Effects of Estrogen Shortage on Hepatic Metabolism and Hormone Replacement Therapy

Overview

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence rises significantly in women after menopause due to estrogen deficiency. Estrogen shortage promotes hepatic lipid accumulation, insulin resistance, and fibrosis, while hormone replacement therapy (HRT) effects on MASLD remain underexplored despite increasing HRT use.

Background

MASLD, formerly known as nonalcoholic fatty liver disease, is the most common chronic liver disease worldwide, affecting about 30% of individuals. It is sexually dimorphic, with lower prevalence in premenopausal women compared to men, but postmenopausal women experience a marked increase in MASLD prevalence and severity. Estrogen deficiency after menopause is strongly implicated in MASLD development through its effects on hepatic and extrahepatic metabolic processes. Despite this, women over 50 are underrepresented in liver disease studies, and the impact of estrogen-based HRT on MASLD progression is not well understood.

Data Highlights

MASLD affects approximately 30% of the population globally. Postmenopausal women show prevalence rates comparable to or exceeding those of men. HRT prescriptions in the UK have increased more than fourfold from 2015 to 2024, reflecting changing attitudes toward menopausal treatment.

Key Findings

• MASLD prevalence is lower in premenopausal women but rises sharply after menopause, correlating with estrogen deficiency.
• Estrogen deficiency promotes hepatic lipid accumulation, insulin resistance, inflammation, fibrosis, and multisystem metabolic dysfunction.
• Estrogen signaling in the liver is mediated primarily via estrogen receptor alpha (ERα), which regulates gene expression and metabolic activity.
• Postmenopausal estrogen production shifts from ovarian to extragonadal sites, with reduced systemic 17β-estradiol (E2) levels impacting liver metabolism.
• Despite the strong mechanistic rationale, the effects of menopausal hormone replacement therapy on MASLD development and progression remain poorly studied.
• Women over 50 are underrepresented in clinical liver disease research, limiting evidence-based, sex-specific treatment strategies.

Clinical Implications

Clinicians should recognize menopause as a critical period for MASLD risk escalation due to estrogen deficiency. While HRT use is increasing, its role in preventing or mitigating MASLD is not yet established, underscoring the need for targeted research and cautious clinical decision-making. Tailored therapeutic strategies considering sex-specific metabolic changes are essential to improve outcomes in postmenopausal women with MASLD.

Conclusion

Estrogen deficiency after menopause significantly contributes to MASLD pathogenesis through complex hepatic and systemic metabolic effects. Further clinical studies are needed to clarify the potential benefits and risks of estrogen-based hormone replacement therapy in managing MASLD in postmenopausal women.

References

1. Author/Source/2024 -- Effects of Estrogen Shortage on Hepatic Metabolism: Considerations for Hormone Replacement Therapy