The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones

Abstract

Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the “sexual dimorphism” is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.

Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease

“…The consequences of Prlr gene inactivation on the female adrenal cortex cannot be attributed to effects on the X-zone since this is normally present in Prlr -/-females (our unpublished results), consistent with data showing that disruption of Stat5-dependent signalling has no influence on X-zone growth kinetics and regression in mice. [25] These data are consistent with the emerging scenario of PRL signalling being involved in shaping sexual dimorphism of several physiopathological phenomena and responses (e.g., pain perception, [26] sensitivity to migraine, [27] response to liver injury [28] ).…”

Increased visceral fat area to skeletal muscle mass ratio is positively associated with the risk of cardiometabolic diseases in a Chinese natural population: A cross‐sectional study

“…Therefore, when visceral fat increases, women are at higher risk of cardiometabolic diseases compared with men. Women may be protected from atherosclerotic cardiovascular disease, MAFLD, and other cardiometabolic diseases due to estrogen before menopause 27–29 . When women are in the postmenopausal stage, the risk of cardiometabolic diseases is further elevated for the protective effect of estrogen has been lost during this stage 30 .…”

Estrogen-related genes influence immune cell infiltration and immunotherapy response in Hepatocellular Carcinoma

“…Therefore, there is an urgent need for effectively predictive biomarkers to assist in screening potential populations that could benefit from immunotherapy, further to guide the rational application of immune drugs in clinical practice, improve patient response rates, and reduce the risk of immunotoxicity in patients. As a potent endogenous antioxidant, estrogen contributes to the development of a variety of liver disorders, including liver fibrosis, NAFLD, and hepatocellular carcinoma (34)(35)(36). In addition to being a consequence of disease progression, abnormal estrogen levels may also play a role in the pathophysiology of the development of chronic liver disorders.…”