Female reproductive factors and metabolic dysfunction-associated steatotic liver disease: an integrated analysis of population cohort, liver imaging, and genetic data.

Abstract

BACKGROUND While premenopausal women are at a lower risk for metabolic dysfunction-associated steatotic liver disease (MASLD) than men within the same age group, the sex advantage becomes minimal after menopause, suggesting a role for female hormones. OBJECTIVE To elucidate the role of reproductive factors in the development of female MASLD, using an integrated analysis. STUDY DESIGN Up to 269,607 women without MASLD during baseline recruitment (2006-2010) of the UK Biobank were included. Among these, there were 21,017 women who did not develop MASLD across the follow-up period (through December 2021) and had the measure of liver proton density fat fraction (PDFF) quantified by magnetic resonance imaging since 2014. Multivariable Cox regression models were applied to assess the prospective relationships of various reproductive factors with incident MASLD. Multiple linear regression models were used to explore the relationships of reproductive factors with liver PDFF. A two-sample Mendelian randomization (MR) analysis was further carried out to investigate the causality for the relationships of certain reproductive factors with MASLD. RESULTS During a median of 12.65 years of follow-up, 3077 incident cases of MASLD were identified. Early menarche, a greater number of live births, younger age at first live birth, and oral contraceptive or hormone replacement therapy (HRT) initiated at a young age were associated with an elevated risk of MASLD and higher levels of liver PDFF. Several other reproductive factors (i.e., a greater number of miscarriages, surgical menopause at a young age, and prolonged use of HRT) were associated with incident MASLD but not with liver PDFF. In the MR analysis, genetically determined earlier age at menarche and younger age at first live birth were significantly associated with an increased risk of MASLD. CONCLUSIONS Several reproductive factors were associated with the risk of and histological feature for MASLD, supporting the role of female hormones in the pathogenesis of MASLD.