In this issue of Liver International, the study by Henney et al. 1 offers timely real-world evidence, suggesting that hormone replacement therapy (HRT) may mitigate both hepatic and cardiometabolic outcomes in perimenopausal women with metabolic dysfunction–associated steatotic liver disease (MASLD). In this context, we would like to revisit the mechanistic rationale, clinical implications, cautionary considerations and potential research questions surrounding HRT in MASLD. In the past years, MASLD has emerged as the leading cause of chronic liver disease worldwide, yet its sex-specific biology remains underrecognised in clinical practice and current guideline recommendations for management 2, 3. The prevalence of MASLD is markedly lower in premenopausal women (9%–18%) than in men (20.2%–41%) 4; however, the prevalence in postmenopausal women rises to over 30%, highlighting postmenopausal women as a high-risk population warranting increased clinical vigilance 5 (Figure 1). Importantly, once MASLD is established, peri-/ postmenopausal women appear to carry a disproportionately higher risk of advanced fibrosis and major adverse liver outcomes (MALO), especially in the absence of estrogenic protection 6. While sex hormones are central to the sexual dimorphism observed in MASLD, they represent only one facet of a complex landscape. Emerging evidence suggests that sex-specific disease trajectories are equally driven by fundamental differences in genetics, epigenetic programming and immunological responses 7. Importantly, the liver is the most sexually dimorphic nonreproductive organ 8; hepatic sex differences are predominantly hepatocyte-specific, spatially zonated within the liver lobule, and dynamically regulated by sex-dependent growth hormone (GH) signalling patterns, which can reprogram large portions of the sex-biased transcriptome 8. Besides, the liver is a bona fide oestrogen-responsive organ. The predominant form of oestrogen, 17β-estradiol, is primarily produced by the ovaries in women; it exerts its biological effects via three main receptors—oestrogen receptor alpha (ERα), oestrogen receptor beta (ERβ) and the G protein-coupled oestrogen receptor (GPER1), all of which are expressed in hepatocytes of both sexes though at a lower level than in the reproductive organs 9, 10. ERα signalling in hepatocytes regulates lipid oxidation, suppresses de novo lipogenesis and dampens inflammatory and fibrogenic pathways while oestrogen deficiency induces hepatic lipid accumulation, inflammatory gene expression and fibrosis 6 (Figure 1). Preclinical studies unveiled that HRT can ameliorate hepatic steatosis and fibrosis by maintaining systemic insulin sensitivity and adipose tissue distribution, thereby indirectly modulating hepatic lipid flux 11. Moreover, oestrogen receptor signalling interacts with genetic risk: the deleterious effect of PNPLA3 I148M appears amplified in women, in part through ERα-mediated transcriptional regulation, underscoring that hormonal milieu modifies genetic susceptibility 12. Generally, HRT is relatively safe and does not increase the risk of overall mortality 13. Henney et al. 1 conducted a large propensity-matched analysis of the effects of HRT on MALO among peri-menopausal women with MASLD from the TriNetX network (21,639 matched individuals per treatment arm), while also considering competing risks (e.g., cardiovascular events) as well as potential adverse effects of HRT (e.g., breast cancer or thromboembolic events). Over 5 years, HRT use was consistently associated with: reduced risk of MALO; lower risk of cirrhosis and ascites in particular; reduced incidence of type 2 diabetes (T2D); reduced major adverse cardiovascular events; no increased risk of breast cancer or venous thromboembolism; reduced endometrial cancer risk. Of note, oestrogen-containing regimens conferred greater benefit than progesterone-only therapy, and women with mild-to-moderate obesity experienced more pronounced risk reduction. These findings align with preclinical data and support the hypothesis that restoring estrogenic signalling during the peri-menopausal window may attenuate both hepatic and systemic metabolic deterioration. Although this study did not find the significant association of HRT with breast cancer and even reported the beneficial effects on endometrial cancer, the potential impact of HRT on breast and gynaecological cancers requires attention 14. Despite encouraging associations, another study based on the UK biobank reported that among postmenopausal women, hormone replacement therapy use was associated with a significantly increased risk of developing MASLD compared with never use, with higher risks observed among those initiating therapy at younger ages, particularly before 45 years and among women with prolonged use of ≥ 15 years, and these associations persisted even in naturally menopausal women, indicating that earlier initiation and longer duration of HRT may confer a dose- and timing-dependent elevation in MASLD risk 15. The study by Henney and coworkers did not specifically address MASLD incidence with or without HRT, leaving the question on the role of HRT for MASLD prevention open. In addition, several limitations need to be considered when interpreting potential benefits of HRT on MASLD outcomes. First, the observational study design, even with robust matching, cannot exclude residual confounding: (i) For patients who have undergone hysterectomy, oestrogen alone can be used. However, the researchers did not perform a stratified analysis based on ‘hysterectomy status’, which is a limitation; (ii) patients in the HRT treatment arm are more likely to receive lipid-lowering, antidiabetic or antihypertensive therapies, which can confer strong protective effects on liver. Second, MASLD is heterogeneous. Data-driven cluster analyses have identified at least two clinically relevant MASLD types 16: (i) hepatic subtypes—higher risk of chronic liver disease progression but lower cardiovascular burden; (ii) systemic subgroup—higher risk of cardiovascular disease and diabetes with comparable liver-related risks. The intriguing possibility is that HRT may be particularly effective in the liver-specific subgroup, which carries the highest risk of progression to MALO. By restoring ERα signalling and modulating hepatic lipid metabolism, HRT might directly target the pathogenic axis most relevant in this group. Moreover, current evidence does not support MASLD as an independent risk factor of cardiovascular diseases 17; thus, in cardiometabolic-dominant MASLD, benefit may depend more on systemic metabolic improvements than on direct hepatic effects since the effects of HRT on cardiovascular events are marginal (i.e., hazard ratio is very close to 1 though significant). Third, extrahepatic safety must be individualised. Although this study did not show increased breast cancer or venous thromboembolism risk, broader literature highlights complexity in HRT associations with dementia and cardiometabolic endpoints, influenced by timing, formulation and menopausal type 18. Last but not least, considering MASLD is embedded within the framework of steatotic liver disease (SLD) and is highly dynamic, the impact of HRT on metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD) should be assessed as well in the future 19. Management of menopausal women with MASLD should begin with careful phenotypic stratification, including noninvasive fibrosis assessment (e.g., validated fibrosis scores and elastography), evaluation of metabolic cluster features such as dysglycaemia and hypertriglycaeridemia, and consideration of possible hepatic phenotypes. Initiation of HRT during the peri-menopausal window may confer greater metabolic benefit. Oestrogen-containing regimens appear to provide more favourable hepatic and metabolic effects, while the route of administration (transdermal versus oral) should be individualised given differential thrombotic risk profiles. Comprehensive risk assessment is essential, including breast cancer, venous thromboembolism, cardiovascular and cognitive risk, alongside longitudinal monitoring of glycemic control and metabolic parameters. Importantly, HRT should be positioned within an integrated care framework, complementing lifestyle modification and emerging pharmacotherapies for MASLD 20. In conclusion, the work by Henney et al. fuels the discussion around sex-specific therapeutic strategies in MASLD. Their findings suggest that HRT, when used for menopausal indications, may confer meaningful hepatic and cardiometabolic benefit, particularly in women at elevated risk of progression to MALO. However, risk stratification and individualised benefit–risk assessment remain essential. Randomised controlled trials focused on peri-menopausal women with MASLD, stratified by phenotype and incorporating mechanistic endpoints, are now needed. Until then, HRT should be viewed not as a dedicated MASLD therapy, but as a potentially synergistic intervention in appropriately selected women, transforming a menopausal transition into a therapeutic window rather than into a metabolic turning point. L.C. drafted the manuscript and drew the figure. F.T. designed the editorial, substantially revised it and supervised the entire research. L.C. is financially supported by China Scholarship Council and the First Hospital of Jilin University. F.T. is supported by the German Research Foundation (DFG CRC/TR 412, Project-ID 535081457, and SFB1382, Project-ID 403224013) and under Germany's Excellence Strategy—EXC 3118/1—project number 533770413. F.T.'s lab has received research grants (funding to the institution) from AstraZeneca, MSD, Gilead, Agomab. F.T. has received honoraria for consulting or lectures from Gilead, Abbvie, Falk, AstraZeneca, Boehringer, Madrigal, MSD, GSK, Ipsen, Pfizer, Mirum, Novo Nordisk, Sanofi. L.C. reports no conflicts of interest. This article is linked to Henney et al. papers. To view these articles, visit https://doi.org/10.1111/liv.70562. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
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