The Impact of Estrogen Deficiency on Liver Metabolism: Implications for Hormone Replacement Therapy

Metabolic dysfunction-associated steatotic liver disease (MASLD; previously nonalcoholic fatty liver disease) is the most common chronic liver condition globally. It affects 1 in 3 individuals and is associated with increased liver and cardiovascular mortality. MASLD is a sexually dimorphic condition, and in women the prevalence and severity of MASLD rises significantly following menopause. Preclinical data shows that lack of estrogen promotes multisystem metabolic dysfunction that is characteristic of MASLD. This not only includes hepatic lipid accumulation, insulin resistance, and fibrosis but also extra-hepatic metabolic processes in adipose and skeletal muscle. There are currently no available MASLD treatments tailored to women. The uptake of estrogen-based menopausal hormone replacement therapy (HRT) has seen a dramatic increase in recent years. Despite the changing attitudes toward HRT and the strong evidence base implicating estrogen deficiency in the development of MASLD, the impact of HRT on MASLD in postmenopausal women is poorly studied. In this review, we discuss the burden of MASLD in women, the effect of estrogen deficiency on the processes that drive MASLD development and progression, and the potential sex-specific therapeutic strategies that may prevent or limit MASLD development after menopause.