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.

Keywords: chronic liver diseases; cirrhosis; mechanism; sex hormone; therapy.

Figure 1

Known mechanisms of the hepatoprotective and hepatotoxic effects of sex hormones (androgen, estrogen, and progesterone) on different liver cell types. Low level of testosterone increases the activity of LPL. The up-regulation of SREBP-1c and FASN lead to liver lipid deposition and aggravated insulin resistance. Those changes, together with the down-regulation of PEPCK and up-regulation of MAPK may lead to steatosis. Estrogen increases the content and oxidation capacity of mitochondria in hepatocytes. PGC1B promotes mitochondrial biogenesis. Estrogen also inhibits the activation of JNK and GPR30 to co-activate PKA and enhance liver PPARα and HNF4α to increase APOA5 expression and reduce TG. Estrogen (via its receptor alpha) induce cholesterol efflux from Kupffer cells with HDL. Estrogen can restore the expression of miR-29a/b to reduce the deposition of type I and III collagen, MDA, and α-SMA, to reduce liver fibrosis and other types of liver damage. Estrogen can also significantly reduce portal vein pressure by stimulating eNOS expression. Elevated progesterone leads to insulin resistance, stimulates PGRMC1 to increase hepatic glucose production, stimulates PGRMC1/2 to promote HEV replication, and inhibits IFN- λ1 expression. In addition, the accumulation of progesterone metabolites (PM2DiS, PM3S, PM3DiS) will increase the risk of ICP. Progesterone stimulates PR-B, PRGMC1, and PRGMC2 to facilitate bile duct cell proliferation. It also causes ROS environment via its receptor signaling, resulting in TGF-β1-activated HSC. APOA5, apolipoprotein A5; α-SMA, alpha-smooth muscle actin; eNOS, endothelial nitric oxide synthase 3; ERα, estrogen receptor alpha; FASN, fatty acid synthase; HDL, high-density lipoprotein; HSC, hepatic stellate cell; GPR30, G protein-coupled receptor 30; HNF4α, hepatocyte nuclear factor 4-alpha; ICP, Intrahepatic cholestasis of pregnancy; IFN-λ1, type III interferon-λ1; JNK, Jun N-terminal kinase; LPL, lipoprotein lipase; IR, insulin resistance; LXRα, liver X receptor alpha; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; mPRα, membrane progestin receptor alpha; PEPCK, phosphoenolpyruvate carboxykinase; PGC1B, proliferator-activated receptor gamma coactivator 1B; PGRMC, progesterone receptor membrane component; PKA, protein kinase A; PM2DiS/PM3DiS/PM3S, progesterone metabolites; PPARα, peroxisome proliferator-activated receptor alpha; PR, progesterone receptor; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase1; SRE, sterol regulatory element; SREBP-1c, sterol regulatory element-binding protein-1c; TG, triglyceride; TGF, transforming growth factor (Created with Biorender.com with a publication license).

Figure 2

Illustration of the involving mechanisms of sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) in liver physiology and pathology. GnRH increases the secretion of FSH through the PKA/CREB pathway, accelerates the differentiation of adipocytes in adipose tissue, which finally lead to hepatic fat accumulation. In amenorrhoea females with cirrhosis, abnormal GnRH secretion leads to low LH and FSH levels. FSH interacts with FSHR to reduce the level of LDLR, weaken the endocytosis of LDL-C, and lead to the increase of circulating LDL-C. After HRT treatment, FSH is inhibited and LDL-C content is improved. FSH activates Gi2 by binding to liver FSHRα/β-Arrestin-2/Akt pathway, which subsequently inhibits the binding between FoxO1 and SREBP-2, drives HMGCR transcription and de novo cholesterol biosynthesis, resulting in increased cholesterol accumulation. Liver transplantation can improve the hormone disorder related to chronic liver disease by restoring the circulating physiological levels of estradiol, FSH, LH, prolactin, testosterone, GH and IGF-1. Inhibition of prolactin by D2R activation leads to reduction of visceral adipose tissue. Prolactin improves hepatic steatosis through PRLR down regulation of FAT/CD36. Prolactin levels are significantly increased in patients with liver cirrhosis. Akt, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; CREB, cAMP response element binding protein; ESLD, End-stage liver disease; FAT, fatty acid translocase; FoxO1, forkhead box protein O1; FSH, follicle-stimulating hormone; FSHR, FSH receptor; GH, growth hormone; GnRH, gonadotrophin-releasing hormone; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HRT, hormone-replacement therapy; IGF, insulin growth factor; LDL, low-density lipoprotein; LDL-C, low-density-lipoprotein cholesterol; LDLR, LDL receptor; LH, luteinizing hormone; LT, liver transplantation; PKA, protein kinase A; PRLR, prolactin receptor (Created with Biorender.com with a publication license).

Figure 3

Possible involving mechanisms of sex/sex-related hormones in the regulation of the gut-liver axis. The intestinal microbiome is a complex microbial ecosystem. Androgen induced dysbacteriosis may aggravate PCOS and reduce the circulating Gln/Glu ratio. The study on the effects of intestinal microorganisms on gut brain mediators and sex hormones in patients with PCOS showed that prolactin, LH and LH/FSH ratio increased significantly, while brain-gut mediators and SCFAs decreased. Estrogen can improve colitis and protect mitochondrial function by ESRRA-mediated autophagy. One of the main regulators of circulating estrogen is the intestinal microbiome via the secretion of GUS. Progesterone promotes the growth of bifidobacteria in the third trimester of pregnancy and transmits it to newborns. Probiotic Lactobacillus rhamnosus GG can prevent epicallopregnanolone sulfate-mediated FXR activation and bile acid synthesis, so as to reduce liver bile acid accumulation and liver injury in ICP patients. Dysfunction of intestinal microbiota may lead to LPS leakage, inflammatory response, and GnRH secretion abnormality. ESRRA, estrogen related receptor alpha; FSH, follicle-stimulating hormone; FXR, farnesoid X receptor; GnRH, gonadotrophin-releasing hormone; GUS, β-glucuronidase; ICP, intrahepatic cholestasis of pregnancy; LH, luteinizing hormone; LPS, lipopolysaccharide; PCOS, polycystic ovary syndrome; SCFA, short chain fatty acid (Created with Biorender.com with a publication license).

Figure 4

Patient care, therapy selection, and balance between desired effects and potential side effects (with special emphasis in the liver) of gender-affirming hormone therapy (GAHT) for transgender populations. AMPK, D2R, dopamine D2 receptor; GnRH, gonadotropin-releasing hormone; MC, menstrual cycle.