modern treatment may start with 200mg intramuscular testosterone, repeated every 10-14 days. Getting a blood level of testosterone on the 13th day will give a "trough" level, assisting the physician in deciding whether the correct dose is being given. Recently some have reported using Arimidex, an aromatase inhibitor used in women for breast cancer, to decrease conversion of testosterone to estrogen in men, and increase serum testosterone levels. While historically men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth. Other side effects can include an elevation of the hematocrit to levels that require blood to be withdrawn (phlebotomy) to prevent complications from it being "too thick". Another is that a man may have some growth in the size of the breasts (gynecomastia), though this is relatively rare. Finally, some physicians worry that Obstructive Sleep Apnea may worsen with testosterone therapy, and should be monitored. Another feasible treatment alternative is human chorionic gonadotropin (hCG). For both men and women, an alternative to testosterone replacement is Clomifene treatment which can stimulate the body to naturally increase hormone levels while avoiding infertility and other side effects as a consequence of direct hormone replacement therapy. For women, estradiol and progesterone are replaced. Some types of fertility defects can be treated, others cannot. Some physicians will also give testosterone to women, mainly to increase libido. Classification Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. The term hypogonadism is usually applied to permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or without fertility defects. The term is less commonly used for infertility without hormone deficiency. There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective.Physicians measure gonadotropins (LH and FSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles, whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain. Affected system Hypogonadism resulting from defects of the gonads is traditionally referred to as primary hypogonadism. Examples include Klinefelter syndrome and Turner syndrome. Mumps is known to cause testicular failure, and in recent years has been immunized against in the US. A varicocele can reduce hormonal production as well. Hypogonadism resulting from hypothalamic or pituitary defects are termed secondary hypogonadism or central hypogonadism (referring to the central nervous system). Examples of Hypothalamic defects include Kallmann syndrome. Examples of Pituitary defects include hypopituitarism. An example of a hypogonadism resulting from the lack of hormone response is androgen insensitivity syndrome, where there are inadequate receptors to bind the testosterone, resulting in a female appearance despite XY chromosomes. Primary or secondary Primary - defect is inherent within the gonad: eg. Noonan syndrome, Turner syndrome (45X,0), Klinefelter syndrome (47XXY), XX males with SRY gene Secondary - defect lies outside of the gonad: eg. Kallmann syndrome and Polycystic ovary syndrome, also called hypogonadotropic hypogonadism. Hemochromatosis and diabetes mellitus can be causes of this as well. Congenital vs. acquired An example of congenital hypogonadism (present at birth) in females is Turner syndrome, and in males is Klinefelter syndrome. It is also one of the signs of CHARGE syndrome. An example of acquired hypogonadism is the Anabolic Steroids Induced Hypogonadism (ASIH), and childhood mumps. Additionally, there is some evidence men whose mothers ingested the endocrine disruptor diethylstilbestrol for potential miscarriage may have hypogonadism. Hormones vs. fertility Hypogonadism can involve just hormone production or just fertility, but most commonly involves both. Examples of hypogonadism that affect hormone production more than fertility are hypopituitarism and Kallmann syndrome; in both cases, fertility is reduced until hormones are replaced but can be achieved solely with hormone replacement. Examples of hypogonadism that affect fertility more than hormone production are Klinefelter syndrome and Kartagener syndrome. Testosterone Testosterone is a key steroid hormone produced in the body, which plays an important role in many fundamental physical processes. Hormones are essentially chemical signaling molecules, that activate certain processes in the body, through a receptor mechanism. A signaling molecule like testosterone, binds with the various chemical receptors in the body, to trigger various bodily processes. A steroid is a particular chemical type of hormone called terpenoid lipid. It is the hormone that initiates most of the sexual developmental processes in a male and also contributes to other vital processes. Hence it is also called the male sex hormone as it manifests all the typical male qualities and physical processes. The testosterone secretion timing and amount is regulated by the hypothalamus and the pituitary gland in the brain through a complex signaling mechanism. It is also produced in the female body but in comparatively very lesser amounts. The female equivalent of testosterone is estrogen, the female sex hormone. Testosterone is synthesized from cholesterol by mostly the Leydig cells in the male testicles. In females, it is synthesized in the ovaries by Thecal cells in very small quantities. In males, testosterone plays the very important role of initiating sperm production in the sertoli cells of the male testes. Drop in the levels of testosterone causes problems in cognitive processes, depression, sleep disorders, fatigue, decrease in libido and erectile dysfunction. It is also known to cause excessive fat accumulation. Hypogonadism may be induced after the chronic use of anabolic/androgenic steroids (AAS). The negative-feedback system of the hypothalamic-pituitary-gonadal axis (HPTA) shuts down pituitary production of gonadotropins after extended exposure to AAS. Coping Hypogonadism can have many psychological effects, especially in younger patients due to infertility and appearance. A supportive family that understands the condition is paramount, as well as psychological treatment. Possible treatments include the use of regular injections or the application of gels or ointments. Testosterone and longevity A longitudinal (18 year) study published by The Endocrine Society and funded by the National Institute on Aging and the American Heart Association stated: Men over 50 may not live as long if they have low testosterone. The study looked at death from any cause in nearly 800 men ages 50 to 91 years who were living in a southern California community and who participated in the Rancho Bernardo Study in the 1980s. At the beginning of the study, almost one-third of these men had suboptimal blood testosterone levels for men their age. The men with low testosterone levels had a 33 percent greater risk of death during the next 18 years than the men with higher testosterone. This difference was not explained by smoking, alcohol intake and level of physical activity or by pre-existing diseases such as diabetes or heart disease. The new study is the second report linking the deficiency of this sex hormone with increased death from all causes over time, said study author Gail Laughlin, PhD.

Andropause or male menopause is a name that has been given to a menopause-like condition in aging men. This relates to the slow but steady reduction of the production of the hormones testosterone and dehydroepiandrosterone in middle-aged men, and the consequences of that reduction, which is associated with a decrease in Leydig cells. Unlike women, middle-aged men do not experience a complete and permanent physiological shutting down of the reproductive system as a normal event. A steady decline in testosterone levels with age (in both men and women) is well documented. Unlike "menopause", the word "andropause" is not currently recognized by the World Health Organization and its ICD-10 medical classification. This is likely because "Andropause" is term of convenience describing the stage of life when symptoms in aging appear in men. While the words are sometimes used interchangeably, hypogonadism a deficiency state in which the hormone testosterone goes below the normal range for even an aging male. As a "state" The impact of low levels of testosterone has been previously reported. In 1944, Heller and Myers[5] identified symptoms of what they labeled the "male climacteric" including loss of libido and potency, nervousness, depression, impaired memory, the inability to concentrate, fatigue, insomnia, hot flushes, and sweating. Heller and Myers found that their subjects had lower than normal levels of testosterone, and that symptoms improved dramatically when patients were given replacement doses of testosterone. Andropause has been observed in association with Alzheimer's disease. In one study, 98.0% of primary care physicians believed that andropause and osteoporosis risk were related. The term "symptomatic late onset hypogonadism" (or "SLOH") is sometimes considered to refer to the same condition as the word "andropause". Some researchers prefer the term "androgen deficiency of the aging male" ("ADAM"), to more accurately reflect the fact that the loss of testosterone production is gradual and asymptotic (in contrast to the more abrupt change associated with menopause) The "D" is sometimes given as "decline" instead of "deficiency". In some contexts, the term "partial androgen deficiency in aging males" ("PADAM") is used instead. As a disorder Proponents Proponents of andropause as a distinct condition claim that it is a biological change experienced by men during mid-life, and often compare it to female menopause. Menopause, however, is a complete cessation of reproductive ability caused by the shutting down of the female reproductive system. Andropause is a decline in the male hormone testosterone. This drop in testosterone levels is considered to lead in some cases to loss of energy and concentration, depression, and mood swings. While andropause does not cause a man's reproductive system to stop working altogether, many will experience bouts of impotence. Andropause is usually caused by a very gradual testosterone deficiency and an increase in sex hormone-binding globulin (SHBG) that occurs from age 35 onwards. By contrast, women have a sudden onset of menopause around age 51. Testosterone declines 10% every decade after age 30 (1% per year). workplace exposure to estrogen. Men who work in the pharmaceutical industry, plastics factories, near incinerators, and on farms that use pesticides are high-risk for early andropause. About 30% of men in their 50’s experience andropause. About 5 million American men do not produce adequate testosterone, which leads to early andropause. In Australia, about 1 in every 200 men under the age of 60 and about 1 in every 10 men over 60 have low testosterone. Regardless of location, the most likely males to develop early andropause are those with diabetes, hypertension, and genetic disorders that produce hypogonadism, including Klinefelter's, Wilson-Turner, and Androgen insensitivity syndromes. Some of the current popular interest in the concept of andropause has been fueled by the book Male Menopause, written by Jed Diamond, a lay person. According to Diamond's view, andropause is a change of life in middle-aged men, which has hormonal, physical, psychological, interpersonal, social, sexual, and spiritual aspects. Diamond claims that this change occurs in all men, generally between the ages of 40 and 55, though it can occur as early as 35 or as late as 65. The term "male menopause" may be a misnomer, as unlike women, men's reproductive systems do not cease to work completely in mid-life; some men continue to father children late into their lives (at age 90 or older[13]). But Diamond claims that, in terms of other life impacts, women’s and men’s experience are somewhat similar phenomena. The concept of andropause is perhaps more widely accepted in Australia and some parts of Europe than it is in the United States. Opponents Many clinicians believe that andropause is not a valid concept, because men can continue to reproduce into old age. Their reproductive systems do not stop working completely, and therefore they do not exhibit the sudden and dramatic drops in hormone levels characteristic of women undergoing menopause. It should be noted that in some men before the age of 60 there is a complete loss of libido, erectile function, and orgasmic ability. Others feel that andropause is simply synonymous with hypogonadism or low testosterone levels. There is opposition to the concept of andropause in Europe as well as the U.S. Some clinicians argue that many of the cited symptoms are not specific enough to warrant describing a new condition. For example, people who are overweight may be misguided into treating a new illness rather than addressing the lifestyle that led to their being overweight. Similarly, energy levels vary from person to person, and for people who are generally inactive, energy levels will automatically be lower overall. While it is true that active and otherwise healthy men could in theory develop andropause-like symptoms, how common and widespread the phenomenon is, and whether genetics, lifestyle, environment, or a combination of factors are responsible, is not yet known. Suggestions for treatment Although there is disagreement over whether or not andropause is a condition to be "diagnosed" and "treated", those who support that position have made several proposals to address andropause and mitigate some of its effects. Morley emphasizes the importance of response to treatment, as well as testosterone level and identifiable symptoms. Mintz, Dotson, & Mukai include an emphasis on hormones other than testosterone. They also focus upon diet, and exercise. Diamond (a lay person) believes that depression is one of the most common problems of middle- aged men, and feels it is greatly under-diagnosed, sometimes with serious consequences.

Menopause is the permanent cessation of ovarian function occurring some time before the end of the natural lifespan. In human females, menopause usually happens more or less in midlife, signaling the end of the fertile phase of a woman's life. The word "menopause" literally means the "end of monthly cycles" from the Greek words pausis (cessation) and the word root men from mensis meaning (month), because the word menopause was created to describe this change (from reproductive to non-reproductive) in human females, where the end of fertility is traditionally indicated by the permanent stopping of monthly menstruation or menses. However menopause also exists in some other animals, many of which do not have monthly menstruation. The date of menopause in human females is formally medically defined as the time of the last menstrual period (or menstrual flow of any amount however small), in a woman who has not had a hysterectomy. Signs and symptoms During the menopause transition years, as the body responds to the rapidly fluctuating and dropping levels of natural hormones, a number of effects may appear. Not every woman experiences bothersome levels of these effects; the range of effects and the degree to which they appear is very variable from person to person. Effects that are due to low estrogen levels (for example vaginal atrophy and skin drying) will continue after the menopause transition years are over; however, many effects that are caused by the extreme fluctuations in hormone levels (for example hot flashes and mood changes) usually disappear or improve significantly once the perimenopause transition is completely over. All the various possible perimenopause effects are caused by an overall drop, as well as dramatic but erratic fluctuations, in the absolute levels and relative levels of estrogens and progesterone. Some of the effects, such as formication (crawling, itching, or tingling skin sensations), may be associated directly with hormone withdrawal. Both users and non-users of hormone replacement therapy identify lack of energy as the most frequent and distressing effect. Other effects can include vasomotor symptoms such as hot flashes and palpitations, psychological effects such as depression, anxiety, irritability, mood swings, memory problems and lack of concentration, and atrophic effects such as vaginal dryness and urgency of urination. The average woman also has increasingly erratic menstrual periods, due to skipped ovulations. Typically, the timing of the flow becomes unpredictable. In addition the duration of the flow may be considerably shorter or longer than normal, and the flow itself may be significantly heavier or lighter than was previously the case, including sometimes long episodes of spotting. Early in the process it is not uncommon to have some 2-week cycles. Further into the process it is common to skip periods for months at a time, and these skipped periods may be followed by a heavier period. The number of skipped periods in a row often increases as the time of last period approaches. At the point when a woman of menopausal age has had no periods or spotting for 12 months she is considered to be one year into post-menopause. Vascular instability - Hot flashes or hot flushes, including night sweats and, in a few people, cold flashes; Possible but contentious increased risk of atherosclerosis; Migraine; Rapid heartbeat Urogenital atrophy, also known as vaginal atrophy - Thinning of the membranes of the vulva, the vagina, the cervix, and also the outer urinary tract, along with considerable shrinking and loss in elasticity of all of the outer and inner genital areas; Itching; Dryness; Bleeding; Watery discharge; Urinary frequency; Urinary incontinence; Urinary urgency; Increased susceptibility to inflammation and infection, for example vaginal candidiasis, and urinary tract infections Skeletal - Back pain; Joint pain, Muscle pain; Osteopenia and the risk of osteoporosis gradually developing over time; Skin, soft tissue - Breast atrophy breast tenderness +/- swelling; Decreased elasticity of the skin Formication (itching, tingling, burning, pins and needles, or sensation of ants crawling on or under the skin); Skin thinning and becoming drier Psychological - Depression and/or anxiety; Fatigue; Irritability; Memory loss, and problems with concentration; Mood disturbance; Sleep disturbance, poor quality sleep, light sleep, insomnia; Sexual - Dyspareunia or painful intercourse; Decreased libido; Problems reaching orgasm; Vaginal dryness and vaginal atrophy Cohort studies have reached mixed conclusions about medical conditions associated with the menopause. For example, a 2007 study found that menopause was associated with hot flashes; joint pain and muscle pain; and depressed mood. In the same study, it appeared that menopause was not associated with poor sleep, decreased libido, and vaginal dryness. However, in contrast to this, a 2008 study did find an association with poor sleep quality.

Methodical recommendationsis prepared by assistant M.V. Morgun, docent O.V. Potapchuk