Hypogonadism precedes liver feminization in chronic alcohol-fed male rats

Abstract

Men who chronically abuse alcohol may display a spectrum of endocrine abnormalities including hypogonadism and feminization, with elevated serum estradiol and low serum testosterone. We examined factors that may result in disruption of hepatic sex hormone homeostasis in alcoholfed male rats and possible consequences of such changes. Rats were fed alcohol-containing or isocaloric diets for 30, 60, and 90 days. In alcohol-fed rats, serum testosterone levels and hepatic activity of 2 androgen-dependent estrogen metabolizing enzymes were reduced (P F .05) at all times, as was activity of androgen receptor. There was also a significant early and progressive decrease in testes/body ratio in alcohol-fed rats. Compared with this early decrease in testosterone-related parameters, there was a significant increase in serum estrogen levels (at 30 and 90 days, 132% and 168% of control values, respectively). An increase in serum ceruloplasmin, an estrogen-responsive liver protein, was apparent at 60 and 90 days, but not at 30 days of alcohol exposure, suggesting that hypogonadism precedes liver feminization. Hepatic estrogen receptor activity was decreased in alcohol-fed rats at 60 and 90 days, the latter despite elevated serum estrogen levels. Hepatic aromatase was slightly increased in alcohol-fed rats, an elevation probably not sufficient to account for observed increases in serum estrogen. Taken together, these data suggest that (1) alcohol induces profound reduction of serum testosterone, resulting in loss of androgen-regulated hepatic functions such as estrogen-metabolizing enzyme activity and activity of androgen receptors; and (2) Hypogonadism and feminization of chronic alcoholic men have long been recognized as clinical syndromes and are most apparent in alcoholic cirrhosis, with defined signs such as gynecomastia, palmar erythema, testicular atrophy, loss of chest hair, and spider angiomata, together with an increased serum estrogen-to-testosterone ratio. 1,2 However, it has also been noted that similar changes occur in men who chronically abuse alcohol but are without cirrhosis or without apparent liver disease. 3,4 This latter finding suggests that changes in sex hormone homeostasis may occur because of the effect of ethanol per se, and not only because of liver disease and the circulatory changes in cirrhosis. With the development of experimental animal models of alcoholic liver disease together with more sensitive research techniques, a debate has existed for the past 3 decades regarding possible underlying mechanisms of this phenomenon in alcoholics. 5 It is now clear that there is an inversion of serum sex hormone levels (low testosterone versus higher estrogen) in alcoholic men, based on a number of studies in rodent models and in humans. However, the failure of sex hormone therapy to substantially correct those changes in patients with alcoholic liver disease 6,7 revealed that such an approach to this problem was simplistic, and that the complete timing and chain of events in the mechanism of sex hormone s...

Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice

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Sex differences in hepatic gene expression in a rat model of ethanol-induced liver injury

“…Serum was prepared from blood by standard centrifugation methods. This animal model has also been used in our previous work (14,50, and references therein).…”

“…In particular, males exposed chronically to alcohol develop a more female pattern of serum sex hormones and of liver gene expression. A striking example of the latter is the alcohol-induced loss of androgen-dependent estrogen metabolizing enzymes in male rats (14,50). The changes noted in some of the genes in male rats, especially those that are under androgen control, may lead to a hypothesis that the major sex hormone, i.e., androgen in male rats and estrogen in female rats, may have an overall protective role.…”

Testosterone Therapy Differently Regulates the Anti‐ and Pro‐Inflammatory Cytokines in the Plasma and Prostate of Rats Submitted to Chronic Ethanol Consumption (UChB)

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