endo overview

The Endocrine System

An Overview

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

A plethora of hormones regulate many of the body’s functions, including growth anddevelopment, metabolism, electrolyte balances, and reproduction. Numerous glandsthroughout the body produce hormones. The hypothalamus produces several releasing andinhibiting hormones that act on the pituitary gland, stimulating the release of pituitaryhormones. Of the pituitary hormones, several act on other glands located in various regionsof the body, whereas other pituitary hormones directly affect their target organs. Otherhormone-producing glands throughout the body include the adrenal glands, which primarilyproduce cortisol; the gonads (i.e., ovaries and testes), which produce sex hormones; thethyroid, which produces thyroid hormone; the parathyroid, which produces parathyroidhormone; and the pancreas, which produces insulin and glucagon. Many of these hormonesare part of regulatory hormonal cascades involving a hypothalamic hormone, one or morepituitary hormones, and one or more target gland hormones. KEY WORDS: endocrine function;hormones; hypothalamus; pituitary gland; gonad function; thyroid; parathyroid; pancreas;biochemical mechanism; biological feedback; biological regulation; hypothalamus-pituitaryaxis; pituitary-adrenal axis; pituitary-thyroid axis; literature review

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For the body to function properly,its various parts and organs mustcommunicate with each other to

ensure that a constant internal environ-ment (i.e., homeostasis) is maintained.For example, neither the body temper-ature nor the levels of salts and minerals(i.e., electrolytes) in the blood mustfluctuate beyond preset limits. Com-munication among various regions ofthe body also is essential for enablingthe organism to respond appropriatelyto any changes in the internal andexternal environments. Two systemshelp ensure communication: the nervoussystem and the hormonal (i.e., neuroen-docrine) system. The nervous systemgenerally allows rapid transmission

(i.e., within fractions of seconds) ofinformation between different bodyregions. Conversely, hormonal commu-nication, which relies on the productionand release of hormones from variousglands and on the transport of thosehormones via the bloodstream, is bettersuited for situations that require morewidespread and longer lasting regulatoryactions. Thus, the two communicationsystems complement each other. Inaddition, both systems interact: Stimulifrom the nervous system can influencethe release of certain hormones andvice versa.

Generally speaking, hormones con-trol the growth, development, andmetabolism of the body; the electrolyte

composition of bodily fluids; and repro-duction. This article provides anoverview of the hormone systemsinvolved in those regulatory processes.The article first summarizes some of thebasic characteristics of hormone-mediated communication within thebody, then reviews the various glandsinvolved in those processes and the

SUSANNE HILLER-STURMHÖFEL, PH.D.,is a science editor of Alcohol Health &Research World.

ANDRZEJ BARTKE, PH.D., is professorand chairman of physiology at SouthernIllinois University School of Medicine,Carbondale, Illinois.

major hormones they produce. Formore in-depth information on thosehormones, the reader should consultendocrinology textbooks (e.g., Con-stanti et al. 1998; Wilson et al. 1998).Finally, the article presents variousendocrine systems in which hormonesproduced in several organs cooperateto achieve the desired regulatory effects.The discussions focus primarily onthe system responses in normal, healthypeople. For information regardingalcohol’s effects on some of the hormonesystems, the reader is referred to sub-sequent articles in this issue of AlcoholHealth & Research World.

What Are Hormones?

Hormones are molecules that are pro-duced by endocrine glands, includingthe hypothalamus, pituitary gland,adrenal glands, gonads, (i.e., testes and ovaries), thyroid gland, parathyroidglands, and pancreas (see figure 1). The term “endocrine” implies that inresponse to specific stimuli, the productsof those glands are released into thebloodstream.1 The hormones then arecarried via the blood to their targetcells. Some hormones have only a fewspecific target cells, whereas otherhormones affect numerous cell typesthroughout the body. The target cellsfor each hormone are characterized bythe presence of certain docking mole-cules (i.e., receptors) for the hormonethat are located either on the cell surfaceor inside the cell. The interactionbetween the hormone and its receptortriggers a cascade of biochemical reac-tions in the target cell that eventuallymodify the cell’s function or activity.

Mechanisms of Action

Several classes of hormones exist, includ-ing steroids, amino acid derivatives,and polypeptides and proteins. Thosehormone classes differ in their general

molecular structures (e.g., size andchemical properties). As a result of thestructural differences, their mechanismsof action (e.g., whether they can entertheir target cells and how they modulatethe activity of those cells) also differ.Steroids, which are produced by thegonads and part of the adrenal gland(i.e., the adrenal cortex), have a molecularstructure similar to that of cholesterol.The molecules can enter their targetcells and interact with receptors in thefluid that fills the cell (i.e., the cytoplasm)

or in the cell nucleus. The hormone-receptor complexes then bind to certainregions of the cell’s genetic material (i.e.,the DNA), thereby regulating the activ-ity of specific hormone-responsive genes.

Amino acid derivatives are modi-fied versions of some of the buildingblocks of proteins. The thyroid glandand another region of the adrenalglands (i.e., the adrenal medulla) pro-duce this type of hormone (i.e., theamino acid derivatives). Like steroids,amino acid derivatives can enter the

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1Conversely, exocrine glands (e.g., sweat glandsand salivary glands) release their secretions to theoutside of the body (e.g., sweat) or into a hollowspace that is open to the outside (e.g., salivareleased into the mouth).

Hypothalamus

Pituitary glandThyroid gland

Parathyroid gland

Testis (in male)

Pancreas(Islets of Langerhans)

Adrenal gland

Ovary(in female)

Figure 1 Schematic representation of the location of the major hormone-producing(i.e., endocrine) organs in the body. (For the purposes of illustration, bothmale and female endocrine organs are presented here.)

cell, where they interact with receptorproteins that are already associatedwith specific DNA regions. Theinteraction modifies the activity ofthe affected genes.

Polypeptide and protein hormonesare chains of amino acids of variouslengths (from three to several hundredamino acids). These hormones arefound primarily in the hypothalamus,pituitary gland, and pancreas. In someinstances, they are derived from inactiveprecursors, or pro-hormones, whichcan be cleaved into one or more activehormones. Because of their chemicalstructure, the polypeptide and proteinhormones cannot enter cells. Instead,they interact with receptors on the

cell surface. The interaction initiatesbiochemical changes in either the cell’smembrane or interior, eventually mod-ifying the cell’s activity or function.

Regulation of Hormone Activity

To maintain the body’s homeostasisand respond appropriately to changesin the environment, hormone produc-tion and secretion must be tightlycontrolled. To achieve this control,many bodily functions are regulatednot by a single hormone but by severalhormones that regulate each other (see figure 2). For example, for manyhormone systems, the hypothalamussecretes so-called releasing hormones,

which are transported via the blood tothe pituitary gland. There, the releasinghormones induce the production andsecretion of pituitary hormones, whichin turn are transported by the blood totheir target glands (e.g., the adrenalglands, gonads, or thyroid). In thoseglands, the interaction of the pituitaryhormones with their respective targetcells results in the release of the hormonesthat ultimately influence the organstargeted by the hormone cascade.

Constant feedback from the targetglands to the hypothalamus and pitu-itary gland ensures that the activity ofthe hormone system involved remainswithin appropriate boundaries. Thus,in most cases, negative feedback mech-anisms exist by which hormonesreleased by the target glands affectthe pituitary gland and/or hypo-thalamus (see figure 2). When certainpredetermined blood levels of thosehormones are reached, the hypothala-mus and/or the pituitary ceaseshormone release, thereby turning off the cascade. In some instances, aso-called short-loop feedback occurs,in which pituitary hormones directlyact back on the hypothalamus.

The sensitivity with which thesenegative feedback systems operate(i.e., the target hormone levels thatare required to turn off hypothalamicor pituitary hormone release) canchange at different physiological statesor stages of life. For example, theprogressive reduction in sensitivity of the hypothalamus and pituitary tonegative feedback by gonadal steroidhormones plays an important role insexual maturation.

Although negative feedback ismore common, some hormone systems are controlled by positivefeedback mechanisms, in which atarget gland hormone acts back onthe hypothalamus and/or pituitary to increase the release of hormonesthat stimulate the secretion of thetarget gland hormone. One suchmechanism occurs during a woman’smenstrual period: Increasing estrogenlevels in the blood temporarily stimulate, rather than inhibit, hormonerelease from the pituitary and hypo-thalamus, thereby further increasing

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Releasing hormone

Pituitary hormone

Target gland hormone

Short-loop feedback

Hypothalamus

Figure 2 Schematic representation of negative feedback mechanisms that controlendocrine system activity. In many cases, the hormones released from thetarget gland act back on the pituitary and/or hypothalamus, repressingfurther hormone release from both organs and thereby shutting off thesystem. For a short-loop negative feedback mechanism, pituitary hormonesact directly back on the hypothalamus, inhibiting the release of hypothalamichormones.

NOTE: + = stimulates; – = inhibits.

Anterior pituitary

Target gland


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 adrenocorticotropichormone (ACTH)

Gonadotropin-releasing hormone (GnRH) Stimulates the pituitary to release luteinizing hormone (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 growth hormone (GH) from the(GHRH) pituitary

Somatostatin Inhibits the release of GH from the pituitary

Dopamine Inhibits the release of prolactin from the pituitary

Anterior pituitary gland ACTH Stimulates the release of hormones from the adrenal cortex

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

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

TSH Stimulates the release of thyroid hormone

GH Promotes the body’s growth and development

Prolactin Controls milk production (i.e., lactation)

Posterior pituitary gland1

Vasopressin Helps control the body’s water and electrolyte levels

Oxytocin Promotes uterine contraction during labor and activatesmilk ejection in nursing women

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

Aldosterone Helps control the body’s water and electrolyte regulation

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

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

Progesterone (produced by the Prepares uterus for pregnancy and mammary glands for corpus luteum) lactation

Thyroid gland Thyroid hormone (i.e., thyroxine [T4] Controls metabolic processes in all cellsand triiodothyronine [T3])

Calcitonin Helps control calcium metabolism (i.e., lowers calcium levels in the blood)

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

Pancreas Insulin Helps control carbohydrate metabolism (i.e., lowers bloodsugar levels)

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

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

estrogen levels and eventually lead-ing to ovulation. Such a mechanismrequires a specific threshold level,however, at which the positive feed-back loop is turned off in order tomaintain a stable system.

The Hypothalamus and Its Hormones

The hypothalamus is a small regionlocated within the brain that controlsmany bodily functions, including eating and drinking, sexual functionsand behaviors, blood pressure and heartrate, body temperature maintenance,the sleep-wake cycle, and emotionalstates (e.g., fear, pain, anger, and pleasure). Hypothalamic hormonesplay pivotal roles in the regulation ofmany of those functions.

Because the hypothalamus is part ofthe central nervous system, the hypothal-amic hormones actually are producedby nerve cells (i.e., neurons). In addition,because signals from other neuronscan modulate the release of hypothal-amic hormones, the hypothalamusserves as the major link between thenervous and endocrine systems. Forexample, the hypothalamus receivesinformation from higher brain centersthat respond to various environmentalsignals. Consequently, hypothalamicfunction is influenced by both theexternal and internal environments aswell as by hormone feedback. Stimulifrom the external environment thatindirectly influence hypothalamicfunction include the light-dark cycle;temperature; signals from other membersof the same species; and a wide varietyof visual, auditory, olfactory, and sensorystimuli. The communication betweenother brain areas and the hypothalamus,which conveys information about theinternal environment, involves electro-chemical signal transmission throughmolecules called neurotransmitters (e.g., aspartate, dopamine, gamma-aminobutyric acid, glutamate, norepin-ephrine, and serotonin). The complexinterplay of the actions of variousneurotransmitters regulates the pro-duction and release of hormones fromthe hypothalamus.

The hypothalamic hormones arereleased into blood vessels that connectthe hypothalamus and the pituitarygland (i.e., the hypothalamic-hypo-physeal portal system). Because theygenerally promote or inhibit the releaseof hormones from the pituitary gland,hypothalamic hormones are commonlycalled releasing or inhibiting hormones.The major releasing and inhibitinghormones include the following (alsosee table, p. 156):

• Corticotropin-releasing hormone(CRH), which is part of the hormonesystem regulating carbohydrate, pro-tein, and fat metabolism as well assodium and water balance in the body

• Gonadotropin-releasing hormone(GnRH), which helps controlsexual and reproductive functions,including pregnancy and lactation(i.e., milk production)

• Thyrotropin-releasing hormone(TRH), which is part of the hormonesystem controlling the metabolicprocesses of all cells and which con-tributes to the hormonal regulationof lactation

• Growth hormone-releasing hor-mone (GHRH), which is anessential component of the systempromoting the organism’s growth

• Somatostatin, which also affects boneand muscle growth but has theopposite effect as that of GHRH

• Dopamine, a substance that functionsprimarily as a neurotransmitter butalso has some hormonal effects,such as repressing lactation until itis needed after childbirth.

The Pituitary and ItsMajor Hormones

The pituitary (also sometimes calledthe hypophysis) is a gland about thesize of a small marble and is locatedin the brain directly below thehypothalamus. The pituitary gland

consists of two parts: the anteriorpituitary and the posterior pituitary.

The Anterior Pituitary

The anterior pituitary produces severalimportant hormones that either stimu-late target glands (e.g., the adrenalglands, gonads, or thyroid gland) toproduce target gland hormones ordirectly affect target organs. The pituitary hormones include adreno-corticotropic hormone (ACTH);gonadotropins; thyroid-stimulatinghormone (TSH), also called thyrotropin;growth hormone (GH); and prolactin.

The first three of those hormones—ACTH, gonadotropins, and TSH—act on other glands. Thus, ACTHstimulates the adrenal cortex to pro-duce corticosteroid hormones—primarily cortisol—as well as smallamounts of female and male sex hor-mones. The gonadotropins comprisetwo molecules, luteinizing hormone(LH) and follicle-stimulating hormone(FSH). These two hormones regulatethe production of female and male sexhormones in the ovaries and testes aswell as the production of the germcells—that is, the egg cells (i.e., ova)and sperm cells (i.e., spermatozoa).TSH stimulates the thyroid gland toproduce and release thyroid hormone.The remaining two pituitary hormones,GH and prolactin, directly affect theirtarget organs.

Growth Hormone. GH is the mostabundant of the pituitary hormones.As the name implies, it plays a pivotalrole in controlling the body’s growthand development. For example, itstimulates the linear growth of thebones; promotes the growth of inter-nal organs, fat (i.e., adipose) tissue,connective tissue, endocrine glands,and muscle; and controls the devel-opment of the reproductive organs.Accordingly, the GH levels in the blood are highest during earlychildhood and puberty and declinethereafter. Nevertheless, even rela-tively low GH levels still may beimportant later in life, and GH deficiency may contribute to somesymptoms of aging.


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In addition to its growth-promotingrole, GH affects carbohydrate, pro-tein, and fat (i.e., lipid) metabolism.Thus, GH increases the levels of thesugar glucose in the blood by reducingglucose uptake by muscle cells andadipose tissue and by promoting glu-cose production (i.e., gluconeogene-sis) from precursor molecules in theliver. (These actions are opposite tothose of the hormone insulin, whichis discussed in the section “The Pancreasand Its Hormones,” p. 160.) GH alsoenhances the uptake of amino acidsfrom the blood into cells, as well astheir incorporation into proteins, andstimulates the breakdown of lipids inadipose tissue.

To elicit these various effects, GHmodulates the activities of numeroustarget organs, including the liver, kid-neys, bone, cartilage, skeletal muscle,and adipose cells. For some of theseeffects, GH acts directly on the targetcells. In other cases, however, GH actsindirectly by stimulating the produc-tion of a molecule called insulin-likegrowth factor 1 (IGF-1) in the liverand kidneys. The blood then trans-ports IGF-1 to the target organs,where it binds to specific receptors onthe cells. This interaction then maylead to the increased DNA produc-tion and cell division that underliethe growth process.

Two hypothalamic hormones con-trol GH release: (1) GHRH, whichstimulates GH release, and (2) somato-statin, which inhibits GH release. Thisregulatory mechanism also involves ashort-loop feedback component, bywhich GH acts on the hypothalamusto stimulate somatostatin release. Inaddition, GH release is enhanced bystress, such as low blood sugar levels(i.e., hypoglycemia) or severe exercise,and by the onset of deep sleep.

Acute and chronic alcohol consump-tion have been shown to reduce the levelsof GH and IGF-1 in the blood. Botheffects have been observed in animals aswell as in humans. Acute alcohol admin-istration also reduces GH secretion inresponse to other stimuli that normallyenhance the hormone’s release. Thosedeleterious effects of alcohol may beparticularly harmful to adolescents, who

require GH for normal developmentand puberty. (For more information onalcohol’s effects on puberty and growth,see the article by Dees and colleagues,pp. 165–169.)

Prolactin. Together with other hor-mones, prolactin plays a central rolein the development of the female breastand in the initiation and maintenanceof lactation after childbirth. Prolactin’sfunction in men, however, is not wellunderstood, although excessive prolactinrelease can lead to reduced sex drive (i.e.,libido) and impotence. Several factorscontrol prolactin release from the ante-rior pituitary. For example, prolactinis released in increasing amounts inresponse to the rise in estrogen levelsin the blood that occurs during preg-nancy. In nursing women, prolactin isreleased in response to suckling by theinfant. Several releasing and inhibitoryfactors from the hypothalamus alsocontrol prolactin release. The mostimportant of those factors is dopamine,which has an inhibitory effect.

Alcohol consumption by nursingwomen can influence lactation boththrough its effects on the release ofprolactin and oxytocin (see the follow-ing section) and through its effects onthe milk-producing (i.e., mammary)glands and the composition of the milk.(For more information on alcohol’s effectson lactation, see the article by Heil andSubramanian, pp. 178–184.)

The Posterior Pituitary

The posterior pituitary does not produce its own hormones; instead,it stores two hormones—vasopressinand oxytocin—that are produced by neurons in the hypothalamus.Both hormones collect at the endsof the neurons, which are located in the hypothalamus and extend tothe posterior pituitary.

Vasopressin, also called arginine vaso-pressin (AVP), plays an important rolein the body’s water and electrolyte econ-omy. Thus, AVP release promotes thereabsorption of water from the urinein the kidneys. Through this mech-anism, the body reduces urine volumeand conserves water. AVP release from

the pituitary is controlled by the con-centration of sodium in the blood as wellas by blood volume and blood pressure.For example, high blood pressure orincreased blood volume results in theinhibition of AVP release. Consequently,more water is released with the urine,and both blood pressure and bloodvolume are reduced. Alcohol also hasbeen shown to inhibit AVP release.Conversely, certain other drugs (e.g.,nicotine and morphine) increase AVPrelease, as do severe pain, fear, nausea,and general anesthesia, thereby result-ing in lower urine production andwater retention.

Oxytocin, the second hormonestored in the posterior pituitary, stim-ulates the contractions of the uterusduring childbirth. In nursing women,the hormone activates milk ejectionin response to suckling by the infant(i.e., the so-called let-down reflex).

The Adrenal Glands and Their Hormones

The adrenal glands are small structureslocated on top of the kidneys. Struct-urally, they consist of an outer layer(i.e., the cortex) and an inner layer(i.e., the medulla). The adrenal cortexproduces numerous hormones, primar-ily corticosteroids (i.e., glucocorticoidsand mineralocorticoids). The cortex isalso the source of small amounts ofsex hormones; those amounts, however,are insignificant compared with theamounts normally produced by theovaries and testes. The adrenal medullagenerates two substances—adrenalineand noradrenaline—that are releasedas part of the fight-or-flight responseto various stress factors.

The primary glucocorticoid inhumans is cortisol (also called hydro-cortisone), which helps control carbo-hydrate, protein, and lipid metabolism.For example, cortisol increases glucoselevels in the blood by stimulating glu-coneogenesis in the liver and promotesthe formation of glycogen (i.e., a mole-cule that serves as the storage form ofglucose) in the liver. Cortisol also reducesglucose uptake into muscle and adiposetissue, thereby opposing the effects of


insulin. Furthermore, in various tissues,cortisol promotes protein and lipidbreakdown into products (i.e., aminoacids and glycerol, respectively) that canbe used for gluconeogenesis.

In addition to those metabolic activ-ities, cortisol appears to protect thebody against the deleterious effects ofvarious stress factors, including acutetrauma, major surgery, severe infections,pain, blood loss, hypoglycemia, andemotional stress. All of these stressfactors lead to drastic increases in thecortisol levels in the blood. For peoplein whom cortisol levels cannot increase(e.g., because they had their adrenalglands removed), even mild stress can be fatal. Finally, high doses of cortisol and other corticosteroids canbe used medically to suppress tissueinflammation in response to injuriesand to reduce the immune responseto foreign molecules.

The primary mineralocorticoid inhumans is aldosterone, which alsohelps regulate the body’s water andelectrolyte balance. Its principal func-tions are to conserve sodium and toexcrete potassium from the body. Forexample, aldosterone promotes thereabsorption of sodium in the kidney,thereby reducing water excretion andincreasing blood volume. Similarly, aldo-sterone decreases the ratio of sodiumto potassium concentrations in sweatand saliva, thereby preventing sodiumloss via those routes. The effect can behighly beneficial in hot climates, wheremuch sweating occurs.

In contrast to the glucocorticoids,pituitary, or hypothalamic, hormonesdo not regulate aldosterone release.Instead, it is controlled primarily byanother hormone system, the renin-angiotensin system, which also controlskidney function. In addition, the levelsof sodium and potassium in the bloodinfluence aldosterone levels.

The Gonads and TheirHormones

The gonads (i.e., the ovaries and testes)serve two major functions. First, theyproduce the germ cells (i.e., ova inthe ovaries and spermatozoa in the

testes). Second, the gonads synthesizesteroid sex hormones that are necessaryfor the development and function ofboth female and male reproductiveorgans and secondary sex characteris-tics (e.g., the adult distribution ofbody hair, such as facial hair in men)as well as for pregnancy, childbirth,and lactation. Three types of sexhormones exist; each with differentfunctions: (1) estrogens (e.g., estradiol),which exert feminizing effects; (2)progestogens (e.g., progesterone),which affect the uterus in preparationfor and during pregnancy; and (3)androgens (e.g., testosterone), whichexert masculinizing effects. In additionto the reproductive functions, sexhormones play numerous essentialroles throughout the body. For exam-ple, they affect the metabolism ofcarbohydrates and lipids, the cardio-vascular system, and bone growthand development.

Estrogens

The major estrogen is estradiol, which,in addition to small amounts of estroneand estriol, is produced primarily inthe ovaries. Other production sites ofestrogens include the corpus luteum,2the placenta, and the adrenal glands.In men and postmenopausal women,most estrogens present in the circula-tion are derived from the conversionof testicular, adrenal, and ovarianandrogens. The conversion occurs inperipheral tissues, primarily adiposetissue and skin.

The main role of estrogens is to coor-dinate the normal development andfunctioning of the female genitalia andbreasts. During puberty, estrogens pro-mote the growth of the uterus, breasts,and vagina; determine the pattern offat deposition and distribution in thebody that results in the typical femaleshape; regulate the pubertal growthspurt and cessation of growth at adultheight; and control the developmentof secondary sexual characteristics. Inadult women, the primary functions

of estrogens include regulating themenstrual cycle, contributing to thehormonal regulation of pregnancy andlactation, and maintaining female libido.(For more information on the menstrualcycle and alcohol’s effects on it, see thearticle by Dees and colleagues, pp. 165–169. For more information on alcohol’seffects on the developing fetus, see thearticle by Gabriel and colleagues, pp.170–177.)

During menopause, estrogen pro-duction in the ovaries ceases. The result-ing reduction in estrogen levels leads tosymptoms such as hot flashes, sweating,pounding of the heart (i.e., palpitations),increased irritability, anxiety, depression,and brittle bones (i.e., osteoporosis). Theadministration of estrogens (i.e., hormonereplacement therapy) can alleviate thosesymptoms and reduce the risk of osteo-porosis and coronary heart disease inpostmenopausal women. At the sametime, however, hormone replacementtherapy may increase the risk of certaintypes of cancer (e.g., breast cancer anduterine [i.e., endometrial] cancer).Alcohol consumption has been shownto increase estrogen levels in the bloodand urine, even in premenopausalwomen who drink two drinks or lessper day (Reichman et al. 1993) and inpostmenopausal women who drink lessthan one drink per day (Gavaler andVan Thiel 1992). These findings suggestthat moderate alcohol consumption mayhelp prevent osteoporosis and coronaryheart disease in postmenopausal women.Other studies, however, have detectedno consistent association between alc-hol consumption and increased estrogenlevels (Dorgan et al. 1994; Purohit 1998).(For more information on the effects ofalcohol on postmenopausal women, seethe articles by Longnecker and Tseng,pp. 185–189, and Gavaler, pp. 220–227.)

Progestogens

The ovaries produce progestogens dur-ing a certain phase of the menstrualcycle and in the placenta for most ofpregnancy. Progestogens cause changesin the uterine lining in preparationfor pregnancy and—together withestrogens—stimulate the developmentof the mammary glands in the breasts


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2The corpus luteum is a group of cells derivedfrom the follicle that releases the ovum during aparticular menstrual cycle.

in preparation for lactation. The pri-mary progestogen is progesterone.

Androgens

The principal androgenic steroid is tes-tosterone, which is secreted primarilyfrom the testes but also, in smallamounts, from the adrenal glands (bothin men and women) and from theovaries. Its main function is to stimulatethe development and growth of the malegenital tract. In addition, testosteronehas strong protein anabolic activities—that is, it promotes protein generation,which leads to increased muscle mass.The specific functions of testosteronevary during different developmentalstages, as follows:

• In the fetus, testosterone primarilyensures the development of theinternal and external male genitalia

• During puberty, testosterone pro-motes the growth of the male sexorgans and is responsible for othermale developmental characteristics,such as the pubertal growth spurtand eventual cessation of growth atadult height; deepening of the voice;growth of facial, pubic, axillary, andbody hair; and increase in muscular-ity and strength

• In the adult male, testosterone pri-marily serves to maintain masculinity,libido, and sexual potency as well asregulate sperm production. Testos-terone levels decline slightly withage, although the drop is not as dras-tic as the reduction in estrogen levelsin women during menopause. (Forinformation on alcohol’s effects onmale reproduction, see the article byEmanuele and Emanuele, pp.195–201.)

The Thyroid and ItsHormones

The thyroid gland, which consists of twolobes, is located in front of the windpipe(i.e., trachea), just below the voice box(i.e., larynx). The gland produces twostructurally related hormones, thyroxine(T4) and triiodothyronine (T3), that

are iodinated derivatives of the aminoacid tyrosine. Both hormones are collec-tively referred to as “thyroid hormone.”T4 constitutes approximately 90 percentof the hormone produced in the thyroidgland. However, T3 is a much moreactive hormone, and most of the T4produced by the thyroid is convertedinto T3 in the liver and kidneys.

Thyroid hormone in general serves toincrease the metabolism of almost all bodytissues. For example, thyroid hormonestimulates the production of certain pro-teins involved in heat generation in thebody, a function that is essential for main-taining body temperature in cold climates.Moreover, thyroid hormone promotesseveral other metabolic processes involv-ing carbohydrates, proteins, and lipidsthat help generate the energy requiredfor the body’s functions. In addition tothose metabolic effects, thyroid hormoneplays an essential role in the developmentof the central nervous system during latefetal and early postnatal developmentalstages. Furthermore, thyroid hormoneexerts an effect similar to that of GH onnormal bone growth and maturation.Finally, thyroid hormone is required forthe normal development of teeth, skin,and hair follicles as well as for the func-tioning of the nervous, cardiovascular,and gastrointestinal systems.

In addition to thyroid hormone, cer-tain cells (i.e., parafollicular C cells) inthe thyroid gland produce calcitonin, ahormone that helps maintain normalcalcium levels in the blood. Specifically,calcitonin lowers calcium levels in theblood by reducing the release of calciumfrom the bones; inhibiting the constanterosion of bones (i.e., bone resorption),which also releases calcium; and inhibitingthe reabsorption of calcium in the kidneys.Those effects are opposite to those ofparathyroid hormone (PTH), which isdiscussed in the following section.

The Parathyroid Glandsand Their Hormones

The parathyroid glands are four pea-sized bodies located behind the thyroidgland that produce PTH. This hormoneincreases calcium levels in the blood,helping to maintain bone quality and

an adequate supply of calcium, which isneeded for numerous functions through-out the body (e.g., muscle movementand signal transmission within cells).Specifically, PTH causes reabsorptionof calcium from and excretion of phos-phate in the urine. PTH also promotesthe release of stored calcium from thebones as well as bone resorption, bothof which increase calcium levels in theblood. Finally, PTH stimulates theabsorption of calcium from the foodin the gastrointestinal tract. Consistentwith PTH’s central role in calcium meta-bolism, the release of this hormone isnot controlled by pituitary hormonesbut by the calcium levels in the blood.Thus, low calcium levels stimulate PTHrelease, whereas high calcium levelssuppress it.

Many of the functions of PTH requireor are facilitated by a substance called1,25-dihydroxycholecalciferol, a deriva-tive of vitamin D. In addition, numerousother hormones are involved in regulat-ing the body’s calcium levels and bonemetabolism, including estrogens, glu-cocorticoids, and growth hormone. (Formore information on the hormonalcontrol of bone and calcium metabolismand on alcohol’s effects on those systems,see the article by Sampson, pp. 190–194.)

The Pancreas and ItsHormones

The pancreas is located in the abdomen,behind the stomach, and serves twodistinctly different functions. First, itacts as an exocrine organ, because themajority of pancreatic cells producevarious digestive enzymes that aresecreted into the gut and which areessential for the effective digestion offood. Second, the pancreas serves as anendocrine organ, because certain cellclusters (i.e., the Islets of Langerhans)produce two hormones—insulin andglucagon—that are released into theblood and play pivotal roles in bloodglucose regulation.

Insulin

Insulin is produced in the beta cells of theIslets of Langerhans. Its primary purpose


is to lower blood glucose levels; in fact,insulin is the only blood sugar-loweringhormone in the body. To this end, insulinpromotes the formation of storage formsof energy (e.g., glycogen, proteins, andlipids) and suppresses the breakdown ofthose stored nutrients. Accordingly, thetarget organs of insulin are primarily thosethat are specialized for energy storage, suchas the liver, muscles, and adipose tissue.Specifically, insulin has the followingmetabolic effects:

• Promotes glucose uptake into cellsand its conversion into glycogen,stimulates the breakdown of glucose,and inhibits gluconeogenesis

• Stimulates the transport of aminoacids into cells and protein synthesisin muscle cells, thereby lowering thelevels of amino acids available forgluconeogenesis in the liver

• Increases fat synthesis in the liverand adipose tissue, thereby lower-ing the levels of glycerol, whichalso can serve as a starting materialfor gluconeogenesis.

The release of insulin is controlledby various factors, including bloodglucose levels; other islet hormones(e.g., glucagon); and, indirectly, otherhormones that alter blood glucose levels (e.g., GH, glucocorticoids, andthyroid hormone).

Glucagon

The second blood-sugar–regulatingpancreatic hormone is glucagon, whichis produced in the alpha cells of the Isletsof Langerhans. Glucagon increases bloodglucose levels; accordingly, its main actionsgenerally are opposite to those of insulin.For example, glucagon increases glyco-gen breakdown and gluconeogenesis inthe liver as well as the breakdown of lipidsand proteins. The release of glucagon isregulated by many of the same factorsas is insulin’s release, but sometimes withthe opposite effect. Thus, an increase inblood glucose levels stimulates insulinrelease but inhibits glucagon release.

A finely tuned balance between the act-ivities of insulin and glucagon is essential

for maintaining blood sugar levels.Accordingly, disturbances of that balance,such as an insulin deficiency or an inabil-ity of the body to respond adequately toinsulin, result in serious disorders, such asdiabetes mellitus. (For more informationon diabetes and on alcohol’s effects oninsulin, glucagon, and the managementof diabetes, see the article by Emanueleand colleagues, pp. 211–219.)

Hormone Systems

As this article has indicated in describ-ing the various endocrine glands andtheir hormones, some hormones arecontrolled directly by the metabolicpathways that they influence. Forexample, blood sugar levels directlycontrol insulin and glucagon releaseby the pancreas, and calcium levels in the blood regulate PTH release.Conversely, many hormones producedby target glands are regulated by pituitaryhormones, which in turn are controlledby hypothalamic hormones. Examplesof such regulatory hormonal cascadesinclude the hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamic-pituitary-gonadal (HPG) axis, and thehypothalamic-pituitary-thyroidal (HPT)axis, which are described briefly in thefollowing sections (see figure 3, p.162).

The HPA Axis

Activation of the HPA axis, whichregulates various metabolic functions,is initiated with the release of CRHfrom the hypothalamus. This releaseoccurs in response to various stimuli,including almost any type of physicalor psychological stress; during the nor-mal sleep-wake cycle; and in responseto certain neurotransmitters. CRHthen stimulates the anterior pituitaryto produce ACTH. (In addition toCRH, AVP from the hypothalamusalso can stimulate ACTH release).ACTH, in turn, activates adrenalhormone production, primarily of cortisol, which mediates thespecific physiological effects of thishormone system.

The activity of the HPA axis is regu-lated by negative feedback mechanisms.

Thus, increased cortisol levels repressCRH release by the hypothalamusand ACTH release by the pituitary. Inaddition, ACTH can directly inhibithypothalamic CRH release.

Any disturbances in the HPA axiscan result in serious medical conse-quences. For example, insufficienthormone production by the adrenalcortex causes Addison’s disease, whichis characterized by muscle weakness,dehydration, loss of appetite (i.e.,anorexia), nausea, vomiting, diarrhea,fever, abdominal pain, tiredness, andmalaise. Patients with this diseaseexhibit low levels of plasma cortisolbut high levels of ACTH. The increasein ACTH levels represents a vainattempt by the pituitary to stimulatehormone production in the unrespon-sive adrenal cortex.

Equally deleterious is the excessiveglucocorticoid production that resultsfrom excess ACTH release (i.e., Cushing’ssyndrome). Those patients experiencesymptoms such as muscle weaknessand wasting, back pain from osteoporo-sis, a tendency to bruise easily, redis-tribution of body fat (i.e., a rounded“moon” face, prominent abdomen,and thin legs), and various psycholog-ical disturbances. Because of the nega-tive feedback mechanism of the HPAaxis, the patient’s cortisol levels arehigh and the ACTH levels are low.

Both acute and chronic alcohol consumption have been shown to acti-vate the HPA axis, and some drinkersdevelop a so-called pseudo-Cushing’ssyndrome that disappears with absti-nence (Veldman and Meinders 1996;Emanuele and Emanuele 1997). (Formore information on alcohol’s effect onthe HPA axis and its relation to alcoholcraving, see the article by Gianoulakis,pp. 202–210.)

The HPG Axis

In both men and women, the HPGaxis is the hormone system that controlsthe release of sex hormones. In bothgenders, the system is activated byGnRH, which is released regularly inshort bursts from the hypothalamus.GnRH then stimulates the release ofFSH and LH from the anterior pituitary.


Vol. 22, No. 3, 1998 161


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 glandreleases ACTH, gonadotropins (i.e., LH and FSH), or TSH. ACTH activates the adrenal glands to release cortisol, whichinduces metabolic effects. Cortisol also acts back on the hypothalamus and pituitary gland by negative feedback. LHand 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 man-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 thyroid hormones T3 and T4, both of which increase cellmetabolism 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.

GnRH

FSHLH

Testosterone

Anteriorpituitary

Testes

Hypothalamus

Male HPG Axis

HPT AxisHPA Axis

+

+

+

+GnRH

FSHLH

Estrogen Progesterone

Anteriorpituitary

Hypothalamus

Female HPG Axis

Ovaries

+

+

+

+

// +

+

Hypothalamus

Anterior pituitary

Adrenal gland

Kidney

Cortisol

CRH

Stress

Metaboliceffects

ACTH

+

+

+

TRH

TSH

Anteriorpituitary

Hypothalamus

Increasesmetabolism

Thyroid

T , T

+

+

+

34

In men, LH stimulates certaincells in the testes (i.e., Leydig cells)to release testosterone. FSH andtestosterone are key regulators ofanother set of testicular cells (i.e.,Sertoli cells), which support andnourish the sperm cells during theirmaturation. The HPG axis in menis regulated through a variety offactors. For example, testosterone is part of a negative feedbackmechanism that inhibits GnRHrelease by the hypothalamus and LH release by the pituitary. Inaddition, the Sertoli cells secrete a

substance called inhibin, whichprevents FSH release from thepituitary. Finally, the Leydig cellsand, to a lesser extent, the Sertolicells produce a substance calledactivin, which stimulates FSH secretion and thus has the oppositeeffects of inhibin.

In women, during the menstrualcycle, LH and FSH stimulate theovarian follicle that contains thematuring egg to produce estradiol.After ovulation has occurred, LH also promotes production of proges-terone and estradiol by the corpus

luteum. Both hormones participatein a negative feedback mechanismthrough most of the menstrual cycle,suppressing GnRH release from the hypothalamus and LH releasefrom the pituitary. Shortly beforeovulation, however, a positive feed-back mechanism is activated bywhich estradiol actually enhances LH release from the pituitary. Theresulting surge in LH levels ultimatelyleads to ovulation, the formation ofthe corpus luteum, and progesteronerelease. Progesterone exerts a negativefeedback on LH and FSH release,


Vol. 22, No. 3, 1998 163

One of the essential hormonal systems regulating normalbody functioning is the hypothalamic-pituitary-thyroid(HPT) axis, which controls the metabolism of all cells. Aswith other hormone systems, alcohol consumption undercertain conditions can modify the release of hormonesinvolved in this axis. In healthy nonalcoholics, alcoholconsumption does not appear to induce any significantchanges in the HPT axis (Emanuele and Emanuele1997). Conversely, some effects of alcohol on the HPTaxis have been observed in alcoholics. The effects differdepending on the drinking status of the alcoholicsstudied. In alcoholics undergoing withdrawal, baselinelevels of thyroid hormone (i.e., T3 and T4) in the blooddiffer only minimally from those in nonalcoholics. Theability of hypothalamic thyrotropin-releasing hormone(TRH) to activate the release of thyroid-stimulatinghormone (TSH) from the pituitary, however, is impairedin these alcoholics (Emanuele and Emanuele 1997).This “blunting” effect may result from alcohol’s influenceon the neurotransmitter dopamine. Dopamine producedin the hypothalamus acts not only as a neurotransmitterbut also as a hormone in that it inhibits the release ofboth TSH and prolactin from the pituitary. Alcoholhas been shown to increase dopaminergic activity andthereby may suppress the TSH response to TRH. Thishypothesis is supported by the fact that prolactin releasein response to TRH also is blunted in alcoholics under-going withdrawal.

Alcohol’s effects on the HPT axis are even more com-plex in abstinent alcoholics (Garbutt et al. 1995). Inthose people, the baseline levels of T3 and sometimes T4 are lower than in nonalcoholics. It is unclear, however,

if this change represents a direct effect of long-term alcohol consumption or results from co-occurring alcohol-related illnesses, because thyroid hormone levels are often reduced in patients with acute or chronicnon-thyroid–related illnesses, such as sepsis, burns, ormajor trauma. In addition to the reduced thyroid hormone levels, however, the TSH response to TRHremains blunted in abstinent alcoholics, whereas the pro-lactin response to TRH has returned to normal levels.This observation indicates that a factor other than dopa-mine likely contributes to this effect, although the exactmechanisms are unknown.

Finally, some intriguing findings have suggested thatabnormal responses of the HPT axis may represent amarker for a person’s vulnerability to alcoholism. Thus,some people who are at high risk for developing alcoholism,such as nonalcoholic sons of alcoholic fathers, tend toexhibit a blunted TSH response to TRH (Emanuele andEmanuele 1997). These observations still require furtherinvestigation, however, for researchers to fully understandtheir significance.

—Susanne Hiller-Sturmhöfel and Andrzej Bartke

ReferencesEMANUELE, N., AND EMANUELE, M.A. The endocrine system: Alcoholalters critical hormonal balance. Alcohol Health & Research World21(1):53–64, 1997.

GARBUTT, J.C.; SILVA, S.G.; AND MASON, G.A. Thyrotropin-releasinghormone (TRH): Clinical neuroendocrine and neurobehavioral findingsof relevance to alcoholism. In: Watson, R.R., ed. Drug and Alcohol AbuseReviews: Volume 6. Alcohol and Hormones. Totowa, NJ: Humana Press,1995. pp. 127–145.

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

causing LH levels to decline again. Inaddition to those mechanisms, FSHrelease from the pituitary is regulatedby inhibin, a substance produced bycertain cells in the ovarian follicle.

Both acute and chronic alcohol con-sumption can interfere with the normalfunctioning of the HPG axis, resultingin reduced fertility or even infertility in both men and women and in men-strual disturbances in women. (For moreinformation on alcohol’s effects on the HPG axis in women and men, see thearticles by Dees and colleagues, pp. 165–169, and by Emanuele and Emanuele,pp. 195–201.)

The HPT Axis

The hormones that make up the HPTaxis control the metabolic processesof all cells in the body and are there-fore crucial for the organism to func-tion normally. The secretion of TRHfrom the hypothalamus activates theHPT axis. After reaching the pitu-itary, TRH stimulates the release of TSH, which in turn promotes theproduction and release of T4 and T3by the thyroid gland. Negative feed-back effects of T4 and T3 on boththe hypothalamus and the pituitaryregulate the HPT system. (For asummary of alcohol’s effects on theHPT axis, see sidebar, p. 163.)

Summary

The neuroendocrine system is ahighly complex and tightly controllednetwork of hormones released byendocrine glands throughout thebody. The levels of some of thehormones are regulated in a fairlystraightforward manner by the endproducts that they influence. Thus,blood sugar levels primarily regulateinsulin and glucagon release by thepancreas. Other hormones (e.g., thoseof the HPA, HPG, and HPT axes)are parts of hormone cascades whoseactivities are controlled throughelaborate feedback mechanisms. Inaddition, numerous indirect inter-actions exist between the varioushormone systems governing bodyfunctioning. For example, hormonessuch as GH and thyroid hormone,through their effects on cellular meta-bolism, may modify blood sugar lev-els and, accordingly, insulin release.Similarly, alcohol’s effects on onehormone system may have indirectconsequences for other systems, therebycontributing to alcohol’s influenceson the functioning of virtually everyorgan in the body. It is important tokeep this interconnectedness of neu-roendocrine systems in mind whenanalyzing alcohol’s impact on varioushormones, which are described inthe remaining articles in this issue. ■

References

CONSTANTI, A.; BARTKE, A.; AND KHARDORI, R.Basic Endocrinology for Students of Pharmacy andAllied Clinical Health Sciences. Amsterdam: HarwoodAcademic Publishers, 1998.

DORGAN, J.F.; REICHMAN, M.E.; JUDD, J.T.; BROWN,C.; LONGCOPE, C.; SCHATZKIN, A.; CAMPBELL,W.S.; FRANZ, C.; KAHLE, L.; AND TAYLOR, P.R.Relation of reported alcohol ingestion to plasmalevels of estrogens and androgens in premenopausalwomen (Maryland, United States). Cancer Causesand Control 5(1):53–60, 1994.

EMANUELE, N., AND EMANUELE, M.A. The endocrinesystem: Alcohol alters critical hormonal balance.Alcohol Health & Research World 21(1):53–64, 1997.

GAVALER, J.S., AND VAN THIEL, D.H. The associ-ation between moderate alcoholic beverage consump-tion and serum estradiol and testosterone levels innormal postmenopausal women: Relationship to theliterature. Alcoholism: Clinical and ExperimentalResearch 16(1):87–92, 1992.

PUROHIT, V. Moderate alcohol consumption andestrogen levels in postmenopausal women: A review.Alcoholism: Clinical and Experimental Research22(5):994–997, 1998.

REICHMAN, M.E.; JUDD, J.T.; LONGCOPE, C.;SCHATZKIN, A.; CLEVIDENCE, B.A.; NAIR, P.P.;CAMPBELL, W.S.; AND TAYLOR, P.R. Effects ofalcohol consumption on plasma and urinary hor-mone concentrations in premenopausal women.Journal of the National Cancer Institute 85(9):722–727, 1993.

VELDMAN, R.G., AND MEINDERS, A.E. On themechanism of alcohol-induced pseudo-Cushing’ssyndrome. Endocrine Reviews 17:262–268, 1996.

WILSON, J.D.; FOSTER, D.W.; KRONENBERG,H.M.; AND LARSEN, P.R., EDS. Williams Textbookof Endocrinology. 9th ed. Philadelphia: W.B.Saunders, 1998.


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