Alcoholic Beverages as a Source of Estrogens Judith S. Gavaler, Ph.D. Alcoholic beverages contain not only alcohol but also numerous other substances (i.e., con- geners) that may contribute to the beverages’ physiological effects. Plants used to produce alcoholic beverages contain estrogenlike substances (i.e., phytoestrogens). Observations that men with alcoholic cirrhosis often show testicular failure and symptoms of feminization have suggested that alcoholic beverages may contain biologically active phytoestrogens as con- geners. Biochemical analyses have identified several phytoestrogens in the congeners of bourbon, beer, and wine. Studies using subjects who produced no estrogen themselves (i.e., rats whose ovaries had been removed and postmenopausal women) demonstrated that phyto- estrogens in alcoholic beverage congeners exerted estrogenlike effects in both animals and humans. Those effects were observed even at moderate drinking levels. KEY WORDS: alcoholic beverage; congener; estrogens; male; female; plant; alcoholic liver cirrhosis; testicular dysfunc- tion; feminization; hypothesis testing; biochemical mechanism; animal model; ovary; moderate AOD use; prolactin; follicle stimulating hormone; luteinizing hormone; cholesterol; globulins; literature review he excessive consumption of drinking also includes people who con- in addition to alcohol itself (i.e., con- alcoholic beverages is associated sume alcoholic beverages only occasionally geners), which determine a beverage’s Twith numerous serious medical, and corresponds to the recommended taste, color, and aroma. Alcoholic bev- social, and legal problems that exact a limits for low-risk alcohol consumption erages differ in both the composition high human and economic price. Despite (U.S. Department of Agriculture and and quantity of congeners. These varia- the monumental problems caused by U.S. Department of Health and Human tions result from the different methods alcohol abuse and dependence, however, Services 1995). the fact is that most people who drink When discussing the risks and bene- consume moderate amounts of alcoholic fits associated with alcoholic beverages, JUDITH S. GAVALER, PH.D., is a profes- beverages. Indeed, an additional direction most people think in terms of the bev- sor at the Oklahoma Medical Research for alcohol research has been generated erages’ alcohol contents. Consequently, Foundation and an adjunct professor of by reports of the beneficial effect of mod- much of the research aimed at determin- biostatistics and epidemiology at the erate drinking on the risk of coronary ing how alcoholic beverages affect the University of Oklahoma College of Public heart disease (CHD) (Klatsky 1994). body has been conducted using alcohol Health, Oklahoma City, Oklahoma. Thus, studies have found that compared solutions to approximate the effects of with abstainers and heavier drinkers, alcoholic beverages. Alcoholic beverages, This work has been supported by National moderate drinkers (i.e., women who con- however, contain numerous substances Institute on Alcohol Abuse and Alcoholism sume up to one standard drink1 per day grants AA–06772 and AA–11184, and men who consume up to two drinks 1A standard drink is defined as a 12-ounce bottle the Office of Research on Women’s per day) have a significantly reduced risk of beer or wine cooler, a 5-ounce glass of wine, or Health, and the Office of Research of CHD. This definition of moderate 1.5 ounces of 80-proof distilled spirits. on Minority Health. 220 Alcohol Health & Research World Alcoholic Beverages as a Source of Estrogens and materials (e.g., grains, fruits, and The estrogen-receptor complexes then compounds, including phytoestrogens. hops) from which the beverages are move into the cell nucleus, where the The hypothesis has been tested in bio- produced. This article explores the transported estrogen is transferred to chemical analyses, animal models, and hypothesis that congeners, particularly nuclear estrogen receptors. The nuclear human studies. The results of those phytoestrogens, contribute to the effects complexes, in turn, interact with a certain analyses are summarized in the follow- of alcoholic beverages on the body. type of genetic molecule (i.e., ribonucleic ing sections. acid [RNA]) in the nucleus, thereby influencing the activity of certain genes Evidence of the Estrogenic and modifying the cell’s function. The Biochemical Analyses Activity of Congeners strength (i.e., specificity and affinity) with which estrogens bind to their recep- To investigate the hypothesis that some Researchers’ interest in the congeners tors differs among the molecules. Thus, of the effects of alcoholic beverages result of alcoholic beverages first was spurred steroidal estrogens exhibit greater affin- from estrogenic congeners, researchers by various reports in the agricultural ity and specificity for estrogen receptors removed all of the alcohol, other volatile literature. For example, some studies than do nonsteroidal phytoestrogens substances, and most of the water con- reported that grazing animals feeding on (Rosenblum et al. 1993; Hertog et al. tained in various alcoholic beverages (e.g., particular forages and grasses showed 1993; Miksicek 1995; Makela et al. 1995) bourbon, wine, and beer) using a tech- evidence of impaired reproduction. Sub- and therefore generally are more pow- nique called rotoevaporation (see figure sequently, using those forages, researchers erful in their actions. 1). The resulting congener concentrates isolated substances that exhibited estro- then were subjected to sophisticated genlike activity and later identified them Phytoestrogens in Alcoholic biochemical analyses, such as gas chro- as estrogenlike substances of plant origin Beverages—A Hypothesis matography and mass spectrometry, (i.e., nonsteroidal phytoestrogens) (see to isolate and identify any estrogenic the following section). Finally, studies Case studies have shown that men with demonstrated that the phytoestrogens liver damage resulting from excessive found in milled by-products and oils alcohol consumption (i.e., alcoholic made from various grains, hops, corn, cirrhosis) often suffer from testicular and rice exhibited biological activity both failure—the inability of the testes to Alcoholic beverage in experimental animals and in studies produce male sex hormones. In addi- (e.g., wine, using cultured cells (see Gavaler et al. tion, those men also frequently show bourbon, 1987a,b; 1995a,b; and references therein). signs and symptoms of feminization, beer) such as enlarged breasts and a redistri- Estrogens and Their Activities bution of body fat into a pattern that mimics that of women (for reviews, see Rotoevaporation Estrogens are female sex hormones that Wright et al. 1992; Gavaler and Van remove are produced primarily in the ovaries. Thiel 1988). These signs and symptoms • Alcohol These hormones play essential roles in are consistent with exposure to high (ethanol) the development and maintenance of levels of estrogen. Surprisingly, however, • Other the female reproductive organs and the levels of the steroidal estrogens in volatile breasts as well as in pregnancy and cirrhotic, feminized men are similar substances lactation. In men, small amounts of to or only slightly elevated compared • Most of the water estrogens are produced in the testes. with the levels in age-matched non- Congener (For more information on estrogens alcoholic men. concentrate for administration to and their functions, see the article by The fact that alcoholic beverages are OVEX rats and Hiller-Sturmhöfel and Bartke, pp. made from many plants and plant by- postmenopausal 153–164.) Based on the structure of products that contain phytoestrogens women the molecules, two main classes of has led to the hypothesis that alcoholic estrogens exist: steroidal and non- beverages contain biologically active steroidal. The steroidal estrogens— phytoestrogens as congeners. According estradiol and estrone—are generated to this hypothesis, two factors might Figure 1 Schematic representation of by the body. Nonsteroidal estrogens, contribute, at least in part, to the femi- the preparation of alcoholic beverage also known as phytoestrogens, are nization observed in men with alcoholic congener concentrates, which can be produced by certain plants. cirrhosis: (1) prolonged exposure to the used to investigate the effects of those Estrogens exert their effects by entering phytoestrogens contained in alcoholic congeners in rats whose ovaries have their target cells, where they bind to beverage congeners and (2) the impaired been removed (OVEX rats) and in docking molecules (i.e., receptors) in the ability of the alcohol-damaged liver to postmenopausal women. fluid that fills the cell (i.e., the cytosol). adequately metabolize and excrete many Vol. 22, No. 3, 1998 221 compounds present. Those analyses identified two phytoestrogens—sitosterol and biochanin A—in bourbon; two A additional phytoestrogens—daidzein Ovariectomized rats and genistein—were present in beer (Rosenblum et al. 1987, 1991). Other 0 Begin daily adminis- phytoestrogens have been identified in tration of water, wine (Hertog et al. 1993). bourbon congeners, In addition, both the congener con- Week 1 or red wine con- centrates and the purified phytoestro- geners equivalent to gens were examined for their ability to one drink (low dose) bind to estrogen receptors and to com- Week 2 or two drinks (high pete with estradiol for binding to dose) per day estrogen receptors in the cytosol (Gavaler