The Endocrine System 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 body. 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 bone 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; gonad function; hormones; cardiovascular disorder; immune disorder; bone; calcium; pancreas; drug therapy; literature review long with the nervous system, length, and pattern of alcohol expo- tions, including reproduction, metab- the endocrine, or hormonal, sure; level of intoxication; and coex- olism, use of nutrients, and growth. A system is the primary regula- isting medical problems, such as tory mechanism for virtually the entire malnutrition and liver dysfunction, NICHOLAS EMANUELE, M.D., is human body. Hormones are chemical must be considered when assessing professor of medicine and director messengers that control and coordi- the impact of alcohol on hormonal of the Division of Endocrinology nate the function of tissues and organs. status. This article summarizes the and Metabolism, Loyola University Each hormone is secreted from a partic- effects of both acute and chronic alco- Medical School, Maywood, Illinois, ular gland and distributed throughout hol exposure on hormonal physiology, 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 animal models. of nerve 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 hypothalamus is the control cen- Hospital. She is also professor of lease of enzymes and changes in cell ter for most of the body’s hormonal systems. Located deep within the molecular and cellular biochemistry membranes. Highly sensitive feed- and a member of the Division on brain, 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). Glucocorticoids have many physio- logical effects; they influence carbohy- drate, lipid, protein, and nucleic acid + Stress metabolism; the cardiovascular sys- tem; bone and calcium metabolism; the central nervous system; 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 immune system, reproduction, and temperature regulation (Miller and Adrenal glands Tyrrell 1995). Although increases in ACTH and glucocorticoids are usually Cortisol Kidneys short-lived (i.e., transient), this stimu- lation has far-reaching consequences + for numerous other organ 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 glucocorticoid in corticotropin-releasing factor (CRF), which in turn increases secretion of adrenocortotropic hormone (ACTH) by the anterior pituitary gland. In humans 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 feedback to both the hypo- terone, with females showing a greater thalamus and the anterior pituitary, 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 – = 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. 93–96. function together as a well-coordinat- tropes, which produce adrenocortico- ed unit known as the hypothalamic- tropic hormone (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 tissue, the corticotropin-releasing factor (CRF) signal (in this case, glucocorticoids) results in a adrenal gland, 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 HEALTH & RESEARCH WORLD Alcohol and the Endocrine System naturally occurring CRF with antibod- animals, 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 neurons 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 infection, 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. 30–41.)