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Alcohol Alters Critical Hormonal Balance

NICHOLAS EMANUELE, M.D., AND MARY ANN EMANUELE, M.D.

Alcohol’s effects on the hormonal (i.e., endocrine) system have widespread consequences for virtually the entire . Alcohol-related hormonal disturbances can result in cardiovascular abnormalities and reproductive deficits in both males and females. Other endocrine problems stemming from excess alcohol consumption include immune dysfunction and disease. Researchers are exploring ways of using hormonal mechanisms to help treat alcoholics as well as to identify people predisposed to alcoholism. KEY WORDS: AODE (alcohol and other drug effects); AODR (alcohol and other drug related) disorder; endocrine function; endocrine disorder; function; ; cardiovascular disorder; immune disorder; bone; ; ; drug ; literature review

long with the , length, and pattern of alcohol expo- tions, including , metab- the endocrine, or hormonal, sure; level of intoxication; and coex- olism, use of , and growth. A system is the primary regula- isting medical problems, such as tory mechanism for virtually the entire malnutrition and dysfunction, NICHOLAS EMANUELE, M.D., is body. Hormones are chemical must be considered when assessing professor of and director messengers that control and coordi- the impact of alcohol on hormonal of the Division of nate the function of tissues and organs. status. This article summarizes the and , Loyola University Each is secreted from a partic- effects of both acute and chronic alco- , Maywood, Illinois, ular and distributed throughout hol exposure on hormonal , and Hines VA Hospital. He is also a the body to act on different tissues. addressing work performed on hu- member of the Division on Research on Drugs of Abuse. Hormones are released as a result mans and models. of impulses or in response to specific physiological or biochemical MARY ANN EMANUELE, M.D., is professor of medicine, Division of events. Following their release, hor- HYPOTHALAMIC-PITUITARY- Endocrinology and Metabolism, mones instigate a cascade of reactions ADRENAL AXIS Loyola University Medical School, within the body, the end result of Maywood, Illinois, and Hines VA which can include synthesis and re- The is the control cen- Hospital. She is also professor of lease of enzymes and changes in ter for most of the body’s hormonal systems. Located deep within the molecular and cellular membranes. Highly sensitive feed- and a member of the Division on , the hypothalamus receives back mechanisms reduce or increase Research on Drugs of Abuse. the amount of different hormones nerve impulses stemming from both being released at any given time. physical and psychological stimuli This work was supported by grants The effects of alcohol on endocrine and releases hormones in response to from the National Institute on function are multiple and complex. those signals. Hypothalamic activity Alcohol Abuse and Alcoholism Several variables, including the type, thus governs numerous body func- (NIAAA)

VOL. 21, NO. 1, 1997 53 and ACTH release, respectively (Miller and Tyrrell 1995). have many physio- logical effects; they influence carbohy- drate, lipid, , and nucleic acid + metabolism; the cardiovascular sys- tem; bone and ; the ; and Hypothalamus growth, development, and reproduc- + tion. Notably, glucocorticoids also CRF modify immunological responses, underscoring the important interrela- Anterior tionship between the endocrine and pituitary immune systems. In addition to their functions within the HPA, both CRF and ACTH have independent effects ACTH on the , reproduction, and temperature regulation (Miller and Adrenal Tyrrell 1995). Although increases in ACTH and glucocorticoids are usually Kidneys short-lived (i.e., transient), this stimu- lation has far-reaching consequences + for numerous other systems. It is Metabolic easy to appreciate how perturbations effects of the system may lead to multiple clinically significant problems.

Figure 1 The hypothalamic-pituitary-adrenal axis. In response to almost any type Animal Studies of stress, either physical or psychological, the hypothalamus secretes The major circulating in corticotropin-releasing factor (CRF), which in turn increases secretion of adrenocortotropic hormone (ACTH) by the anterior . In is cortisol; in rodents, it is corti- response, within minutes, the adrenal glands, located atop the two costerone. In rats, it is clear that acute kidneys, increase secretion of cortisol. The released cortisol initiates a alcohol administration leads to dose- series of metabolic effects aimed at alleviating the harmful effects of the related increases in ACTH and corticos- stress state and, through direct negative to both the hypo- terone, with females showing a greater and the , decreases the concentration of ACTH response than males.3 Consistent evi- and cortisol in the blood once the state of stress abates. dence shows that alcohol’s effect is + = excites through enhanced release of CRF. For Ð = inhibits example, destruction of the paraventric- ular nucleus (the hypothalamic area where CRF is made), neutralization of The hypothalamus, the anterior CRF binds to specific receptors on pituitary gland, and the adrenal glands special pituitary cells called cortico- 1For definitions of this and other technical terms, see the central glossary, pp. 93Ð96. function together as a well-coordinat- tropes, which produce adrenocortico- ed unit known as the hypothalamic- (ACTH). Upon CRF 2Feedback is a regulatory mechanism for a pituitary-adrenal (HPA) axis (see system (e.g., the HPA axis) in which some of stimulation, ACTH production and the output or by-products of the system (e.g., figure 1). Cells in the hypothalamus secretion is enhanced. ACTH is then glucocorticoids) returns as input (e.g., to the (i.e., the paraventricular nucleus) pro- transported through the general blood hypothalamus and the pituitary gland). Negative duce most of a key hormone called feedback is what occurs when the returning circulation to its target , the corticotropin-releasing factor (CRF) signal (in this case, glucocorticoids) results in a , where it stimulates reduction in system output (here, the diminished in humans. The hypothalamus secretes release of CRF and ACTH). Conversely, posi- CRF into the hypothalamic-pituitary production of adrenal hormones, pri- 1 tive feedback leads to an increase in system portal system, the network of blood marily glucocorticoids. Glucocorti- output. vessels that functionally connects the coids then feed back in a negative 3 2 For a review of the effects of both acute and hypothalamus and the anterior pitu- fashion to both the hypothalamus and chronic alcohol administration to rats, see Rivier itary gland. At the pituitary gland, the pituitary gland to decrease CRF 1996.

54 ALCOHOL & RESEARCH WORLD Alcohol and the Endocrine System

naturally occurring CRF with antibod- , chronically alcohol-exposed Chronic alcohol adminstration causes ies, or blockade of CRF receptors with animals show increased baseline (i.e., a profound decrease in HPA activity in certain chemicals all interrupt the basal) levels of CRF mRNA and de- “elderly” (i.e., 15-month-old) rats ability of alcohol to stimulate the HPA. creased hypothalamic CRF content. (Nolan et al. 1991). Furthermore, incubation of rodent These data suggest that chronic alco- As previously indicated, the func- hypothalamic slices in alcohol leads to hol exposure increases the synthesis tions of the endocrine and immune acute release of CRF (Pascal de Waele and release of CRF, a theory that has systems are intimately interconnected. and Gianoulakis 1993). Although been confirmed in a study of rats by For example, alcohol-exposed rats there is no question that acute alcohol Redei and colleagues (1988). The have an impaired ACTH response to administration stimulates CRF release, increased release of CRF would ex- interleukin-1α and interleukin-1β, two it remains unresolved whether this plain the increased levels of ACTH chemicals key to the overall immune stimulation occurs through a direct and adrenal corticosterone. As indi- response that are produced by immune- effect on CRF-producing in cated above, because of tolerance the system cells. Alcohol-induced dys- the hypothalamus or indirectly, through level of HPA activation after chronic function (i.e., hyperactivity) of the other input from the hypothalamus or alcohol exposure is not as great as HPA axis may alter immune function other areas of the brain (i.e., extrahy- following acute alcohol exposure. and thus the capacity of the body to pothalamic input) to CRF neurons. What mechanism could account for stave off , an ability compro- In addition to having effects on the this tolerance? First, at the brain level, mised in alcoholic humans. (For more brain (whether hypothalamic, extrahy- in hypothalami from rats chronically information on alcohol’s effects on pothalamic, or both), it is conceivable exposed to alcohol, CRF release is not the immune system, see the article by that alcohol might stimulate ACTH or as high as in control, non-alcohol- Szabo, pp. 30Ð41.) corticosterone release, acting directly at exposed animals. Second, at the pitu- the pituitary gland or at the target organ itary level, chronic alcohol exposure Human Studies (i.e., the ). However, no decreases both pituitary CRF binding consistent pattern of response has been and the activity of adenylate cyclase, a One manifestation of alcohol’s effect observed. Some studies suggest a direct enzyme key to normal cell function. on the HPA axis resembles a disorder pituitary stimulation of ACTH release, The decreased binding of CRF to the called Cushing’s syndrome, a disease yet others show no direct effect of corticotropes at the pituitary gland stemming from an excess of cortisol. alcohol. Similarly, some data show a may be a direct effect of alcohol or Clinical signs of the syndrome include direct stimulatory effect of alcohol on may result from the alcohol-induced of the (with purplish adrenal cortex, whereas other findings increase in CRF release; like many stretch marks); a round, red ; high show no change. hormones, CRF down-regulates its ; muscle weakness; easy Thus, in animals, acute alcohol binding to receptors as a result of bruisability; acne; ; osteoporo- administration transiently activates the feedback from the HPA axis. In any sis; and a variety of psychological HPA axis, mainly by stimulating case, compared with the pituitary disturbances. Women also may devel- release of hypothalamic CRF, which glands of control rats, pituitaries of op facial (i.e., ) and then enhances ACTH and subsequent rats chronically exposed to alcohol menstrual disturbances. Some corticosterone release. The HPA axis demonstrate decreased ACTH output. instances of Cushing’s syndrome are of rodents chronically exposed to Thus, in rats chronically treated with caused by prolonged use of high-dose alcohol, however, remains activated alcohol, a given amount of CRF pro- glucocorticoids as therapy for other (i.e., ACTH and corticosterone levels duces less of an ACTH response and medical conditions; aside from drug- are increased compared with levels in consequent diminished corticosterone induced Cushing’s syndrome, howev- control animals), although some de- output than in control rats; in other er, about two-thirds of the cases of gree of tolerance develops. That is, words, tolerance develops. The appar- Cushing’s syndrome are caused by the HPA axis is more activated after ent reason that the HPA axis is still ACTH-producing pituitary tumors. chronic alcohol exposure than after no activated after chronic alcohol admin- The therapy for the syndrome is exposure, but not as activated as after istration is that CRF secretion to remove the tumors. Another acute alcohol exposure. As is the case remains, overall, above control levels. 15 percent of Cushing’s cases result with acute alcohol administration, Interestingly, age may modify the from an , and the re- chronic alcohol exposure seems to ability of chronic alcohol administra- mainder of cases are generally caused cause hyperactivity of the HPA axis tion to activate the HPA. Although in by nonpituitary and nonadrenal tumors through effects, either direct or indi- young rats (i.e., ages 3 to 6 months), (generally seen in the , the pan- rect, on CRF. Levels of CRF messen- alcohol can chronically stimulate HPA creas, and the gut) that abnormally ger RNA (mRNA) are an indicator of activity, alcohol actually decreases produce ACTH. Therapy is the surgi- the rate of CRF synthesis and overall ACTH and corticosterone activity in cal or, in some cases, pharmacological CRF levels. Compared with control “middle-aged” (i.e., 9-month-old) rats. treatment of these tumors.

VOL. 21, NO. 1, 1997 55 A. Female reproductive axis B. Male reproductive axis

Hypothalamus Hypothalamus + + LHRH LHRH

Anterior Anterior pituitary pituitary

/ + + + + / LH FSH LH FSH

+ +

Ovaries Testes + +

Estrogen

Figure 2 The hypothalamic-pituitary-gonadal axis in males and females. The hypothalamus secretes - releasing hormone (LHRH), which controls the anterior pituitary gland’s secretion of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In the female reproductive axis (A), these two gonadotropic hormones stimulate the to secrete and progesterone, which circulate back to the hypothalamic-pituitary unit and either inhibit or excite the production of FSH, LH, and LHRH. In the male reproductive axis (B), the gonadotropic hormones stimulate production of testosterone by the testes; testosterone also feeds back to the hypothalamus and pituitary to inhibit production of LHRH and the pituitary . + = excites Ð = inhibits

Some drinkers develop a condition Cushing’s syndrome should not be feedback from the target organs, the called alcohol-induced pseudo- surprising. Whether the syndrome (i.e., the testes and ovaries), to Cushing’s syndrome. It is indistinguish- results from alcohol’s effects on the the hypothalamus, where a key repro- able from true Cushing’s syndrome, brain or at the pituitary or adrenal ductive hormone, luteinizing hormone- although it tends to be clinically more levels, however, is not clear. None- releasing hormone (LHRH), is released mild. Proof that the pseudo-Cushing’s theless, the existence of alcohol-in- into the portal blood system (figure 2). syndrome results from alcohol con- duced pseudo-Cushing’s syndrome Upon reaching the pituitary gland, sumption and not from tumorous over- indicates that alcohol consumption LHRH attaches to specific receptors production of ACTH or cortisol derives somehow leads to a clinically signifi- and activates a complicated cascade of from the observation that its symptoms cant activation of the HPA axis in biochemical events that results in the and signs disappear with abstinence humans. (For a recent review of the synthesis and release of the two go- from alcohol, usually within 2 to 4 data on alcohol’s effects on the HPA nadotropin hormones, luteinizing months. The prevalence of this syn- axis in alcoholics and nonalcoholics, hormone (LH) and follicle-stimulating drome among alcoholics is unknown, see Veldman and Meinders 1996.) hormone (FSH). but clinical experience indicates that LH is largely responsible for go- most alcoholics do not have the full- nadal production of , which blown syndrome. HYPOTHALAMIC-PITUITARY- are hormones that have masculinizing Based on alcohol’s ability to acti- GONADAL AXIS effects (e.g., testosterone). FSH is vate the HPA axis in animals important for normal development and (Thiagarajan et al. 1989), the exis- The hypothalamic-pituitary-gonadal maturation of in the male and tence of alcohol-induced pseudo- axis is a involving ovarian follicles in the female. The

56 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and the Endocrine System

gonadal hormones—including testos- causing a large midcycle surge of LH bone growth and development. In terone in the male and estrogen and and FSH secretion, which in turn addition, gonadal hormones are im- progesterone in the female—then cir- triggers and the start of the portant mediators of the central ner- culate back to the hypothalamic-pituitary . vous system and play a role in the unit and encourage or discourage fur- Following ovulation, the granulosa immune system. A disturbance of the ther release of LHRH, LH, and FSH in cells of the dominant follicle undergo hypothalamic-pituitary-gonadal axis a finely tuned system (Molitch 1995; a process called luteinization, con- thus can result not only in altered Santen 1995; Erickson 1995). verting the follicle into a body called fertility but also in problems such as Because of female reproductive the . The corpus luteum osteoporosis, muscle weakness, and cyclicity, the hormonal physiology is is the key endocrine structure of the impaired immune function. more complex in women than in men luteal phase; its major secretory pro- (Erickson 1995). The 28-day human is the hormone progesterone, Animal Studies reproductive cycle can be divided into which further prepares the uterine two phases: a 14-day , wall for a fertilized ovum and is The effects of both acute and chronic which begins with the first day of crucial to the successful maintenance alcohol administration have been stud- menses, followed by a 14-day luteal of early . ied primarily in male rats. (Although phase. Ovulation, the release of the Although the products of the go- studies in females exist, they are rela- egg (i.e., ovum) from the , oc- nads are essential to reproduction, tively few in number, and thus the data curs at the midpoint of the 28-day testosterone, estrogen, and proges- on males will be presented first.) A cycle (see figure 3). terone, like the glucocorticoids, all direct effect of alcohol on testosterone The ovary is made up of millions have actions throughout the body. secretion in male rats has been amply of follicles, each consisting of a single These effects include roles in carbo- documented (Cicero 1982; Emanuele et ovum in a multilayered envelope of hydrate and lipid metabolism, the al. 1993; Purohit 1993), and a secondary hormone-producing cells called gran- cardiovascular system, and normal impact of alcohol on the hypothalamic- ulosa cells. During each reproductive cycle, just one of the follicles is re- cruited to become the dominant folli- cle, which will ovulate. (The process by which only one follicle per cycle

becomes dominant is not well under- Ovulation stood.) FSH is the key pituitary hor- mone of the follicular phase; under FSH stimulation, the dominant follicle undergoes a normal developmental process. As the follicular phase pro- Progesterone gresses and the ovary is readied for ovulation, the granulosa cells multiply and secrete increasing amounts of the estrogen called . Estradiol causes increased thick- ness of the uterine wall, preparing it for implantation of the fertilized

ovum. Estradiol also feeds back to the FSH and LH Estradiol hypothalamic-pituitary unit to cause two important effects: First, through , estradiol progres- 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Day sively decreases output of FSH. Second, estradiol sensitizes the pituitary gland Estradiol Progesterone FSH LH to the effects of LHRH. The second function is important because at the end of the 14-day follicular phase Figure 3 Fluctuations in the levels of estradiol, progesterone, luteinizing hormone (i.e., at midcycle), progressively rising (LH), and follicle-stimulating hormone (FSH) over the 28-day female estradiol emanating from the domi- reproductive cycle. nant ovarian follicle causes a burst of SOURCE: Adapted from Guyton, A.C. Textbook of Medical Physiology. 7th ed. Philadelphia: W.B. Saunders, LHRH secretion from the hypothala- 1986. p. 969. mus into the portal blood system,

VOL. 21, NO. 1, 1997 57 pituitary unit also has been noted. is inconsistent with the presence of a of the moderate drinkers who con- Animal studies measuring concentra- low testosterone level, indicating that sumed more than three drinks per day tion of LHRH in the hypothalamic- the hypothalamic-pituitary-gonadal had significant problems, including pituitary portal system have found a axis is relatively suppressed by alcohol. delayed ovulation and failure to ovu- sharp fall in LHRH secretion after an late (i.e., anovulation). Shortening of acute alcohol in anesthetized Studies in Men the luteal phase also was observed. male rats (Ching et al. 1988). Studies Menstrual problems did not appear to on rat hypothalami, however, have Diminished sexual function in alcoholic occur in the women who were occa- failed to detect an alteration in either men has been clinically noted over sional drinkers or who were moderate basal or stimulated LHRH release after many years; early studies largely at- drinkers consuming fewer than two exposure to alcohol (Emanuele et al. tributed this problem to liver disease. drinks per day. A dose-response rela- 1990). Thus, the hypothalamic effects However, when young, healthy, non- tionship appears to exist between on LHRH may be mediated in brain alcoholic volunteers were exposed alcohol consumption and the frequen- areas outside the hypothalamus, indi- acutely to alcohol, a fall in testos- cy of menstrual problems. This notion rectly affecting hypothalamic function. terone was consistently demonstrated. also is supported by epidemiological The result is a reduction in (i.e., attenu- A central defect in the human hypotha- surveys showing that prevalence of ated) LHRH release and, consequently, lamic-pituitary unit was first suggested menstrual disturbances grows with a diminished response. when it was noted that LH levels in increasing alcohol consumption. Researchers studying the effects of men failed to increase as expected The mechanism of these problems alcohol on the mRNA of LH, an indi- for the concomitant decrease in testos- is not entirely clear. However, it is of cator of the rate of LH synthesis, have terone levels, and both LH and FSH interest that acute alcohol administra- observed a drop specifically in pitu- failed to increase after stimulation with tion has been reported to raise estro- clomiphene citrate, a drug that acts at itary LH RNA levels in rats (Eman- gen levels. Whether this rise is due to the hypothalamus level to increase uele et al. 1993). The lowered amount an increased estrogen secretion, en- LHRH production (Cicero 1982). Inter- of LH being produced by the pituitary hanced conversion of estrogen from estingly, in younger men who were results in lowered testosterone levels precursor substances, decreased metab- given alcohol and LHRH to stimulate because the gonads are unstimulated. olism, or a combination of these fac- their pituitary glands’ production of In addition, alcohol directly affects tors is uncertain. Nonetheless, it has LH, testosterone levels actually in- the Leydig cells, the testosterone- been demonstrated that estrogen ad- creased, suggesting enhanced sensitivity. producing cells of the , which ministration can disrupt the reproduc- Thus, a central effect of alcohol in demonstrate marked inhibition of tive cycle, at least in part because humans also has been implied after testosterone secretion after acute alco- estrogen can suppress FSH (Mello et acute alcohol exposure. hol exposure. Thus, acute alcohol al. 1993). Recall that a rise in FSH early administration to adult male rodents in the follicular phase of the repro- results in lowered testosterone levels Studies in Women ductive cycle is crucial to the proper through both a central effect on the Even moderate in healthy maturation of the dominant ovarian hypothalamic-pituitary unit and direct women can lead to significant reproduc- follicle, from which ovulation will suppression of activity. tive problems. (For a review, see Mello occur and the corpus luteum will de- Over time, the hypothalamic- et al. 1993). Mendelson and Mello velop. This knowledge gives rise to the pituitary unit appears to become (1988) studied a group of healthy, well- idea that alcohol intake could lead to somewhat resistant to the deleterious nourished women during a 35-day increased estrogen, inhibiting FSH consequences of alcohol, although stay on a clinical research unit. The and disrupting and testosterone levels remain low. It has first and last 7 days were alcohol-free. subsequent corpus luteum function. In been noted that the hypothalamic- During the middle 21 days, each par- addition, alcohol has been shown to pituitary unit of male rodents chroni- ticipant could drink alcohol as de- suppress progesterone, the main secre- cally exposed to alcohol demonstrated sired. At the end of the 35 days, the tory product of the corpus luteum. little or no change in hypothalamic women classified themselves as heavy Thus, even moderate amounts of alco- LHRH and the rate of pituitary LH drinkers (7.8 ± 0.7 drinks/day, n = 5), hol may cause infertility (through and FSH production (Emanuele et al. moderate drinkers (3.8 ± 0.2 drinks/ suppressing ovulation) and an increased 1993). In theory, hypothalamic day, n = 12), or occasional drinkers risk for spontaneous abortion (through LHRH and pituitary LH and FSH (1.2 ± 0.2 drinks/day, n = 9). Each interfering with the pregnancy-main- levels should actually increase in an ’s alcohol intake within the taining function of the corpus luteum). attempt to stimulate the gonads to clinical research unit was similar to Careful longitudinal studies of the produce testosterone. Thus, the lack her reported level of consumption for effects of abstinence from alcohol on of change in LHRH, LH, and FSH the previous 6Ð8 years. Sixty percent reproductive abnormalities are not levels after chronic alcohol exposure of the heavy drinkers and 50 percent available. Anecdotal evidence, how-

58 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and the Endocrine System

ever, indicates that alcohol-induced stimulate discrete target organs, no Under GRF stimulation, pituitary GH reproductive abnormalities are re- single peripheral tissue clearly feeds production is enhanced. Another im- versible upon discontinuing alcohol back negatively on release portant hormone in this system is intake. Not all drinkers have repro- (Molitch 1995). . Hypothalamic somato- ductive abnormalities, indicating Human and animal studies on both statin, produced by the paraventricular either variable susceptibility to the sexes have demonstrated that both nucleus, arrives at the pituitary effects of alcohol and/or the develop- acute and chronic alcohol exposure through the portal system, where it ment of tolerance to its effects. There- leads to a stimulation of prolactin re- activates somatostatin receptors. fore, some women who consume lease (Emanuele et al. 1993). Alcohol- Somatostatin then inhibits GH secre- alcohol will continue to have regular induced reduction of ’s tion. Thus the interplay between hy- menses and become pregnant.4 inhibitory effect may underlie this pothalamic GRF and somatostatin Women who have ingested alcohol phenomenon; however, alcohol’s in- tightly regulates the amount of GH long enough and frequently enough to fluence on other hypothalamic factors being produced by the pituitary gland. develop liver cirrhosis are ill and mal- that modify prolactin release also may Once pituitary GH has been syn- nourished, putting them in a different account for prolactin stimulation. In thesized and released, a key target for category from the otherwise healthy, addition, data from several laborato- this hormone is the liver, which produces well-nourished women discussed ries show that alcohol applied to the insulinlike growth factor 1 (IGF-1), a above. Nonetheless, whether from anterior pituitary can stimulate pro- chemical that carries out many of the alcohol or the attendant sickness, women lactin release, indicating a direct effect actions of GH (e.g., protein formation with alcoholic cirrhosis, too, have of alcohol on the pituitary. Whatever and ) at the tissue level. reproductive and menstrual abnormali- the cause, elevated prolactin frequently IGF-1 also feeds back at the hypotha- ties. Their hormonal profiles are some- is associated with reproductive lamus and the pituitary to reduce GH what different from those of social deficits in both males and females. synthesis and secretion (Molitch drinkers, however. Women with alco- High prolactin levels can cause impo- 1995). The normal pulsatility of GH holic cirrhosis tend to have low, rather tence in males and disruption of nor- release (i.e., its release in pulses) has than high, estrogen and elevated levels mal ovulatory cycles in females. made it difficult to examine the ef- of LH and FSH. This pattern is similar Clearly, however, elevated prolactin fects of alcohol on this system. For to what is normally seen in levels are not the only cause for im- this reason, IGF-1 has sometimes and suggests that over the long term, paired reproductive capabilities: been used as a marker of integrated alcoholic women may have premature Alcoholic females can have reproduc- GH action and is a more convenient ovarian failure. This area requires tive abnormalities with or without tool for monitoring alcohol-induced further study. excessive prolactin (Teoh et al. 1995). changes in the hypothalamic-pituitary- The suckling of infants is well GH axis. known to induce prolactin release; Although an obvious need for nor- PROLACTIN although alcohol normally stimulates mal GH exists during pubertal years, an increase in prolactin, the suckling recent studies have demonstrated a The hormone prolactin, secreted by the effect is actually diminished (i.e., anterior pituitary gland, supports lacta- beneficial effect of GH on aging tis- blunted) in alcohol-ingesting women, sues (Rudman et al. 1990). The numer- tion and feeding. For most of impairing breast feeding and leading the other anterior pituitary hormones, ous effects of IGF-1 on carbohydrate and to negative consequences for infant lipid metabolism, the cardiovascular the net effect of the hypothalamus is health (Subramanian 1995). stimulatory; for prolactin, however, system, bone growth and development, the action of the hypothalamus is in- and immune-system function may make this hormone extremely impor- hibitory. Much of this inhibitory effect on prolactin synthesis and release is tant to normal bodily functions, not mediated by dopamine, a neurotrans- The hypothalamic-pituitary-growth just in adolescents but also in . mitter delivered from the hypothala- hormone (GH) axis functions in a Both acute and chronic alcohol mus, although many other manner similar to the other integrated exposure consistently have been hypothalamic regulatory factors may neuroendocrine systems previously shown to diminish serum GH and modify prolactin release to a lesser described (figure 4). The arcuate and IGF-1 levels in animals and humans of extent. Also in contrast to the other ventromedial nuclei of the hypothala- both sexes. Animal studies also have anterior pituitary hormones, which mus produce large amounts of growth demonstrated a small but significant hormone releasing factor (GRF), which fall in mRNA for GH in normal adult 4Alcohol ingestion during pregnancy can lead to is secreted into the hypothalamic-pitu- male rats acutely exposed to alcohol. a variety of defects in the offspring, collectively In addition to attenuation of basal known as fetal alcohol syndrome (FAS). For itary portal system and then to the more information on FAS, see Alcohol Health anterior pituitary, where it binds to GH and IGF levels, blunted GH re- & Research World Vol. 18, No. 1, 1994. GRF receptors on the pituitary gland. sponses to other factors known to

VOL. 21, NO. 1, 1997 59 1993). Further support for this con- tention is provided by animal data demonstrating that alcohol directly inhibits pituitary GH secretion but has no direct effect on GRF mRNA in cultured hypothalami. Thus, the consistently noted pro- found blunting of GH and IGF-1 levels Hypothalamus in both rodents and humans appears to be partially mediated by a suppressive GRF Somatostatin effect at the pituitary level. This low- + ering of GH and IGF-1 is particularly deleterious to adolescents, who are Anterior dependent on these hormones for the pituitary normal pubertal process to occur. gland + + Older people, however, also suffer negative consequences from a loss of these hormones, such as impaired immune function and muscle weakness. GH

Direct HYPOTHALAMIC-PITUITARY- effects AXIS Liver Muscle and adipose The hypothalamic-pituitary-thyroid (HPT) axis is of paramount impor- tance to the mammalian . Because the metabolic processes of IGF-1 Indirect every cell in the body depend on nor- effects mal amounts of thyroid hormone, disruption of this unit has widespread Tissues + = excites and bone and organs negative effects on tissue function. Ð = inhibits The paraventricular and periven- tricular nuclei of the hypothalamus Figure 4 The hypothalamic-pituitary-growth hormone axis. The hypothalamus produce and secrete thyrotropin- secretes growth hormone-releasing factor (GRF), prompting the anterior releasing hormone (TRH) into the pituitary to secrete growth hormone (GH). The hypothalamus also hypothalamic-pituitary portal system produces somatostatin, which acts to inhibit GH secretion; the balance of (figure 5). TRH stimulates the thyro- GRF and somatostatin provides the regulatory mechanism for the GH trope cells of the anterior pituitary axis. Once GH has been released, a key target for the hormone is the gland to produce thyroid-stimulating liver, which produces insulinlike growth factor-1 (IGF-1), a chemical that hormone (TSH), which then stimu- carries out many of the tasks of GH at the cellular level (e.g., normal lates the synthesis and secretion of function of the immune system, carbohydrate and lipid metabolism, and . The principal thy- bone growth and development). IGF-1 also feeds back to the hypo- thalamus and pituitary to reduce GH secretion. GH acts to inhibit its own roid hormones are thyroxine (T4) and secretion by inhibiting secretion of GRF and promoting secretion of triiodothyronine (T3). Although the somatostatin. thyroid gland secretes both of these hormones following TSH stimulation, most (about 70 percent) of the circu- increase GH release in healthy hu- sharp fall in serum GH and IGF levels, lating T3 is derived from the liver’s mans, such as clonidine, an antihyper- yet a concomitant rise in hypothalamic conversion of T4. The circulating tensive medication, and -induced GRF mRNA was noted (Tentler et al. thyroid hormones, primarily T3, feed , have been reported 1993). Because GH is known to atten- back in a negative fashion at both the after acute alcohol exposure. Both uate GRF mRNA, the rise in GRF hypothalamic and the anterior pitu- clonidine and hypoglycemia act on the mRNA following alcohol administration itary level (Molitch 1995; Utiger hypothalamus to increase GRF re- is believed to represent an indirect 1995). (For reviews of alcohol’s ef- lease. It is interesting that acute alco- effect secondary to alcohol’s inhibi- fects on the HPT axis, see Garbutt et hol given to male rats resulted in a tion of pituitary GH (Tentler et al. al. 1995; Mason et al. 1995.)

60 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and the Endocrine System

Alcohol administered to healthy nonalcoholics does not appear to cause any clinically important change in the two circulating thyroid hor- mones, T4 and T3. Furthermore, nei- ther basal nor TRH stimulation of TSH are affected by alcohol. The Hypothalamus situation is somewhat different and + quite intriguing in alcoholics. Studied TRH during alcohol withdrawal, minor changes, at most, occur in T4 and T3. Anterior Although basal TSH levels are un- pituitary changed from levels in control sub- jects, a blunted TSH response to TRH + TSH has been consistently reported during alcohol withdrawal. TRH is an impor- Thyroid tant stimulator of prolactin, and it is notable that the prolactin response to + TRH also is blunted during alcohol Cells withdrawal. Since dopamine is a po- tent inhibitor of prolactin and, to a T4 , T3 lesser degree, of TSH, a reasonable + = excites Increases hypothesis is that the blunted TSH Ð = inhibits metabolism and prolactin responses were the re- sult of an alcohol-induced excess of Figure 5 The hypothalamic-pituitary-thyroid axis. The hypothalamus produces and dopaminergic activity at the pituitary secretes thyrotropin-releasing hormone (TRH), stimulating cells of the level. In fact, administration of the anterior pituitary to produce thyroid-stimulating hormone (TSH). TSH dopamine- blocker metoclo- then stimulates secretion of thyroxine (T4) and triiodothyronine (T3) by the pramide partially restored TSH and thyroid gland, the primary effect of which is to regulate cell metabolism. prolactin responses during alcohol T4 and T3 both feed back to the hypothalamus and the pituitary to reduce withdrawal, indicating that part of the TRH and TSH secretion. reason for the blunted response was SOURCE: Guyton, A.C. Human Physiology and Mechanisms of Disease. 5th ed. Philadephia: W.B. Saunders, too much dopamine or an increased 1992. pp. 566Ð568. responsiveness to dopamine of the prolactin-producing cells (Garbutt et al. 1995; Mason et al. 1995). does not seem to be caused by exces- abnormality that predisposes people to When abstinent alcoholics were sive dopaminergic inhibition, as it is that disease. studied (Garbutt et al. 1995), baseline during alcohol withdrawal; if this were Soon after TRH was isolated and T3 and, sometimes, T4 levels were the case, the prolactin response would sequenced, it was found not only in lower than in nonalcoholic control be impaired as well. Psychologically the hypothalamus but also widely subjects. The decline in thyroid hor- depressed individuals also have blunted distributed in the extrahypothalamic mones might not result from alcohol TSH responses to TRH, but associated central nervous system (Mason et al. consumption itself but rather from an depression is not the mechanism here, 1995). Such mapping studies suggested attendant illness. The fall in T3 and T4 because no relationship exists between that the TRH functioned not only as a is a common adaptation of thyroid personal or family history of depres- hypothalamic hormone, with tradi- hormone economy in acute or chronic sion and blunted TSH responsiveness tional neuroendocrine effects, but also nonthyroidal illness, a situation known in alcoholics. Whatever the reason, it probably as a that as the euthyroid sick syndrome. (For is of great interest that young nonalco- could have a variety of functions, example, the euthyroid sick syndrome holic men with alcoholic fathers (who including effects on behavior. One of occurs in situations such as sepsis, are at high risk for alcoholism them- the earliest behavioral effects observ- burns, and major trauma.) In any case, selves) also tend to have abnormal ed in animals was TRH’s ability to the TSH response to TRH remains TSH responsiveness to TRH, usually a counteract the hypnotic and motor- blunted in abstinent alcoholics, as blunted response. This finding sug- impairing effects of alcohol. Along during alcohol withdrawal, but the gests that TSH change might be a these lines, an exciting effect current- prolactin response normalizes. The marker for vulnerability to alcohol and ly under study is the ability of TRH to reason for this effect is not clear. It might point to some neurobiological decrease craving for alcohol. Exper-

VOL. 21, NO. 1, 1997 61 iments have used TA-0910, a degrada- Another school of suggests that PANCREATIC FUNCTION tion-resistant compound (i.e., one that the most important deleterious effect of is difficult to destroy) whose chemical alcohol on bone is not mediated Control of blood is a finely structure resembles TRH (i.e., is a through PTH but rather by direct inhibi- tuned process involving the key hor- TRH analog) (Mason et al. 1995). tion of the function of bone-forming mone insulin, which is produced by special cells of the pancreas called β TA-0910 dose-dependently reduced cells called osteoblasts (Kimble 1997; cells. (For more information on the rats’ consumption of alcohol and Klein 1997; Sampson 1997). effects of alcohol on the pancreas, see increased their intake of tap Contributing to the problem of during the 24-hour postinjection inter- the article by Apte and colleagues, pp. bone demineralization is alcohol- 13Ð20.) Insulin synthesis and secretion val. These early data suggest the pos- induced testosterone suppression. The sibility that alcohol intake is based in are controlled by a complex cascade of importance of androgens for maintain- part on deficient extrahypothalamic hormonal signals and enzymes that ing bone mass in adult males is well β TRH neural systems and offer the operate within each cell, resulting in exciting prospect of the use of TRH established (Kelly et al. 1990). Andro- the release of insulin into the blood analogs clinically in the treatment of gens also appear to increase bone circulation. Once insulin reaches its alcoholism. formation at critical areas in the long appropriate target cells, especially liver, of the body and at areas of the muscle, and bone, it binds to a receptor bones (i.e., cortical) that promote and activates a process by which pro- ALCOHOL, CALCIUM BALANCE, normal bone growth. Several lines of teins called glucose transporters are AND BONE evidence firmly correlate reduced produced and brought to the surfaces of skeletal mass with reduced testos- the various target cells. They then facil- To form bone that is structurally sound, terone levels in men (Orwoll and Klein itate entry of glucose into these cells, normal calcium and phosphorous bal- 1995): Men who experience testos- which can be used immediately for ance is essential. Active D terone deprivation for any reason energy or stored for the cells’ future use. (i.e., cholecalciferol) is formed primar- throughout their have decreased The effect of alcohol ingestion on ily in the in the presence of sun- blood glucose in diabetic individuals bone mass. Thus, low testosterone light; smaller amounts are obtained is highly dependent on whether the through diet. The active form of vita- levels resulting from alcohol ingestion alcohol intake is acute or chronic and min D next is metabolized to a more can result in osteoporosis, causing whether it is consumed in the fed or active form in the liver (i.e., 25-hydroxy- increased risk of bone fractures. A fasted state.5 Research shows that cholecalciferol), then to an even more reduction in bone mass of 50 percent when nonfasted diabetics drink alco- potent form in the , (i.e., 1,25- has been reported in chronic alcoholics hol acutely, no seriously harmful dihydroxycholecalciferol) under the (Feitelberg et al. 1987; Moniz 1994), effect on blood glucose occurs. (For a control of (PTH). confirming the magnitude of this prob- review of alcohol’s effects on dia- The most active form of , lem. Thus, the problem with accelerat- betes, see Swade and Emanuele in 1,25-dihydroxycholecalciferol, is ed osteoporosis in males exposed to press.) The effect of chronic alcohol responsible for normal calcium ab- alcohol seems to be related to calcium intake is quite different, however. Ben sorption from the intestinal tract. The malabsorption with subsequent PTH and colleagues (1991) studied 46 impact of alcohol on calcium metab- elevation and low testosterone levels. diabetics who were “habitual olism has been explored, and studies Coupled with the problem of osteo- drinkers”; 35 diabetics with no sub- generally have confirmed that alcohol porosis is the fact that the increase in stantial drinking history; and 40 non- will impair calcium absorption from PTH release not only encourages more diabetic, nondrinking control subjects. the upper part of the gastrointestinal avid calcium absorption from the GI One of the parameters examined was (GI) tract (i.e., the jejunum and ) tract but also results in enhanced phos- hemoglobin A1C values. Hemoglobin (Kelly et al. 1990). This impairment in A1C is a form of hemoglobin that has phorous into the urine, with calcium absorption leads to a fall in a glucose component attached to it the resultant effect of low serum phos- serum calcium levels, which feeds (i.e., is glycosylated). The higher the back to the parathyroid glands, result- phorous levels (i.e., hypophospha- average blood glucose, the greater the ing in an increase in secretion by this temia). Hypophosphatemia has percentage of hemoglobin that is gland of parathyroid hormone (PTH). profound effects on muscles, resulting glycosylated. Hemoglobin A1C levels Elevated PTH, in turn, leads to calci- in weakness of the and pelvic reflect average blood glucose control um resorption or calcium withdrawal girdle muscles, making it difficult for from bone, leading to demineralization patients to perform simple maneuvers 5A fed state is one in which a person has con- of the bone and bone disease (i.e., such as rising from a sitting position sumed normal quantities of food over the 8 hours and climbing stairs. (For more infor- preceding measurement of blood components or osteoporosis). (For more information other physiological factors; a fasted state is one on alcohol’s effects on the GI tract, see mation on hypophosphatemia, see the in which a person has consumed no food for at the article by Bode and Bode, pp. 76Ð83.) article by Epstein, pp. 84Ð92). least the 8 hours preceding measurements.

62 ALCOHOL HEALTH & RESEARCH WORLD Alcohol and the Endocrine System

over the preceding 2 to 3 months; depleted, the body turns to gluconeo- axis in the male. Alcoholism: Clinical and higher A1C values indicate poorer genesis, its second line of defense. Experimental Research 6:207Ð215, 1982. blood-glucose control. Hemoglobin Gluconeogenesis is the formation of EMANUELE, M.A.; TENTLER, J.J.; REDA, D.; A1C values were significantly higher new glucose from amino acids and KIRSTEINS, L.; EMANUELE, N.V.; AND LAWRENCE, in the diabetics who were habitual other chemical substances, a process A.M. The effect of in vitro ethanol exposure on LHRH release from perifused rat hypothalami. drinkers than in nondrinking diabet- occurring primarily in the liver. In Endocrine Research 16:313Ð321, 1990. ics; the nondrinking diabetics had conditions of alcoholic hypoglycemia, hemoglobin A1C values significantly patients are usually starved, and their EMANUELE, M.A.; HALLORAN, M.M.; UDDIN, S.; TENTLER, J.J.; EMANUELE, N.V.; LAWRENCE, higher than the nondrinking, nondia- glycogen reserve has already been A.M.; AND KELLEY, M.R. The effects of alcohol betic control subjects. depleted. Furthermore, the metabolism on the neuroendocrine control of reproduction. Ben and colleagues (1991) also of alcohol shuts down the process of In: Zakhari, S., ed. Alcohol and the Endocrine measured levels of C , a by- gluconeogenesis; consequently, no System. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 23. product of insulin synthesis that is a glucose can be formed. Because of NIH Pub. No. 93Ð3533. Bethesda, MD: the good measure of insulin secretion. depleted glycogen reserves and im- Institute, 1993. pp. 89Ð116. Compared with the nondiabetic, non- paired gluconeogenesis, the person ERICKSON, G.F. The ovary: Basic principles and drinking control subjects, C-peptide becomes hypoglycemic. Some of the concepts. In: Felig, P.; Baxter, J.D.; and Frohman, levels were significantly lower in the most profound hypoglycemia seen L.A., eds. Endocrinology and Metabolism. New two diabetic groups. Comparisons of clinically is alcoholic hypoglycemia, York: McGraw-Hill, 1995. pp. 973Ð1048. the two diabetic groups, however, which can lead to permanent neurolog- FEITELBERG, S.; EPSTEIN, S.; AND ISMAIL, F. showed no significant difference in C ical consequences, such as paralysis, Deranged bone metabolism in chronic . Thus, although the alcohol- , coma, or even death. alcoholism. Metabolism 36:322Ð326, 1987. drinking diabetics had higher-than- GARBUTT, J.C.; SILVA, S.G.; AND MASON, G.A. average blood glucose levels (as Thyrotropin-releasing hormone (TRH): Clinical reflected in the hemoglobin A1C lev- CONCLUSION neuroendocrine and neurobehavioral findings of els) compared with the non-alcohol- relevance to alcoholism. In: Watson, R.R., ed. The effects of alcohol on the Drug and Alcohol Abuse Reviews, Vol. 6: drinking diabetics, the two groups’ endocrine system have far-reaching Alcohol and Hormones. Totowa, NJ: Humana insulin secretion was equivalent. Thus, Press, 1995. pp. 127Ð145. consequences not only for hormone the mechanism of elevated glucose is KELLY, P.J.; POCOCK, N.A.; SAMBROOK, P.N.; likely explained by an alcohol-associ- production but also for the function of virtually every . Alcohol- AND EISMAN, J.A. Dietary calcium, sex hor- ated increase in insulin resistance or mones and bone mineral density in men. British the inability of insulin to work proper- related problems include immune Medical Journal 300:1361Ð1364, 1990. ly at the cellular level. This condition dysfunction as a result of disturbances in cortisol, testosterone, GH, and KIMBLE, R.B. Alcohol, , and estrogen of insulin resistance is aggravated by in the control of bone remodeling. Alcoholism: the sedentary lifestyle and poor prolactin; reproductive problems; Clinical and Experimental Research 21:385Ð habits of some alcoholics. cardiovascular abnormalities stem- 391, 1997. ming from disrupted glucose and lipid In the fed state, chronic alcohol KLEIN, R.F. Alcohol-induced bone disease: consumption raises blood glucose; in balance; and bone disease, among Impact of ethanol on osteoblast proliferation. others. The role of hormones, such as Alcoholism: Clinical and Experimental Research the fasted state, alcohol can produce 21:392Ð399, 1997. low blood glucose (i.e., hypoglycemia) TRH, in the genesis of alcoholism is in both diabetics and nondiabetics. In an exciting area of research; findings MASON, G.A.; REZVANI, A.H.; AND GARBUTT, J.C. Effects of TA-0910, a thyrotropin-releasing addition to simply not eating, alcoholic in this area may produce innovative treatments for the disorder. hormone analog, on alcohol intake in alcohol- hypoglycemia occurs for two main preferring rats. In: Watson, R.R., ed. Drug and reasons. In the state, the body Alcohol Abuse Reviews, Vol. 6: Alcohol and has two major defense mechanisms to Hormones. Totowa, NJ: Humana Press, 1995. REFERENCES pp. 161Ð176. prevent hypoglycemia: glycogenolysis and gluconeogenesis. 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64 ALCOHOL HEALTH & RESEARCH WORLD