sign in sign up
<<
Home , Adrenal cortex, Adrenal gland, Adrenal medulla, Anterior pituitary, Endocrine gland, Endocrine system

The

An Overview

Susanne Hiller-Sturmhöfel, Ph.D., and Andrzej Bartke, Ph.D.

A plethora of regulate many of the body’s functions, including growth and development, , balances, and . Numerous throughout the body produce hormones. The produces several releasing and inhibiting hormones that act on the pituitary , stimulating the release of pituitary hormones. Of the pituitary hormones, several act on other glands located in various regions of the body, whereas other pituitary hormones directly affect their target organs. Other -producing glands throughout the body include the adrenal glands, which primarily produce ; the (i.e., and testes), which produce hormones; the , which produces thyroid hormone; the parathyroid, which produces ; and the , which produces and . Many of these hormones are part of regulatory hormonal cascades involving a hypothalamic hormone, one or more pituitary hormones, and one or more target gland hormones. KEY WORDS: endocrine function; hormones; hypothalamus; ; function; thyroid; parathyroid; pancreas; biochemical mechanism; biological ; biological regulation; hypothalamus-pituitary axis; pituitary-adrenal axis; pituitary-thyroid axis; literature review

or the body to function properly, (i.e., within fractions of seconds) of composition of bodily fluids; and repro- its various parts and organs must information between different body duction. This article provides an Fcommunicate with each other to regions. Conversely, hormonal commu- overview of the hormone systems ensure that a constant internal environ- nication, which relies on the production involved in those regulatory processes. ment (i.e., ) is maintained. and release of hormones from various The article first summarizes some of the For example, neither the body temper- glands and on the transport of those basic characteristics of hormone- ature nor the levels of and minerals hormones via the bloodstream, is better mediated communication within the (i.e., ) in the must suited for situations that require more body, then reviews the various glands fluctuate beyond preset limits. Com- widespread and longer lasting regulatory involved in those processes and the munication among various regions of actions. Thus, the two communication the body also is essential for enabling systems complement each other. In SUSANNE HILLER-STURMHÖFEL, PH.D., the to respond appropriately addition, both systems interact: Stimuli is a science editor of Health & to any changes in the internal and from the can influence Research World. external environments. Two systems the release of certain hormones and help ensure communication: the nervous vice versa. ANDRZEJ BARTKE, PH.D., is professor system and the hormonal (i.e., neuroen- Generally speaking, hormones con- and chairman of at Southern docrine) system. The nervous system trol the growth, development, and Illinois University School of , generally allows rapid transmission metabolism of the body; the electrolyte Carbondale, Illinois.

Vol. 22, No. 3, 1998 153 major hormones they produce. For molecular structures (e.g., size and or in the nucleus. The hormone- more in-depth information on those chemical properties). As a result of the complexes then bind to certain hormones, the reader should consult structural differences, their mechanisms regions of the cell’s genetic material (i.e., textbooks (e.g., Con- of action (e.g., whether they can enter the DNA), thereby regulating the activ- stanti et al. 1998; Wilson et al. 1998). their target cells and how they modulate ity of specific hormone-responsive . Finally, the article presents various the activity of those cells) also differ. derivatives are modi- endocrine systems in which hormones , which are produced by the fied versions of some of the building produced in several organs cooperate gonads and part of the blocks of . The thyroid gland to achieve the desired regulatory effects. (i.e., the adrenal ), have a molecular and another region of the adrenal The discussions focus primarily on structure similar to that of . glands (i.e., the ) pro- the system responses in normal, healthy The molecules can enter their target duce this type of hormone (i.e., the people. For information regarding cells and interact with receptors in the amino acid derivatives). Like steroids, alcohol’s effects on some of the hormone fluid that fills the cell (i.e., the ) amino acid derivatives can enter the systems, the reader is referred to sub- sequent articles in this issue of Alcohol Health & Research World.

What Are Hormones?

Hormones are molecules that are pro- Hypothalamus duced by endocrine glands, including Thyroid gland the hypothalamus, pituitary gland, Pituitary gland adrenal glands, gonads, (i.e., testes and ovaries), thyroid gland, parathyroid glands, and pancreas (see figure 1). The term “endocrine” implies that in response to specific stimuli, the products of those glands are released into the bloodstream.1 The hormones then are carried via the blood to their target cells. Some hormones have only a few specific target cells, whereas other hormones affect numerous cell types throughout the body. The target cells for each hormone are characterized by the presence of certain docking mole- cules (i.e., receptors) for the hormone Adrenal gland that are located either on the cell surface Pancreas or inside the cell. The interaction (Islets of between the hormone and its receptor Langerhans) triggers a cascade of biochemical reac- tions in the target cell that eventually modify the cell’s function or activity. (in )

Mechanisms of Action Testis Several classes of hormones exist, includ- (in male) ing steroids, amino acid derivatives, and polypeptides and proteins. Those hormone classes differ in their general

1Conversely, exocrine glands (e.g., sweat glands Figure 1 Schematic representation of the location of the major hormone-producing and salivary glands) release their to the (i.e., endocrine) organs in the body. (For the purposes of illustration, both outside of the body (e.g., sweat) or into a hollow male and female endocrine organs are presented here.) space that is open to the outside (e.g., saliva released into the mouth).

154 Alcohol Health & Research World The Endocrine System

cell, where they interact with receptor cell surface. The interaction initiates which are transported via the blood to proteins that are already associated biochemical changes in either the cell’s the pituitary gland. There, the releasing with specific DNA regions. The membrane or interior, eventually mod- hormones induce the production and interaction modifies the activity of ifying the cell’s activity or function. of pituitary hormones, which the affected genes. in turn are transported by the blood to Polypeptide and hormones Regulation of Hormone Activity their target glands (e.g., the adrenal are chains of amino acids of various glands, gonads, or thyroid). In those lengths (from three to several hundred To maintain the body’s homeostasis glands, the interaction of the pituitary amino acids). These hormones are and respond appropriately to changes hormones with their respective target found primarily in the hypothalamus, in the environment, hormone produc- cells results in the release of the hormones pituitary gland, and pancreas. In some tion and secretion must be tightly that ultimately influence the organs instances, they are derived from inactive controlled. To achieve this control, targeted by the hormone cascade. precursors, or pro-hormones, which many bodily functions are regulated Constant feedback from the target can be cleaved into one or more active not by a single hormone but by several glands to the hypothalamus and pitu- hormones. Because of their chemical hormones that regulate each other itary gland ensures that the activity of structure, the polypeptide and protein (see figure 2). For example, for many the hormone system involved remains hormones cannot enter cells. Instead, hormone systems, the hypothalamus within appropriate boundaries. Thus, they interact with receptors on the secretes so-called releasing hormones, in most cases, mech- anisms exist by which hormones released by the target glands affect the pituitary gland and/or hypo- (see figure 2). When certain predetermined blood levels of those Hypothalamus hormones are reached, the hypothala- mus and/or the pituitary ceases hormone release, thereby turning off the cascade. In some instances, a Releasing hormone so-called short-loop feedback occurs, Short-loop in which pituitary hormones directly feedback act back on the hypothalamus. The sensitivity with which these negative feedback systems operate (i.e., the target hormone levels that are required to turn off hypothalamic or pituitary hormone release) can Pituitary hormone change at different physiological states or stages of . For example, the progressive reduction in sensitivity Target gland of the hypothalamus and pituitary to negative feedback by gonadal hormones plays an important role in sexual maturation. Although negative feedback is more common, some hormone Target gland hormone systems are controlled by mechanisms, in which a target gland hormone acts back on the hypothalamus and/or pituitary Figure 2 Schematic representation of negative feedback mechanisms that control to increase the release of hormones endocrine system activity. In many cases, the hormones released from the target gland act back on the pituitary and/or hypothalamus, repressing that stimulate the secretion of the further hormone release from both organs and thereby shutting off the target gland hormone. One such system. For a short-loop negative feedback mechanism, pituitary hormones mechanism occurs during a ’s act directly back on the hypothalamus, inhibiting the release of hypothalamic menstrual period: Increasing hormones. levels in the blood temporarily stimulate, rather than inhibit, hormone NOTE: + = stimulates; Ð = inhibits. release from the pituitary and hypo- thalamus, thereby further increasing

Vol. 22, No. 3, 1998 155 Hormones Produced by the Major Hormone-Producing (i.e., Endocrine) Glands and Their Primary Functions

Endocrine Gland Hormone Primary Hormone Function

Hypothalamus Corticotropin-releasing hormone (CRH) Stimulates the pituitary to release adrenocorticotropic hormone (ACTH)

Gonadotropin-releasing hormone (GnRH) Stimulates the pituitary to release (LH) and follicle-stimulating hormone (FSH)

Thyrotropin-releasing hormone (TRH) Stimulates the pituitary to release thyroid-stimulating hormone (TSH)

Growth hormone-releasing hormone Stimulates the release of (GH) from the (GHRH) pituitary

Somatostatin Inhibits the release of GH from the pituitary

Dopamine Inhibits the release of from the pituitary

Anterior pituitary gland ACTH Stimulates the release of hormones from the

LH In women, stimulates the production of sex hormones (i.e., ) in the ovaries as well as during ; in men, stimulates production in the testes

FSH In women, stimulates follicle development; in men, stimu- lates production

TSH Stimulates the release of thyroid hormone

GH Promotes the body’s growth and development

Prolactin Controls milk production (i.e., ) 1 gland Helps control the body’s and electrolyte levels

Oxytocin Promotes during labor and activates milk ejection in women

Adrenal cortex Cortisol Helps control , protein, and metabolism; protects against

Aldosterone Helps control the body’s water and electrolyte regulation

Testes Testosterone Stimulates development of the male reproductive organs, sperm production, and protein

Ovaries Estrogen (produced by the follicle) Stimulates development of the female reproductive organs

Progesterone (produced by the Prepares for and mammary glands for ) lactation

Thyroid gland Thyroid hormone (i.e., thyroxine [T4] Controls metabolic processes in all cells and [T3]) Helps control metabolism (i.e., lowers calcium levels in the blood)

Parathyroid gland Parathyroid hormone (PTH) Helps control (i.e., increases calcium levels in the blood)

Pancreas Insulin Helps control (i.e., lowers blood sugar levels)

Glucagon Helps control carbohydrate metabolism (i.e., increases blood sugar levels)

1These hormones are produced in the hypothalamus but stored in and released from the posterior pituitary gland.

156 Alcohol Health & Research World The Endocrine System

estrogen levels and eventually lead- The hypothalamic hormones are consists of two parts: the anterior ing to ovulation. Such a mechanism released into blood vessels that connect pituitary and the posterior pituitary. requires a specific threshold level, the hypothalamus and the pituitary however, at which the positive feed- gland (i.e., the hypothalamic-hypo- The Anterior Pituitary back loop is turned off in order to physeal portal system). Because they maintain a stable system. generally promote or inhibit the release The anterior pituitary produces several of hormones from the pituitary gland, important hormones that either stimu- hypothalamic hormones are commonly late target glands (e.g., the adrenal The Hypothalamus called releasing or inhibiting hormones. glands, gonads, or thyroid gland) to and Its Hormones The major releasing and inhibiting produce target gland hormones or hormones include the following (also directly affect target organs. The The hypothalamus is a small region see table, p. 156): pituitary hormones include adreno- located within the that controls corticotropic hormone (ACTH); many bodily functions, including • Corticotropin-releasing hormone ; thyroid-stimulating and drinking, sexual functions (CRH), which is part of the hormone hormone (TSH), also called thyrotropin; and behaviors, and system regulating carbohydrate, pro- growth hormone (GH); and prolactin. rate, body temperature maintenance, tein, and metabolism as well as The first three of those hormones— the -wake cycle, and emotional and water balance in the body ACTH, gonadotropins, and TSH— states (e.g., , , anger, and act on other glands. Thus, ACTH pleasure). Hypothalamic hormones • -releasing hormone stimulates the adrenal cortex to pro- play pivotal roles in the regulation of (GnRH), which helps control duce hormones— many of those functions. sexual and reproductive functions, primarily cortisol—as well as small Because the hypothalamus is part of including pregnancy and lactation amounts of female and male sex hor- the , the hypothal- (i.e., milk production) mones. The gonadotropins comprise amic hormones actually are produced two molecules, luteinizing hormone by cells (i.e., ). In addition, • Thyrotropin-releasing hormone (LH) and follicle-stimulating hormone because signals from other neurons (TRH), which is part of the hormone (FSH). These two hormones regulate can modulate the release of hypothal- system controlling the metabolic the production of female and male sex amic hormones, the hypothalamus processes of all cells and which con- hormones in the ovaries and testes as serves as the major link between the tributes to the hormonal regulation well as the production of the germ nervous and endocrine systems. For of lactation cells—that is, the egg cells (i.e., ova) example, the hypothalamus receives and sperm cells (i.e., spermatozoa). information from higher brain centers • Growth hormone-releasing hor- TSH stimulates the thyroid gland to that respond to various environmental mone (GHRH), which is an produce and release thyroid hormone. signals. Consequently, hypothalamic essential component of the system The remaining two pituitary hormones, function is influenced by both the promoting the organism’s growth GH and prolactin, directly affect their external and internal environments as target organs. well as by hormone feedback. Stimuli • , which also affects from the external environment that and muscle growth but has the Growth Hormone. GH is the most indirectly influence hypothalamic opposite effect as that of GHRH abundant of the pituitary hormones. function include the light-dark cycle; As the name implies, it plays a pivotal temperature; signals from other members • , a substance that functions role in controlling the body’s growth of the same species; and a wide variety primarily as a but and development. For example, it of visual, auditory, olfactory, and sensory also has some hormonal effects, stimulates the linear growth of the stimuli. The communication between such as repressing lactation until it ; promotes the growth of inter- other brain areas and the hypothalamus, is needed after . nal organs, fat (i.e., adipose) , which conveys information about the , endocrine glands, internal environment, involves electro- and muscle; and controls the devel- chemical signal transmission through opment of the reproductive organs. molecules called The Pituitary and Its Accordingly, the GH levels in (e.g., aspartate, dopamine, gamma- Major Hormones the blood are highest during early aminobutyric acid, glutamate, norepin- childhood and and decline ephrine, and ). The complex The pituitary (also sometimes called thereafter. Nevertheless, even rela- interplay of the actions of various the hypophysis) is a gland about the tively low GH levels still may be neurotransmitters regulates the pro- size of a small marble and is located important later in life, and GH duction and release of hormones from in the brain directly below the deficiency may contribute to some the hypothalamus. hypothalamus. The pituitary gland symptoms of aging.

Vol. 22, No. 3, 1998 157 In addition to its growth-promoting require GH for normal development the pituitary is controlled by the con- role, GH affects carbohydrate, pro- and puberty. (For more information on centration of sodium in the blood as well tein, and fat (i.e., lipid) metabolism. alcohol’s effects on puberty and growth, as by and blood pressure. Thus, GH increases the levels of the see the article by Dees and colleagues, For example, high blood pressure or sugar in the blood by reducing pp. 165–169.) increased blood volume results in the glucose uptake by muscle cells and inhibition of AVP release. Consequently, and by promoting glu- Prolactin. Together with other hor- more water is released with the , cose production (i.e., gluconeogene- mones, prolactin plays a central role and both blood pressure and blood sis) from precursor molecules in the in the development of the female volume are reduced. Alcohol also has . (These actions are opposite to and in the initiation and maintenance been shown to inhibit AVP release. those of the hormone insulin, which of lactation after childbirth. Prolactin’s Conversely, certain other (e.g., is discussed in the section “The Pancreas function in men, however, is not well and morphine) increase AVP and Its Hormones,” p. 160.) GH also understood, although excessive prolactin release, as do severe pain, fear, nausea, enhances the uptake of amino acids release can lead to reduced sex drive (i.e., and general , thereby result- from the blood into cells, as well as ) and impotence. Several factors ing in lower urine production and their incorporation into proteins, and control prolactin release from the ante- water retention. stimulates the breakdown of in rior pituitary. For example, prolactin , the second hormone adipose tissue. is released in increasing amounts in stored in the posterior pituitary, stim- To elicit these various effects, GH response to the rise in estrogen levels ulates the contractions of the uterus modulates the activities of numerous in the blood that occurs during preg- during childbirth. In nursing women, target organs, including the liver, kid- nancy. In nursing women, prolactin is the hormone activates milk ejection neys, bone, , , released in response to suckling by the in response to suckling by the infant and adipose cells. For some of these infant. Several releasing and inhibitory (i.e., the so-called let-down reflex). effects, GH acts directly on the target factors from the hypothalamus also cells. In other cases, however, GH acts control prolactin release. The most indirectly by stimulating the produc- important of those factors is dopamine, The Adrenal Glands tion of a molecule called insulin-like which has an inhibitory effect. and Their Hormones growth factor 1 (IGF-1) in the liver Alcohol consumption by nursing and kidneys. The blood then trans- women can influence lactation both The adrenal glands are small structures ports IGF-1 to the target organs, through its effects on the release of located on top of the kidneys. Struct- where it binds to specific receptors on prolactin and oxytocin (see the follow- urally, they consist of an outer layer the cells. This interaction then may ing section) and through its effects on (i.e., the cortex) and an inner layer lead to the increased DNA produc- the milk-producing (i.e., mammary) (i.e., the medulla). The adrenal cortex tion and cell division that underlie glands and the composition of the milk. produces numerous hormones, primar- the growth process. (For more information on alcohol’s effects ily (i.e., Two hypothalamic hormones con- on lactation, see the article by Heil and and ). The cortex is trol GH release: (1) GHRH, which Subramanian, pp. 178–184.) also the source of small amounts of stimulates GH release, and (2) somato- sex hormones; those amounts, however, , which inhibits GH release. This The Posterior Pituitary are insignificant compared with the regulatory mechanism also involves a amounts normally produced by the short-loop feedback component, by The posterior pituitary does not ovaries and testes. The adrenal medulla which GH acts on the hypothalamus produce its own hormones; instead, generates two substances— to stimulate somatostatin release. In it stores two hormones—vasopressin and noradrenaline—that are released addition, GH release is enhanced by and oxytocin—that are produced as part of the fight-or-flight response stress, such as low blood sugar levels by neurons in the hypothalamus. to various stress factors. (i.e., ) or severe , Both hormones collect at the ends The primary in and by the onset of deep sleep. of the neurons, which are located is cortisol (also called hydro- Acute and chronic alcohol consump- in the hypothalamus and extend to ), which helps control carbo- tion have been shown to reduce the levels the posterior pituitary. hydrate, protein, and . of GH and IGF-1 in the blood. Both Vasopressin, also called vaso- For example, cortisol increases glucose effects have been observed in as pressin (AVP), plays an important role levels in the blood by stimulating glu- well as in humans. Acute alcohol admin- in the body’s water and electrolyte econ- coneogenesis in the liver and promotes istration also reduces GH secretion in omy. Thus, AVP release promotes the the formation of (i.e., a mole- response to other stimuli that normally of water from the urine cule that serves as the storage form of enhance the hormone’s release. Those in the kidneys. Through this mech- glucose) in the liver. Cortisol also reduces deleterious effects of alcohol may be anism, the body reduces urine volume glucose uptake into muscle and adipose particularly harmful to adolescents, who and conserves water. AVP release from tissue, thereby opposing the effects of

158 Alcohol Health & Research World The Endocrine System

insulin. Furthermore, in various tissues, testes). Second, the gonads synthesize of estrogens include regulating the cortisol promotes protein and lipid steroid sex hormones that are necessary , contributing to the breakdown into products (i.e., amino for the development and function of hormonal regulation of pregnancy and acids and glycerol, respectively) that can both female and male reproductive lactation, and maintaining female libido. be used for . organs and secondary sex characteris- (For more information on the menstrual In addition to those metabolic activ- tics (e.g., the adult distribution of cycle and alcohol’s effects on it, see the ities, cortisol appears to protect the , such as facial hair in men) article by Dees and colleagues, pp. 165– body against the deleterious effects of as well as for pregnancy, childbirth, 169. For more information on alcohol’s various stress factors, including acute and lactation. Three types of sex effects on the developing , see the trauma, major , severe , hormones exist; each with different article by Gabriel and colleagues, pp. pain, blood loss, hypoglycemia, and functions: (1) estrogens (e.g., ), 170–177.) emotional stress. All of these stress which exert feminizing effects; (2) During , estrogen pro- factors lead to drastic increases in the (e.g., ), duction in the ovaries ceases. The result- cortisol levels in the blood. For people which affect the uterus in preparation ing reduction in estrogen levels leads to in whom cortisol levels cannot increase for and during pregnancy; and (3) symptoms such as hot flashes, sweating, (e.g., because they had their adrenal (e.g., testosterone), which pounding of the heart (i.e., ), glands removed), even mild stress exert masculinizing effects. In addition increased irritability, anxiety, depression, can be fatal. Finally, high doses of to the reproductive functions, sex and brittle bones (i.e., ). The cortisol and other corticosteroids can hormones play numerous essential administration of estrogens (i.e., hormone be used medically to suppress tissue roles throughout the body. For exam- replacement ) can alleviate those in response to ple, they affect the metabolism of symptoms and reduce the risk of osteo- and to reduce the immune response and lipids, the cardio- porosis and coronary heart disease in to foreign molecules. vascular system, and bone growth postmenopausal women. At the same The primary in and development. time, however, hormone replacement humans is , which also therapy may increase the risk of certain helps regulate the body’s water and Estrogens types of (e.g., and electrolyte balance. Its principal func- uterine [i.e., endometrial] cancer). tions are to conserve sodium and to The major estrogen is estradiol, which, Alcohol consumption has been shown excrete from the body. For in addition to small amounts of to increase estrogen levels in the blood example, aldosterone promotes the and , is produced primarily in and urine, even in premenopausal reabsorption of sodium in the , the ovaries. Other production sites of women who drink two drinks or less thereby reducing water and estrogens include the corpus luteum,2 per day (Reichman et al. 1993) and in increasing blood volume. Similarly, aldo- the , and the adrenal glands. postmenopausal women who drink less sterone decreases the ratio of sodium In men and postmenopausal women, than one drink per day (Gavaler and to potassium concentrations in sweat most estrogens present in the circula- Van Thiel 1992). These findings suggest and saliva, thereby preventing sodium tion are derived from the conversion that moderate alcohol consumption may loss via those routes. The effect can be of testicular, adrenal, and ovarian help prevent osteoporosis and coronary highly beneficial in hot climates, where androgens. The conversion occurs in heart disease in postmenopausal women. much sweating occurs. peripheral tissues, primarily adipose Other studies, however, have detected In contrast to the glucocorticoids, tissue and . no consistent association between alc- pituitary, or hypothalamic, hormones The main role of estrogens is to coor- hol consumption and increased estrogen do not regulate aldosterone release. dinate the normal development and levels (Dorgan et al. 1994; Purohit 1998). Instead, it is controlled primarily by functioning of the female genitalia and (For more information on the effects of another hormone system, the - . During puberty, estrogens pro- alcohol on postmenopausal women, see system, which also controls mote the growth of the uterus, breasts, the articles by Longnecker and Tseng, kidney function. In addition, the levels and ; determine the pattern of pp. 185–189, and Gavaler, pp. 220–227.) of sodium and potassium in the blood fat deposition and distribution in the influence aldosterone levels. body that results in the typical female Progestogens shape; regulate the pubertal growth spurt and cessation of growth at adult The ovaries produce progestogens dur- The Gonads and Their height; and control the development ing a certain phase of the menstrual Hormones of secondary sexual characteristics. In cycle and in the placenta for most of adult women, the primary functions pregnancy. Progestogens cause changes The gonads (i.e., the ovaries and testes) in the uterine lining in preparation serve two major functions. First, they 2The corpus luteum is a group of cells derived for pregnancy and—together with produce the germ cells (i.e., ova in from the follicle that releases the ovum during a estrogens—stimulate the development the ovaries and spermatozoa in the particular menstrual cycle. of the mammary glands in the breasts

Vol. 22, No. 3, 1998 159 in preparation for lactation. The pri- are iodinated derivatives of the amino an adequate supply of calcium, which is mary is progesterone. acid . Both hormones are collec- needed for numerous functions through- tively referred to as “thyroid hormone.” out the body (e.g., muscle movement Androgens T4 constitutes approximately 90 percent and signal transmission within cells). of the hormone produced in the thyroid Specifically, PTH causes reabsorption The principal androgenic steroid is tes- gland. However, T3 is a much more of calcium from and excretion of phos- tosterone, which is secreted primarily active hormone, and most of the T4 phate in the urine. PTH also promotes from the testes but also, in small produced by the thyroid is converted the release of stored calcium from the amounts, from the adrenal glands (both into T3 in the liver and kidneys. bones as well as , both in men and women) and from the Thyroid hormone in general serves to of which increase calcium levels in the ovaries. Its main function is to stimulate increase the metabolism of almost all body blood. Finally, PTH stimulates the the development and growth of the male tissues. For example, thyroid hormone absorption of calcium from the genital tract. In addition, testosterone stimulates the production of certain pro- in the . Consistent has strong protein anabolic activities— teins involved in heat generation in the with PTH’s central role in calcium meta- that is, it promotes protein generation, body, a function that is essential for main- bolism, the release of this hormone is which leads to increased muscle mass. taining body temperature in cold climates. not controlled by pituitary hormones The specific functions of testosterone Moreover, thyroid hormone promotes but by the calcium levels in the blood. vary during different developmental several other metabolic processes involv- Thus, low calcium levels stimulate PTH stages, as follows: ing carbohydrates, proteins, and lipids release, whereas high calcium levels that help generate the energy required suppress it. • In the fetus, testosterone primarily for the body’s functions. In addition to Many of the functions of PTH require ensures the development of the those metabolic effects, thyroid hormone or are facilitated by a substance called internal and external male genitalia plays an essential role in the development 1,25-dihydroxycholecalciferol, a deriva- of the central nervous system during late tive of . In addition, numerous • During puberty, testosterone pro- fetal and early postnatal developmental other hormones are involved in regulat- motes the growth of the male sex stages. Furthermore, thyroid hormone ing the body’s calcium levels and bone organs and is responsible for other exerts an effect similar to that of GH on metabolism, including estrogens, glu- male developmental characteristics, normal bone growth and maturation. cocorticoids, and growth hormone. (For such as the pubertal growth spurt Finally, thyroid hormone is required for more information on the hormonal and eventual cessation of growth at the normal development of teeth, skin, control of bone and calcium metabolism adult height; deepening of the voice; and hair follicles as well as for the func- and on alcohol’s effects on those systems, growth of facial, pubic, axillary, and tioning of the nervous, cardiovascular, see the article by Sampson, pp. 190–194.) body hair; and increase in muscular- and gastrointestinal systems. ity and strength In addition to thyroid hormone, cer- tain cells (i.e., parafollicular C cells) in The Pancreas and Its • In the adult male, testosterone pri- the thyroid gland produce calcitonin, a Hormones marily serves to maintain masculinity, hormone that helps maintain normal libido, and sexual potency as well as calcium levels in the blood. Specifically, The pancreas is located in the , regulate sperm production. Testos- calcitonin lowers calcium levels in the behind the , and serves two terone levels decline slightly with blood by reducing the release of calcium distinctly different functions. First, it age, although the drop is not as dras- from the bones; inhibiting the constant acts as an exocrine , because the tic as the reduction in estrogen levels erosion of bones (i.e., bone resorption), majority of pancreatic cells produce in women during menopause. (For which also releases calcium; and inhibiting various digestive that are information on alcohol’s effects on the reabsorption of calcium in the kidneys. secreted into the gut and which are male reproduction, see the article by Those effects are opposite to those of essential for the effective of Emanuele and Emanuele, pp.195–201.) parathyroid hormone (PTH), which is food. Second, the pancreas serves as an discussed in the following section. endocrine organ, because certain cell clusters (i.e., the Islets of Langerhans) The Thyroid and Its produce two hormones—insulin and Hormones The Parathyroid Glands glucagon—that are released into the and Their Hormones blood and play pivotal roles in blood The thyroid gland, which consists of two glucose regulation. lobes, is located in front of the windpipe The parathyroid glands are four pea- (i.e., ), just below the voice box sized bodies located behind the thyroid Insulin (i.e., ). The gland produces two gland that produce PTH. This hormone structurally related hormones, thyroxine increases calcium levels in the blood, Insulin is produced in the beta cells of the (T4) and triiodothyronine (T3), that helping to maintain bone quality and Islets of Langerhans. Its primary purpose

160 Alcohol Health & Research World The Endocrine System

is to lower blood glucose levels; in fact, for maintaining blood sugar levels. Thus, increased cortisol levels repress insulin is the only blood sugar-lowering Accordingly, disturbances of that balance, CRH release by the hypothalamus hormone in the body. To this end, insulin such as an insulin deficiency or an inabil- and ACTH release by the pituitary. In promotes the formation of storage forms ity of the body to respond adequately to addition, ACTH can directly inhibit of energy (e.g., glycogen, proteins, and insulin, result in serious disorders, such as hypothalamic CRH release. lipids) and suppresses the breakdown of mellitus. (For more information Any disturbances in the HPA axis those stored nutrients. Accordingly, the on diabetes and on alcohol’s effects on can result in serious medical conse- target organs of insulin are primarily those insulin, glucagon, and the management quences. For example, insufficient that are specialized for energy storage, such of diabetes, see the article by Emanuele hormone production by the adrenal as the liver, muscles, and adipose tissue. and colleagues, pp. 211–219.) cortex causes Addison’s disease, which Specifically, insulin has the following is characterized by muscle weakness, metabolic effects: dehydration, loss of appetite (i.e., Hormone Systems anorexia), nausea, vomiting, , • Promotes glucose uptake into cells , abdominal pain, tiredness, and and its conversion into glycogen, As this article has indicated in describ- malaise. Patients with this disease stimulates the breakdown of glucose, ing the various endocrine glands and exhibit low levels of plasma cortisol and inhibits gluconeogenesis their hormones, some hormones are but high levels of ACTH. The increase controlled directly by the metabolic in ACTH levels represents a vain • Stimulates the transport of amino pathways that they influence. For attempt by the pituitary to stimulate acids into cells and protein synthesis example, blood sugar levels directly hormone production in the unrespon- in muscle cells, thereby lowering the control insulin and glucagon release sive adrenal cortex. levels of amino acids available for by the pancreas, and calcium levels Equally deleterious is the excessive gluconeogenesis in the liver in the blood regulate PTH release. glucocorticoid production that results Conversely, many hormones produced from excess ACTH release (i.e., Cushing’s • Increases fat synthesis in the liver by target glands are regulated by pituitary syndrome). Those patients experience and adipose tissue, thereby lower- hormones, which in turn are controlled symptoms such as muscle weakness ing the levels of glycerol, which by hypothalamic hormones. Examples and wasting, back pain from osteoporo- also can serve as a starting material of such regulatory hormonal cascades sis, a tendency to bruise easily, redis- for gluconeogenesis. include the hypothalamic-pituitary- tribution of body fat (i.e., a rounded adrenal (HPA) axis, the hypothalamic- “moon” face, prominent abdomen, The release of insulin is controlled pituitary-gonadal (HPG) axis, and the and thin legs), and various psycholog- by various factors, including blood hypothalamic-pituitary-thyroidal (HPT) ical disturbances. Because of the nega- glucose levels; other islet hormones axis, which are described briefly in the tive feedback mechanism of the HPA (e.g., glucagon); and, indirectly, other following sections (see figure 3, p.162). axis, the patient’s cortisol levels are hormones that alter blood glucose high and the ACTH levels are low. levels (e.g., GH, glucocorticoids, and The HPA Axis Both acute and chronic alcohol thyroid hormone). consumption have been shown to acti- Activation of the HPA axis, which vate the HPA axis, and some drinkers Glucagon regulates various metabolic functions, develop a so-called pseudo-Cushing’s is initiated with the release of CRH syndrome that disappears with absti- The second blood-sugar–regulating from the hypothalamus. This release nence (Veldman and Meinders 1996; pancreatic hormone is glucagon, which occurs in response to various stimuli, Emanuele and Emanuele 1997). (For is produced in the alpha cells of the Islets including almost any type of physical more information on alcohol’s effect on of Langerhans. Glucagon increases blood or ; during the nor- the HPA axis and its relation to alcohol glucose levels; accordingly, its main actions mal sleep-wake cycle; and in response craving, see the article by Gianoulakis, generally are opposite to those of insulin. to certain neurotransmitters. CRH pp. 202–210.) For example, glucagon increases glyco- then stimulates the anterior pituitary gen breakdown and gluconeogenesis in to produce ACTH. (In addition to The HPG Axis the liver as well as the breakdown of lipids CRH, AVP from the hypothalamus and proteins. The release of glucagon is also can stimulate ACTH release). In both men and women, the HPG regulated by many of the same factors ACTH, in turn, activates adrenal axis is the hormone system that controls as is insulin’s release, but sometimes with hormone production, primarily the release of sex hormones. In both the opposite effect. Thus, an increase in of cortisol, which mediates the genders, the system is activated by blood glucose levels stimulates insulin specific physiological effects of this GnRH, which is released regularly in release but inhibits glucagon release. hormone system. short bursts from the hypothalamus. A finely tuned balance between the act- The activity of the HPA axis is regu- GnRH then stimulates the release of ivities of insulin and glucagon is essential lated by negative feedback mechanisms. FSH and LH from the anterior pituitary.

Vol. 22, No. 3, 1998 161 HPA Axis HPT Axis

+ Stress

Hypothalamus Hypothalamus + + CRH TRH

Anterior Anterior pituitary pituitary

+ TSH ACTH

Thyroid Adrenal gland

+ Kidney

+ T4 , T3 Cortisol

Increases Metabolic metabolism effects

Female HPG Axis Male HPG Axis

Hypothalamus Hypothalamus + + GnRH GnRH

Anterior Anterior pituitary pituitary

/ + + + + / LH FSH LH FSH

+ +

Ovaries Testes + +

Estrogen Progesterone Testosterone

Figure 3 Schematic representation of the HPA, HPG, and HPT axes. For each system, the hypothalamus secretes releasing hormones (i.e., CRH, GnRH, and TRH) that act on the pituitary gland. In response to those stimuli, the pituitary gland releases ACTH, gonadotropins (i.e., LH and FSH), or TSH. ACTH activates the adrenal glands to release cortisol, which induces metabolic effects. Cortisol also acts back on the hypothalamus and pituitary gland by negative feedback. LH and FSH in women stimulate the ovaries to produce estrogens and progesterone. Depending on the phase of the men- strual cycle, those hormones act back on the hypothalamus and pituitary gland in either a stimulatory or inhibitory - ner. In men, LH stimulates the testes to release testosterone, which feeds back on the hypothalamus and pituitary. Finally, TSH stimulates the thyroid gland to produce the T3 and T4, both of which increase cell metabolism as well as feed back on the hypothalamus and pituitary.

NOTE: = stimulates; = inhibits; ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; HPA = hypothalamic-pituitary-adrenal; HPG = hypothalamic-pituitary-gonadal; HPT = hypothalamic-pituitary-thyroid; LH = luteinizing hormone; T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.

162 Alcohol Health & Research World The Endocrine System

Alcohol’s Effects on the Hypothalamic-Pituitary-Thyroid Axis

One of the essential hormonal systems regulating normal if this change represents a direct effect of long-term body functioning is the hypothalamic-pituitary-thyroid alcohol consumption or results from co-occurring (HPT) axis, which controls the metabolism of all cells. As alcohol-related illnesses, because thyroid hormone with other hormone systems, alcohol consumption under levels are often reduced in patients with acute or chronic certain conditions can modify the release of hormones non-thyroid–related illnesses, such as sepsis, , or involved in this axis. In healthy nonalcoholics, alcohol major trauma. In addition to the reduced thyroid consumption does not appear to induce any significant hormone levels, however, the TSH response to TRH changes in the HPT axis (Emanuele and Emanuele remains blunted in abstinent alcoholics, whereas the pro- 1997). Conversely, some effects of alcohol on the HPT lactin response to TRH has returned to normal levels. axis have been observed in alcoholics. The effects differ This observation indicates that a factor other than dopa- depending on the drinking status of the alcoholics mine likely contributes to this effect, although the exact studied. In alcoholics undergoing withdrawal, baseline mechanisms are unknown. levels of thyroid hormone (i.e., T3 and T4) in the blood Finally, some intriguing findings have suggested that differ only minimally from those in nonalcoholics. The abnormal responses of the HPT axis may represent a ability of hypothalamic thyrotropin-releasing hormone marker for a person’s vulnerability to alcoholism. Thus, (TRH) to activate the release of thyroid-stimulating some people who are at high risk for developing alcoholism, hormone (TSH) from the pituitary, however, is impaired such as nonalcoholic sons of alcoholic fathers, tend to in these alcoholics (Emanuele and Emanuele 1997). exhibit a blunted TSH response to TRH (Emanuele and This “blunting” effect may result from alcohol’s influence Emanuele 1997). These observations still require further on the neurotransmitter dopamine. Dopamine produced investigation, however, for researchers to fully understand in the hypothalamus acts not only as a neurotransmitter their significance. but also as a hormone in that it inhibits the release of —Susanne Hiller-Sturmhöfel and Andrzej Bartke both TSH and prolactin from the pituitary. Alcohol has been shown to increase dopaminergic activity and thereby may suppress the TSH response to TRH. This References hypothesis is supported by the fact that prolactin release EMANUELE, N., AND EMANUELE, M.A. The endocrine system: Alcohol alters critical hormonal balance. Alcohol Health & Research World in response to TRH also is blunted in alcoholics under- 21(1):53–64, 1997. going withdrawal. Alcohol’s effects on the HPT axis are even more com- GARBUTT, J.C.; SILVA, S.G.; AND MASON, G.A. Thyrotropin-releasing hormone (TRH): Clinical neuroendocrine and neurobehavioral findings plex in abstinent alcoholics (Garbutt et al. 1995). In of relevance to alcoholism. In: Watson, R.R., ed. and Alcohol Abuse those people, the baseline levels of T3 and sometimes Reviews: Volume 6. Alcohol and Hormones. Totowa, NJ: Humana Press, T4 are lower than in nonalcoholics. It is unclear, however, 1995. pp. 127–145.

In men, LH stimulates certain substance called inhibin, which luteum. Both hormones participate cells in the testes (i.e., Leydig cells) prevents FSH release from the in a negative feedback mechanism to release testosterone. FSH and pituitary. Finally, the Leydig cells through most of the menstrual cycle, testosterone are key regulators of and, to a lesser extent, the Sertoli suppressing GnRH release from another set of testicular cells (i.e., cells produce a substance called the hypothalamus and LH release Sertoli cells), which support and activin, which stimulates FSH from the pituitary. Shortly before nourish the sperm cells during their secretion and thus has the opposite ovulation, however, a positive feed- maturation. The HPG axis in men effects of inhibin. back mechanism is activated by is regulated through a variety of In women, during the menstrual which estradiol actually enhances factors. For example, testosterone cycle, LH and FSH stimulate the LH release from the pituitary. The is part of a negative feedback ovarian follicle that contains the resulting surge in LH levels ultimately mechanism that inhibits GnRH maturing egg to produce estradiol. leads to ovulation, the formation of release by the hypothalamus and After ovulation has occurred, LH the corpus luteum, and progesterone LH release by the pituitary. In also promotes production of proges- release. Progesterone exerts a negative addition, the Sertoli cells secrete a terone and estradiol by the corpus feedback on LH and FSH release,

Vol. 22, No. 3, 1998 163 causing LH levels to decline again. In Summary References addition to those mechanisms, FSH CONSTANTI, A.; BARTKE, A.; AND KHARDORI, R. release from the pituitary is regulated The neuroendocrine system is a Basic Endocrinology for Students of and by inhibin, a substance produced by highly complex and tightly controlled Allied Clinical Health Sciences. Amsterdam: Harwood certain cells in the ovarian follicle. network of hormones released by Academic Publishers, 1998. Both acute and chronic alcohol con- endocrine glands throughout the DORGAN, J.F.; REICHMAN, M.E.; JUDD, J.T.; BROWN, sumption can interfere with the normal body. The levels of some of the C.; LONGCOPE, C.; SCHATZKIN, A.; CAMPBELL, functioning of the HPG axis, resulting hormones are regulated in a fairly W.S.; FRANZ, C.; KAHLE, L.; AND TAYLOR, P.R. straightforward manner by the end Relation of reported alcohol ingestion to plasma in reduced or even levels of estrogens and androgens in premenopausal in both men and women and in men- products that they influence. Thus, women (Maryland, United States). Cancer Causes strual disturbances in women. (For more blood sugar levels primarily regulate and Control 5(1):53–60, 1994. insulin and glucagon release by the information on alcohol’s effects on the EMANUELE, N., AND EMANUELE, M.A. The endocrine HPG axis in women and men, see the pancreas. Other hormones (e.g., those system: Alcohol alters critical hormonal balance. articles by Dees and colleagues, pp. 165– of the HPA, HPG, and HPT axes) Alcohol Health & Research World 21(1):53–64, 1997. are parts of hormone cascades whose 169, and by Emanuele and Emanuele, GAVALER, J.S., AND VAN THIEL, D.H. The associ- activities are controlled through pp. 195–201.) ation between moderate alcoholic beverage consump- elaborate feedback mechanisms. In tion and estradiol and testosterone levels in addition, numerous indirect inter- normal postmenopausal women: Relationship to the The HPT Axis actions exist between the various literature. Alcoholism: Clinical and Experimental hormone systems governing body Research 16(1):87–92, 1992. The hormones that make up the HPT functioning. For example, hormones PUROHIT, V. Moderate alcohol consumption and axis control the metabolic processes such as GH and thyroid hormone, estrogen levels in postmenopausal women: A review. of all cells in the body and are there- Alcoholism: Clinical and Experimental Research through their effects on cellular meta- 22(5):994–997, 1998. fore crucial for the organism to func- bolism, may modify blood sugar lev- tion normally. The secretion of TRH els and, accordingly, insulin release. REICHMAN, M.E.; JUDD, J.T.; LONGCOPE, C.; from the hypothalamus activates the SCHATZKIN, A.; CLEVIDENCE, B.A.; NAIR, P.P.; Similarly, alcohol’s effects on one CAMPBELL, W.S.; AND TAYLOR, P.R. Effects of HPT axis. After reaching the pitu- hormone system may have indirect alcohol consumption on plasma and urinary hor- itary, TRH stimulates the release consequences for other systems, thereby mone concentrations in premenopausal women. of TSH, which in turn promotes the contributing to alcohol’s influences Journal of the National Cancer Institute 85(9): 722–727, 1993. production and release of T4 and T3 on the functioning of virtually every by the thyroid gland. Negative feed- organ in the body. It is important to VELDMAN, R.G., AND MEINDERS, A.E. On the mechanism of alcohol-induced pseudo-Cushing’s back effects of T4 and T3 on both keep this interconnectedness of neu- syndrome. Endocrine Reviews 17:262–268, 1996. the hypothalamus and the pituitary roendocrine systems in mind when regulate the HPT system. (For a analyzing alcohol’s impact on various WILSON, J.D.; FOSTER, D.W.; KRONENBERG, H.M.; AND LARSEN, P.R., EDS. Williams Textbook summary of alcohol’s effects on the hormones, which are described in of Endocrinology. 9th ed. Philadelphia: W.B. HPT axis, see sidebar, p. 163.) the remaining articles in this issue. Saunders, 1998.

164 Alcohol Health & Research World