The liver has long been viewed as a broadly similar organ in men and women, with differences often attributed mainly to reproductive biology. A new review argues that this picture is incomplete. Sexual dimorphism—the systematic biological differences between males and females that extend beyond reproductive traits—shapes liver physiology, metabolism, immunity and susceptibility to disease. The analysis by Ajay Jain and Sanjay P. Monga, published in Nature Reviews Gastroenterology & Hepatology, brings together evidence showing that sex influences how the liver processes nutrients, responds to hormones, regulates inflammation and develops disease. The authors emphasize that these differences are not controlled by a single pathway. Oestrogen is a major regulator, but genes on the sex chromosomes, epigenetic mechanisms, immune-cell behaviour and environmental or sociodemographic factors also contribute.
One of the most important drivers is oestrogen signalling. Oestrogens enter cells and bind to nuclear receptors, particularly oestrogen receptor alpha and oestrogen receptor beta, which can regulate gene transcription. In the liver, these receptors influence pathways involved in lipid handling, glucose homeostasis, inflammation, fibrosis and cell proliferation. Oestrogen receptor activity can also affect gene expression indirectly through rapid signalling at the cell membrane and through interactions with other transcription factors. These mechanisms help explain why liver physiology may change substantially across the life course. Before menopause, endogenous oestrogen may protect against some forms of metabolic and inflammatory injury. After ovarian oestrogen production declines, that protection can weaken, although the extent of the effect varies among individuals and depends on age, adiposity, diet, medications and other biological factors.
The review describes the liver as an organ in which sex hormones interact with a complex regulatory architecture rather than functioning as isolated switches. Growth hormone signalling, for example, is sexually dimorphic and helps establish patterns of hepatic gene expression that differ between males and females. In experimental models, the frequency and pattern of growth hormone release can influence the activity of transcription factors such as STAT5, which in turn controls broad sets of liver genes. These hormonal signals regulate enzymes involved in detoxification, lipid oxidation, bile-acid metabolism and steroid processing. The result is a sex-biased molecular landscape in which the same physiological challenge may activate different genes, metabolic pathways or repair responses in male and female livers.
Sex chromosomes add another layer of complexity. The X chromosome contains many genes involved in immune regulation, cellular signalling and metabolism, while the Y chromosome carries genes with effects that extend beyond male reproductive development. In females, one X chromosome is generally inactivated in each cell, but some genes escape this process and remain active from both copies. The degree of escape can vary among tissues and individuals, creating potential differences in gene dosage. X-chromosome inactivation can also become less uniform with age, a phenomenon known as skewing, which may influence immune and metabolic traits. These mechanisms mean that sex-related liver biology cannot be reduced to circulating oestrogen concentrations alone. Cellular genetic composition remains relevant even when hormone levels change.
Epigenetic regulation provides another explanation for persistent differences between male and female livers. Epigenetic processes alter gene activity without changing the underlying DNA sequence. DNA methylation, histone modifications and non-coding RNAs can influence whether genes are accessible to the transcriptional machinery. Diet, obesity, alcohol exposure, inflammation and endocrine changes can all reshape these regulatory marks. In the liver, epigenetic mechanisms help control genes involved in fatty-acid synthesis, mitochondrial energy production, insulin signalling and detoxification. Because sex hormones can influence chromatin-modifying enzymes, and because sex chromosomes can affect the expression of epigenetic regulators, hormonal and genetic effects may reinforce one another. These changes could help explain why liver responses differ not only between sexes but also across developmental stages and disease states.
Immune biology is equally important. The liver continuously encounters molecules arriving from the intestine through the portal circulation, including microbial products and dietary components. It must therefore maintain immune tolerance while remaining capable of responding rapidly to pathogens and tissue damage. Sex differences in innate and adaptive immunity can alter this balance. Oestrogen may affect the activity of macrophages, natural killer cells, T cells and B cells, while sex-chromosome-linked genes can influence immune receptor signalling. In some settings, stronger immune activation may improve pathogen control; in others, it may increase the risk of chronic inflammation or autoimmunity. This framework helps explain why women are more susceptible to autoimmune liver diseases, including primary biliary cholangitis, even though they experience lower rates of several common metabolic and malignant liver disorders.
The clinical consequences of hepatic sexual dimorphism are particularly visible in metabolic-dysfunction-associated steatotic liver disease, or MASLD. The condition begins with abnormal fat accumulation in hepatocytes and can progress to steatohepatitis, fibrosis, cirrhosis and liver cancer. Population studies generally show that women, especially before menopause, have a lower incidence of MASLD than men, although the difference can narrow or reverse with ageing and hormonal changes. Oestrogen may limit hepatic fat accumulation by improving lipid oxidation, insulin sensitivity and adipose-tissue function. It may also reduce inflammatory signalling and fibrogenic responses. However, the review cautions that risk is not determined by sex alone. Body-fat distribution, menopause, diabetes, sleep, medication use, socioeconomic conditions and access to healthcare can substantially modify an individual’s risk.
Viral hepatitis also reveals the complexity of sex-specific liver responses. Infection with hepatitis B or hepatitis C virus can produce different outcomes depending on viral characteristics, host genetics, immune activity and the duration of infection. Sex-related differences in innate antiviral signalling and T-cell responses may influence viral clearance, persistence and the degree of liver injury. A more vigorous immune response can help eliminate a virus, but persistent or poorly regulated activation may damage hepatocytes and promote fibrosis. Hormonal effects on viral replication and on inflammatory pathways may further alter disease progression. These mechanisms are clinically relevant because the same viral infection can follow different trajectories in different patients, and because sex may interact with age, pregnancy, antiviral treatment and coexisting metabolic disease.
Liver cancer is another area in which sexual dimorphism is striking. Hepatocellular carcinoma occurs more frequently in men across many populations, even when major risk factors such as viral hepatitis, alcohol-related injury or metabolic disease are taken into account. Multiple mechanisms may contribute, including androgen and oestrogen signalling, differences in immune surveillance, inflammatory responses, carcinogen metabolism and the regulation of hepatocyte proliferation. Oestrogen receptor pathways have been reported to suppress certain inflammatory and tumour-promoting signals in experimental systems, whereas chronic activation of other pathways can support malignant transformation. At the same time, women may be more susceptible to some benign liver tumours, illustrating that a lower cancer risk does not translate into uniform protection from all hepatic neoplasms. Tumour biology therefore needs to be interpreted through the combined effects of sex, hormones, genetics, metabolism and the surrounding tissue environment.
The authors argue that recognizing hepatic sexual dimorphism could improve both research and clinical care. Many laboratory studies historically used male animals or failed to analyse results separately by sex, potentially obscuring biologically meaningful patterns. Clinical trials have also not always been designed to detect sex-specific treatment effects. Future research will need to integrate hormone status, sex-chromosome biology, epigenetic profiles, immune-cell composition, life stage and social determinants of health. Such work could support more precise screening strategies, improve risk prediction and reveal why patients respond differently to metabolic, antiviral, immunological or anticancer therapies. The central message is that male and female livers are not simply exposed to different hormone concentrations; they are regulated by interconnected genetic, endocrine, metabolic and immune systems. Understanding those systems may lead to more effective prevention and treatment while offering a broader view of how biological sex shapes human disease.
Subject of Research: Sexual dimorphism in liver physiology and liver disease
Article Title: Sexual dimorphism in the liver
Article References: Jain, A., Monga, S.P. Sexual dimorphism in the liver. Nature Reviews Gastroenterology & Hepatology (2026). https://doi.org/10.1038/s41575-026-01244-2
Image Credits: AI Generated
DOI: 10.1038/s41575-026-01244-2
Keywords: liver biology, sexual dimorphism, oestrogen signalling, sex chromosomes, epigenetics, immune function, MASLD, autoimmune liver disease, viral hepatitis, liver cancer
