Ethanol-induced increase in cytosolic estrogen receptors in human male liver: A possible explanation for biochemical feminization in chronic liver disease due to alcohol

Villa, Erica; Baldini, G; Rossini, Gian Paolo; Pasquinelli, Claudio; Melegari, Margherita; Cariani, Elisabetta; Tata, C.; Bellentani, Stefano; Ferrari, A.; Manenti, F.

doi:10.1002/hep.1840080623

Cited by 30 publications

(25 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…39 For example, some evidence from human studies showed only an increased cytosolic ER protein in patients with active alcoholic liver disease and current drinking, but a determination of nuclear ER activity was not performed. 38 In summary, our data suggest that alcohol induces an early and profound reduction of serum testosterone levels, which further results in loss of androgen-regulated hepatic functions such as estrogen-metabolizing enzyme activity and the activity of androgen receptors. Such alcohol-induced hypogonadism precedes the changes in hepatic sex hormone homeostasis and subsequent feminization in male rats.…”

Section: Discussionmentioning

confidence: 64%

“…This delay of the serum increase in ceruloplasmin may suggest that hypogonadism precedes an expression of liver feminization. This apparently discrepant relationship between serum estrogen levels and activity of hepatic estrogen receptors reflects already existing different opinions about ER activity in alcoholic liver disease 10,[36][37][38][39] that may result from difficulties in comparing experimental animal models and human studies, insufficient data from animal models, and variability of findings in human studies. 39 For example, some evidence from human studies showed only an increased cytosolic ER protein in patients with active alcoholic liver disease and current drinking, but a determination of nuclear ER activity was not performed.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hypogonadism precedes liver feminization in chronic alcohol-fed male rats

et al. 2000

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Hypogonadism precedes liver feminization in chronic alcohol-fed male rats

et al. 2000

View full text Add to dashboard Cite

show abstract

“…The hyperestrogenemia commonly seen in male alcoholic cirrhosis adds to the complexity of this relationship. It has been shown that prolonged ethanol consumption induces an increase in the hepatic estrogen receptors in males, especially in patients with alcoholic hepatitis (Villa et al, 1988). However, our study was not powerful e n o u g h d u e to the very small number of HCC patients who were carriers-to study the interaction between cirrhosis or alcohol and HBsAg or any interaction of risk factors with sex.…”

Section: Discussionmentioning

confidence: 80%

Risk factors for hepatocellular carcinoma in catalonia, spain

Mayans

Calvet

Bruix

et al. 1990

Intl Journal of Cancer

View full text Add to dashboard Cite

The influence of hepatitis B virus infection, alcohol consumption, tobacco smoking and use of oral contraceptives on the risk of hepatocellular carcinoma (HCC) was evaluated in a hospital-based case-control study in Catalonia, in the Mediterranean coastal area of north-eastern Spain. A total of 96 HCC cases (86.5% of them with associated liver cirrhosis) and 190 age- and sex-matched controls were studied. The odds ratio of HCC and 95% confidence interval among hepatitis B surface antigen (HBsAg) carriers was 4.9 (1.3-21.9). The OR was not significantly elevated in smokers, and a marginally significant increased risk was found among users of oral contraceptives based on 6 female cases. There was a significant dose-response relationship between alcohol consumption and risk of HCC (chi 2 for trend: 24.3, p less than 0.001). Although hepatitis B infection was strongly associated with HCC, alcohol abuse leading to cirrhosis appears to be one of the main causes of HCC in this region.

show abstract

“…Moderate to high ethanol intake is also reported to influence sex hormone levels in men; in particular, plasma testosterone levels decrease, probably via alcohol-induced inhibition of testosterone (18). In addition, ethanol induces an increase in cytosolic ER in the human male liver, a possible explanation for feminization in chronic liver disease due to alcohol (19). However, the influence of such variations in endogenous sex hormone levels and ER on cardiovascular physiology in men with obesity or chronic liver disease is unknown.…”

Section: Evidence Of a Role For Endogenous Estrogens In Menmentioning

confidence: 94%

Cardiovascular Actions of Estrogens in Men

Sudhir¹

1999

Journal of Clinical Endocrinology & Metabolism

View full text Add to dashboard Cite

C ardiovascular disease is the major cause of death among both men and women in developed countries. Coronary artery disease, the single most important component of cardiovascular disease, is responsible for about one quarter of all deaths. It is well recognized that, at all ages, women are relatively protected against cardiovascular disease in comparison with men, and many observational studies have suggested that estrogen treatment of postmenopausal women significantly reduces cardiovascular risk (1). Further, the Postmenopausal Estrogen/Progestin Intervention (PEPI) Study (2), which assessed the effect of hormonal therapy on cardiovascular risk factors over a 3-yr period, showed beneficial effects on lipoproteins in all treatment groups and concluded that the best regimen for women with an intact uterus was estrogen plus micronized progesterone, and the best regimen for women without a uterus was unopposed estrogen. However, the recently concluded Heart Estrogen/ progestin Replacement Study (HERS) found no significant evidence of a clinical benefit of hormonal therapy in women with established coronary artery disease (3). The question of whether such therapy is useful in women as primary prevention against cardiovascular disease is being addressed by the Women's Health Initiative, the results of which will not be known for several more years (4).Although in men estrogens are produced in significant quantities by local tissue aromatization of androgenic precursors from the testes and adrenal glands (5), there has been relatively limited study of the biological role of these hormones or their clinical implications. An investigation conducted 25 years ago into the cardiovascular effects of estrogen administration in men after myocardial infarction, the "Coronary Drug Project" showed an excess of deaths and recurrent infarction in the treatment group. This trial, which employed high doses of conjugated equine estrogens, was subsequently abandoned, and the subject has not been studied in detail since (6). Data gathered over the last quarter century on the epidemiology of cardiovascular disease, the mechanisms of actions of estrogens in women and men, and the biological role of endogenously produced estrogens in men, suggest that it might be time to re-open the Coronary Drug Project file, and re-assess the potential for estrogen therapy in men. Newer approaches to treatment and an ability to identify more precisely individuals at risk of coronary heart disease (CHD) may lead to new clinical applications for this group of hormones. Evidence of a role for endogenous estrogens in men Endogenous estrogens, lipoproteins, and glucose metabolism.There is now compelling evidence that endogenous production of estrogens in men plays an important role in cardiovascular health and disease. Physiological levels of estrogen have been reported to play a role in influencing plasma lipoprotein concentrations in men. When selective estrogen deficiency was induced in young men by administration of combined drug therapy with a GnRH ant...

show abstract

Ethanol-induced increase in cytosolic estrogen receptors in human male liver: A possible explanation for biochemical feminization in chronic liver disease due to alcohol

Cited by 30 publications

References 25 publications

Hypogonadism precedes liver feminization in chronic alcohol-fed male rats

Hypogonadism precedes liver feminization in chronic alcohol-fed male rats

Risk factors for hepatocellular carcinoma in catalonia, spain

Cardiovascular Actions of Estrogens in Men

Contact Info

Product

Resources

About