Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease

Author:

Grossmann Mathis12ORCID,Wierman Margaret E34,Angus Peter15,Handelsman David J6

Affiliation:

1. Department of Medicine Austin Health, University of Melbourne, Heidelberg, Victoria, Australia

2. Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia

3. Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado

4. Research Service, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado

5. Departments of Gastroenterology and Hepatology, Heidelberg, Victoria, Australia

6. ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, New South Wales, Australia

Abstract

Abstract The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function affects the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone–binding globulin (SHBG). The liver senses the body’s metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction. Sex steroids impact the pathogenesis of nonalcoholic fatty liver disease, including development of hepatic steatosis, fibrosis, and carcinogenesis. Preclinical studies in male rodents demonstrate that androgens protect against hepatic steatosis and insulin resistance both via androgen receptor signaling and, following aromatization to estradiol, estrogen receptor signaling, through regulating genes involved in hepatic lipogenesis and glucose metabolism. In female rodents in contrast to males, androgens promote hepatic steatosis and dysglycemia, whereas estradiol is similarly protective against liver disease. In men, hepatic steatosis is associated with modest reductions in circulating testosterone, in part consequent to a reduction in circulating SHBG. Testosterone treatment has not been demonstrated to improve hepatic steatosis in randomized controlled clinical trials. Consistent with sex-dimorphic preclinical findings, androgens promote hepatic steatosis and dysglycemia in women, whereas endogenous estradiol appears protective in both men and women. In both sexes, androgens promote hepatic fibrosis and the development of hepatocellular carcinoma, whereas estradiol is protective.

Funder

National Health and Medical Research Council

Publisher

The Endocrine Society

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

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