National Institute on Alcohol Abuse and Alcoholism No. 26 PH 352 October 1994

Alcohol and Hormones

Hormones are chemical messengers that control and coordinate the functions of all tissues and organs. Each hormone is secreted from a particular gland and distributed throughout the body to act on tissues at different sites. Two areas of the brain, the hypothalamus and the pituitary, release hormones, as do glands in other parts of the body, such as the thyroid, adrenal glands, gonads, pancreas, and parathyroid. For hormones to function properly, their amount and the timing of their release must be finely coordinated, and the target tissues must be able to respond to them accurately. Alcohol can impair the functions of the hormone-releasing glands and of the target tissues, thereby causing serious medical consequences.

Hormones control four major areas of body function: production, utilization, and storage of energy; reproduction; maintenance of the internal environment (e.g., blood pressure and bone mass); and growth and development. This Alcohol Alert describes how, by interfering with hormone actions, alcohol can alter blood sugar levels and exacerbate or cause diabetes (1-4); impair reproductive functions (5,6); and interfere with calcium metabolism and bone structure, increasing the risk of osteoporosis (7). Conversely, hormones also may affect alcohol consumption by influencing alcohol-seeking behavior.

Alcohol Impairs Regulation of Blood Sugar Levels

The sugar glucose is the main energy source for all tissues. Glucose is derived from three sources: from food; from synthesis (manufacture) in the body; and from the breakdown of glycogen, a form of glucose that the body stores in the liver. Hormones help to maintain a constant concentration of glucose in the blood. This is especially important for the brain because it cannot make or store glucose but depends on glucose supplied by the blood. Even brief periods of low glucose levels (hypoglycemia) can cause brain damage.

Two hormones that are secreted by the pancreas and that regulate blood glucose levels are insulin and glucagon. Insulin lowers the glucose concentration in the blood; glucagon raises it. Because prevention of hypoglycemia is vital for the body, several hormones from the adrenal glands and pituitary back up glucagon function.

Alcohol consumption interferes with all three glucose sources and with the actions

of the regulatory hormones. Chronic heavy drinkers often have insufficient dietary intake of glucose (8). Without eating, glycogen stores are exhausted in a few hours (1). In addition, the body's glucose production is inhibited while alcohol is being metabolized (2). The combination of these effects can cause severe hypoglycemia 6 to 36 hours after a binge- drinking episode (1).

Even in well-nourished people, alcohol can disturb blood sugar levels. Acute alcohol consumption, especially in combination with sugar, augments insulin secretion and causes temporary hypoglycemia (9). In addition, studies in healthy subjects (10) and insulin-dependent diabetics (3) have shown that acute alcohol consumption can impair the hormonal response to hypoglycemia.

Chronic heavy drinking, in contrast, has been associated with excessive blood glucose levels (hyperglycemia). Chronic alcohol abuse can reduce the body's responsiveness to insulin and cause glucose intolerance in both healthy individuals (11) and alcoholics with liver cirrhosis (12). In fact, 45 to 70 percent of patients with alcoholic liver disease are glucose intolerant or are frankly diabetic (1). In animals, chronic alcohol administration also increases secretion of glucagon and other hormones that raise blood g lucose levels (13).

Alcohol consumption can be especially harmful in people with a predisposition to hypoglycemia, such as patients who are being treated for diabetes (3,4). Alcohol can interfere with the management of diabetes in different ways. Acute as well as chronic alcohol consumption can alter the effectiveness of hypoglycemic medications (14,15). Treatment of diabetes by tight control of blood glucose levels is difficult in alcoholics, and both hypoglycemic and hyperglycemic episodes are common (4). In a Japanese study, alcoholics with diabetes had a significantly lower survival rate than other alcoholics (16).

Alcohol Impairs Reproductive Functions

The human reproductive system is regulated by many hormones. The most important are androgens (e.g., testosterone) and estrogens (e.g., estradiol). They are synthesized mainly by the testes and the ovaries and affect reproductive functions in various target tissues. Other reproductive hormones are synthesized in the hypothalamus and pituitary. Although men and women produce many of the same hormones, their relative concentrations and their functions vary.

In men, reproductive hormones are responsible for sexual maturation, sperm development and thus fertility, and various aspects of male sexual behavior. In women, hormones promote the development of secondary sexual characteristics, such as breast development and distribution of body hair; regulate the menstrual cycle; and are necessary to maintain pregnancy. Chronic heavy drinking can interfere with all these functions. Its most severe consequences in both men and women include inadequate functioning of the testes and ovaries, resulting in hormonal deficiencies, sexual dysfunction, and infertility (5,6).

Alcohol is directly toxic to the testes, causing reduced testosterone levels in men. In a study of normal healthy men who received alcohol for 4 weeks, testosterone levels declined after only 5 days and continued to fall throughout the study period (17). Prolonged testosterone deficiency may contribute to a "femininization" of male sexual characteristics, for example breast enlargement (18).

In addition, animal studies have shown that acute alcohol administration affects the release of hormones from the hypothalamus and pituitary (5). Even without a detectable reduction of testosterone levels, changes in these hormones can contribute to the impairment of male sexual and reproductive functions (19). Alcohol also may interfere with normal sperm structure and movement by inhibiting the metabolism of vitamin A (20), which is essential for sperm development.

In premenopausal women, chronic heavy drinking can contribute to a multitude of reproductive disorders. These include cessation of menstruation, irregular menstrual cycles, menstrual cycles without ovulation, early menopause, and increased risk of spontaneous abortions (6,21,22). These dysfunctions can be caused by alcohol's interfering directly with the hormonal regulation of the reproductive system or indirectly through other disorders associated with alcohol abuse, such as liver disease, pancreatic disease, malnutrition, or fetal abnormalities (6).

Although most of these reproductive problems were found in alcoholic women, some also were observed in women classified as social drinkers, who drank about three drinks per day during a 3-week study (23). A significant number of these women had abnormal menstrual cycles and a delay or lack of ovulation.

Alcohol also affects reproductive hormones in postmenopausal women. After menopause, estradiol levels decline drastically because the hormone is no longer synthesized in the ovaries, and only small amounts are derived from the conversion of testosterone in other tissues. This estradiol deficiency has been associated with an increased risk for cardiovascular disease and osteoporosis in po stmenopausal women (24). Alcohol can increase the conversion of testosterone into estradiol (25). Accordingly, postmenopausal women who drank (24,26) were found to have higher estradiol levels than abstaining women. Studies have shown that in postmenopausal women, three to six drinks per week may reduce the risk of cardiovascular disease (27) without significantly impairing bone quality (24) or increasing the risk of alcoholic liver disease (28) or breast cancer (29).

Alcohol Impairs Calcium Metabolism and Bone Structure

Calcium exists in two forms in the body. The main reservoirs are the bones and teeth, where the calcium content determines the strength and the stiffness of the bones. The rest of the body's calcium is dissolved in the body fluids. Calcium is important for many body functions, including communication between and within cells. The overall calcium levels depend on how much calcium is in the diet, how much is absorbed into the body, and how much is excreted. Calcium absorption, excretion, and distribution between bones and body fluids are regulated by several hormones, namely parathyroid hormone (PTH); vitamin D-derived hormones; and calcitonin, which is made by specific cells in the thyroid.

Alcohol can interfere with calcium and bone metabolism in several ways. Acute alcohol consumption can lead to a transient PTH deficiency and increased urinary calcium excretion, resulting in loss of calcium from the body (30). Chronic heavy drinking can disturb vitamin D metabolism, resulting in inadequate absorption of dietary calcium (31).

Studies in alcoholics also have shown that alcohol is directly toxic to bone-forming cells and inhibits their activity (32-34). In addition, chronic heavy drinking can adversely affect bone metabolism indirectly, for example by contributing to nutritional deficiencies of calcium or vitamin D (7). Liver disease and altered levels of reproductive hormones, both of which can be caused by alcohol, also affect bone metabolism (7).

Calcium deficiency can lead to bone diseases, such as osteoporosis. Osteoporosis is characterized by a substantial loss of bone mass and, consequently, increased risk of fractures. It affects 4 million to 6 million mainly older Americans, especially women after menopause. In alcoholics, the risk of osteoporosis is increased (35). Because many falls are related to alcohol use (36), adverse alcohol effects on bone metabolism pose a serious health problem.

Studies with abstinent alcoholics have found that alcohol-induced changes in bone metabolism, including toxic effects on bone-forming cells, are at least partially reversible after cessation of drinking (32,33,37,38).

Hormones May Influence Alcohol-Seeking Behavior

The effects of alcohol on different hormonal pathways may in turn influence alcohol-

seeking behavior. For example, in animals, alcohol-seeking behavior appears to be regulated in part through a system called the renin-angiotensin system, which controls blood pressure and salt concentrations in the blood. In rats, activation of this system through alcohol consumption caused the animals to reduce their alcohol intake (39). The mechanism and relevance of this effect are currently under investigation.

Alcohol and Hormones--A Commentary by

NIAAA Director Enoch Gordis, M.D.

Alcohol's wide-ranging effects on the hormone system present many practical clinical concerns. For example, managing diabetes, particularly with the current emphasis on stringent control of blood sugar, is complicated by alcohol's interference with blood sugar levels. In the emergency room, stupor in patients with alcohol on their breath often is not caused by alcohol intoxication, but by the hypoglycemia (low blood sugar) that is a complication of heavy drinking. Failure to treat the hypoglycemia could have life-threatening consequences. Heavy drinking has a major effect on the reproductive system, affecting libido, fertility, and pregnancy. Heavy drinking also places postmenopausal women at risk for fractures from falls due to their increased risk for osteoporosis from alcohol's effect on blood estrogen levels coupled with their increased risk of falling due to drinking. However, it is possible that moderate alcohol use may help protect postmenopausal women against osteoporosis by raising blood estrogen levels. Scientists are working to discover for which population this may be true and at what drinking levels. Finally, research on how alcohol's interactions with hormones may contribute to the pathological drive to consume alcohol is just beginning and may provide valuable insight into the mechanisms by which alcohol-seeking behavior can be controlled.

References

(1) Gordon, G.G., & Lieber, C.S. Alcohol, hormones, and metabolism. In: Lieber, C.S., ed. Medical and Nutritional Complications of Alcoholism. New York: Plenum Publishing Corp., 1992. pp. 55-90. (2) Sneyd, J.G.T. Interactions of ethanol and carbohydrate metabolism. In: Crow, K.E., and Batt, R.D., eds. Human Metabolism of Alcohol, Vol. 3. Boca Raton, FL: CRC Press, 1989. pp. 115-124. (3) Avogaro, A.; Beltramello, P.; Gnudi, L.; Maran, A.; Valerio, A.; Miola, M.; Marin, N.; Crepladi, C.; Confortin, L.; Costa, F.; MacDonald, I.; & Tiengo, A. Alcohol intake impairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients: Evidence for a critical role of free fatty acids. Diabetes 42(11):1626-1634, 1993. (4) Crane, M., & Sereny, G. Alcohol and diabetes. British Journal of Addiction 83(12):1357-1358, 1988. (5) Emanuele, M.A.; Halloran, M.M.; Uddin, S.; Tentler, J.J.; Emanuele, N.V.; Lawrence, A.M.; & Kelley, M.R. The effects of alcohol on the neuroendocrine control of reproduction. In: Zakhari, S., ed. Alcohol and the Endocrine System. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 23. NIH Pub. No. 93-3533. Bethesda, MD: National Institutes of Health, 1993. pp. 89-116. (6) Mello, N.K.; Mendelson, J.H.; & Teoh, S.K. An overview of the effects of alcohol on neuroendocrine function in women. In: Zakhari, S., ed. Alcohol and the Endocrine System. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 23. NIH Pub. No 93-3533. Bethesda, MD: National Institutes of Health, 1993. pp. 139-170. (7) Laitinen, K., & Valimaki, M. Bone and the "comforts of life." Annals of Medicine 25(4):413-425, 1993. (8) Palmer, T.N.; Cook, E.B.; & Drake, P.G. Alcohol abuse and fuel homeostasis. In: Palmer, T.N., ed. Alcoholism: A Molecular Perspective. NATO ASI Series. Series A, Life Sciences Vol. 206. New York: Plenum Press, 1991. pp. 223-235. (9) O'Keefe, S.J., & Marks, V. Lunchtime gin and tonic a cause of reactive hypoglycemia. Lancet 1(8025):1286-1288, 1977. (10) Kolaczynski, J.W.; Ylikahri, R.; Harkonen, M.; & Koivisto, V.A. Acute effect of ethanol on counterregulatory response and recovery from insulin-induced hypoglycemia. Journal of Clinical Endocrinology and Metabolism 67(2):384-388, 1988. (11) Shah, J.H. Alcohol decreases insulin sensitivity in healthy subjects. Alcohol and Alcoholism 23(2):103-109, 1988. (12) Letiexhe, M.R.; Scheen, A.J.; Gerard, P.L.; Bastens, B.H.; Pirotte, J.; Belaiche, J.; & Lefebvre, P.J. Insulin secretion, clearance, and action on glucose metabolism in cirrhotic patients. Journal of Clinical Endocrinology and Metabolism 77(5):1263-1268, 1993. (13) Adams, M.A., & Hirst, M. Adrenal and urinary catecholamines during and after severe ethanol intoxication in rats: A profile of changes. Pharmacology, Biochemistry and Behavior 21(1):125-131, 1984. (14) Lewis, H., & Kendall, M.J. Alcohol and treatment of diabetes. Journal of Clinical Pharmacy and Therapeutics 13:312-328, 1988.

(15) Angelini, P.; Vendemiale, G.; & Altomare, E. Alcohol and diabetes mellitus. Alcologia 4(2):109-111, 1992. (16) Yokoyama, A.; Matsushita, S.; Ishii, H.; Takagi, T.; Maruyama, K.; & Tsuchiya, M. Impact of diabetes mellitus on the prognosis of alcoholics. Alcohol and Alcoholism 29(2)181-186, 1994. (17) Gordon, G.C.; Altman, K.; Southren, A.L.; Rubin, E.; & Lieber, C.S. The effects of alcohol (ethanol) administration on sex hormone metabolism in normal men. New England Journal of Medicine 295:793-797, 1976. (18) Bannister, P., & Lowosky, M.S. Ethanol and hypogonadism. Alcohol and Alcoholism 22(3):213-217, 1987. (19) Bartke, A. Chronic disturbances of the hypothalamic-pituitary-testicular axis: Effects on sexual behavior and fertility. In: Zakhari, S., ed. Alcohol and the Endocrine System. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 23. NIH Pub. No. 93-3533. Bethesda, MD: National Institutes of Health, 1993, pp. 69-87. (20) Leo, M.A., & Lieber, C.S. Hepatic vitamin A depletion in alcoholic liver injury. New England Journal of Medicine 307(10):597-601, 1982. (21) Alcohol and abortion. New Zealand Medical Journal 92:353, 1980. (22) Kline, J.; Levin, B.; Stein, Z.; Susser, M.; & Warburton, D. Epidemiologic detection of low dose effects on the developing fetus. Environmental Health Perspectives 42:119-126, 1981. (23) Mendelson, J.H., & Mello, N.K. Chronic alcohol effects on anterior pituitary and ovarian hormones in healthy women. Journal of Pharmacological and Experimental Therapy 245:407-412, 1988. (24) Gavaler, J.S., & Van Thiel, D.H. The association between moderate alcoholic beverage consumption and serum estradiol and testosterone levels in normal postmenopausal women: Relationship to the literature. Alcoholism: Clinical and Experimental Research 16(1):87-92, 1992. (25) Gordon, G.G.; Southren, A.L.; Vittek, J.; & Lieber, C.S. Effect of alcohol ingestion on hepatic aromatase activity and plasma steroid hormones in the rat. Metabolism 28(1):20-24, 1979. (26) Gavaler, J.S., & Van Thiel, D.H. Hormonal status of postmenopausal women with alcohol-induced cirrhosis: Further findings and a review of the literature. Hepatology 16(2):312-319, 1992. (27) Stampfer, M.J.; Colditz, G.A.; Willett, W.C.; Speizer, F.E.; & Hennekens, C.H. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. New England Journal of Medicine 319:267-273, 1988. (28) Gavaler, J.S.; Kelly, R.H.; Wight, C.; Sanghvi, A.; Cauley, J.; Belle, S.; & Brandt, K. Does moderate alcoholic beverage consumption affect liver function/injury tests in postmenopausal women? Alcoholism: Clinical and Experimental Research 12(2):337, 1988. (29) Willett, W.C.; Stampfer, M.J.; Colditz, G.A.; Rosner, B.A.; Hennekens, C.H.; & Speizer, F.E. Moderate alcohol consumption and the risk of breast cancer. New England Journal of Medicine 316:1174-1180, 1987. (30) Laitinen, K.; Lamberg-Allardt, C.; Tunninen, R.; Karonen, S.L.; Tahetla, R.; Ylikahri, R.; & Valimaki, M. Transient hypoparathyroidism during acute alcohol intoxication. New England Journal of Medicine 324(11):721-727, 1991. (31) Bjorneboe, A.-E.A.; Bjorneboe, A.; Johnsen, J.; Skylv, N.; Oftebro, H.; Gautvik,K.M.; Hoiseth, A.; Morland, J.; & Drevon, C.A. Calcium status and calcium-regulating hormones in alcoholics. Alcoholism: Clinical and Experimental Research 12(2):229-232, 1988. (32) Jaouhari, J.; Schiele, F.; Pirollet, P.; Lecomte, E.; Paille, F.; & Artur, Y. Concentration and hydroxyapatite binding capacity of plasma osteocalcin in chronic alcoholic men: Effect of a three-week withdrawal therapy. Bone and Mineral 21(3):171-178, 1993. (33) Pepersack, T.; Fuss, M.; Otero, J.; Bergmann, P.; Valsamis, J.; & Corvilain, J. Longitudinal study of bone metabolism after ethanol withdrawal in alcoholic patients. Journal of Bone and Mineral Research 7(4):383-387, 1992. (34) Bikle, D.D.; Stesin, A.; Halloran, B.; Steibach, L.; & Recker, R. Alcohol-induced bone disease: Relationship to age and parathyroid hormone levels. Alcoholism: Clinical and Experimental Research 17(3)690-695, 1993. (35) Rico, H. Alcohol and bone disease. Alcohol and Alcoholism 25(4):345-352, 1990. (36) Hingson, R., & Howland, J. Alcohol as a risk factor for injury or death resulting from accidental falls: A review of the literature. Journal of Studies on Alcohol 48(3):212-219, 1987. (37) Gonzalez-Calvin, J.L.; Garcia-Sanchez, A.; Bellot, V.; Munoz-Torres, M.; Raya-Alvarez, E.; & Salvatierra-Rios, D. Mineral metabolism, osteoblastic function and bone mass in chronic alcoholism. Alcohol and Alcoholism 28(5):571-579, 1993. (38) Laitinen, K.; Lamberg-Allardt, C.; Tunninen, R.; Harkonen, M.; & Valimaki, M. Bone mineral density and abstention-induced changes in bone and mineral metabolism in noncirrhotic male alcoholics. American Journal of Medicine 93(6):642-650, 1992. (39) Grupp, L.A. The renin-angiotensin system as a regulator of alcohol consumption: A review and some new insights. In: Zakhari, S., ed. Alcohol and the Endocrine System. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 23. NIH Pub. No. 93-3533. Bethesda, MD: National Institutes of Health, 1993. pp. 37-65.

ACKNOWLEDGMENT: The National Institute on Alcohol Abuse and Alcoholism wishes to acknowledge the valuable contributions of Judith Fradkin, M.D., Chief, Endocrinology and Metabolic Diseases Program Branch, National Institute of Diabetes and Digestive and Kidney Diseases, to the development of this Alcohol Alert.

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