Effect of Hormone Replacement Therapy on Liver and Cardiometabolic Outcomes in Peri‐Menopausal MASLD

ABSTRACT

Background
Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most common chronic liver disease globally. Menopause is associated with increased hepatic fat deposition and thus metabolic dysfunction, contributing to heightened risk of progressive liver and cardiovascular disease. Hormone replacement therapy (HRT), supported by pre‐clinical data, may be associated with a lower risk.


Methods
We performed a retrospective cohort study using the TriNetX global federated research network. Eligible participants were peri‐menopausal women (ICD‐10 codes N95/Z78.0, AND age 40–65 years) with pre‐existing MASLD (based on ICD‐10 codes K76.0/K75.81 or positive modified hepatic steatosis index plus ≥ 1 metabolic syndrome, MetS, trait). Patients initiating HRT (oestrogen ± progesterone) were compared with untreated controls using 1:1 propensity score matching for demographics, comorbidities, biochemistry and medications. The primary outcome was a composite of major adverse liver outcomes (MALO: portal hypertension, varices, ascites, spontaneous bacterial peritonitis, encephalopathy, hepatorenal/pulmonary syndromes, cirrhosis, decompensated liver disease, hepatocellular carcinoma, liver transplant). Secondary outcomes were individual MALO components, type 2 diabetes (T2D), major adverse cardiovascular events (MACE), breast and endometrial cancer, and venous thromboembolism (VTE). Cox regression generated hazard ratios (HRs) with 95% CIs over 5 years. Sensitivity analyses adjusted for geography, hormone type, and degree of obesity.


Results
After matching, 21 639 patients were included in each treatment arm. HRT was associated with a significantly reduced risk of MALO (HR 0.80; 0.71, 0.9), largely driven by reductions in ascites and SBP (0.78; 0.64, 0.95), and liver cirrhosis (0.75; 0.63, 0.90), and reduced risk of cardiometabolic outcomes: T2D (0.90; 0.84, 0.96), and MACE (0.90; 0.83, 0.98). HRT was not associated with increased risk of breast cancer or VTE, whilst endometrial cancer risk was reduced (0.49; 0.40, 0.61). Oestrogen was linked to greater benefits compared to progesterone, and patients with mild–moderate obesity experienced more significant risk reduction.


Conclusion
Treatment of peri‐menopausal symptoms with HRT, in patients with pre‐existing MASLD, is associated with a lower 5‐year risk of major liver and cardiometabolic disease. These findings support early basic science research and should prompt a closer examination through clinical trials.