Sex-Dependent Differences in Cholestasis: Why Estrogen Signaling May Be a Key Pathophysiological Driver

Area of Science:

• Hepatology
• Endocrinology
• Immunology

Background:

• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are significant cholestatic liver diseases with high morbidity and mortality.
• Sex-based differences in clinical outcomes and disease prevalence exist, with men experiencing worse outcomes in PBC and women showing protection in PSC.
• Estrogen's role in cholestasis is complex, as it can induce cholestasis but may also offer protection in certain contexts.

Purpose of the Study:

• To review the sexual dimorphism observed in the clinical presentation of PBC and PSC.
• To explore the role of estrogen signaling in the pathogenesis of these cholestatic liver diseases.
• To identify potential therapeutic targets related to estrogen signaling and other factors implicated in cholestasis.

Main Methods:

• Literature review of studies on sexual dimorphism in PBC and PSC.
• Analysis of estrogen signaling pathways and their relation to cholestasis.
• Identification of molecular targets, including estrogen receptors, FXR, and non-coding RNAs.

Main Results:

• Men with PBC have poorer outcomes, while female sex appears protective against PSC complications.
• Estrogen signaling, while implicated in cholestasis, presents a complex picture regarding its protective or detrimental effects.
• Estrogen-related receptor, estrogen receptor-α, estrogen receptor-β, farnesoid X receptor, mast cells, and lncRNA H19 are identified as key players.

Conclusions:

• Sexual dimorphism in PBC and PSC suggests underlying sex-dependent biological mechanisms.
• Estrogen signaling pathways and related molecules represent promising targets for therapeutic intervention in cholestatic liver diseases.
• Further research into these sex-specific interactions is crucial for developing targeted treatments for PBC and PSC.