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

Abstract

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are cholestatic liver diseases that have significant clinical impact with debilitating symptoms and mortality. While PBC is predominantly seen in perimenopausal and postmenopausal women, men who are diagnosed with PBC have worse clinical outcomes and all-cause mortality. In contrast, 60% to 70% of patients with PSC are men; the data indicate that female sex may be an independent factor against PSC-related complications. These findings suggest a sex-dependent biological basis for these differences. Estrogen has been implicated in the pathogenesis of intrahepatic cholestasis of pregnancy and may induce cholestasis through a variety of interactions. However, it is unclear why some sexual dimorphic features may provide a protective effect despite known estrogen models that induce cholestasis. This article provides a brief introductory background and discusses the sexual dimorphism in clinical presentation in PSC and PBC. It also explores the role of estrogen signaling in pathogenesis and how it relates to intrahepatic cholestasis of pregnancy. Studies have already targeted certain molecules involved in estrogen signaling, and this review discusses these studies that identify estrogen-related receptor, estrogen receptor-α, estrogen receptor-β, farnesoid X receptor, and mast cells as possible targets, in addition to long noncoding RNA H19-induced cholestasis and sexual dimorphism. It also explores these interactions and their role in the pathogenesis of PBC and PSC.

Figure 1

Primary biliary cholangitis, primary sclerosing cholangitis, and intrahepatic cholestasis of pregnancy are believed to be driven by a combination of genetic, environmental, hormonal, and autoimmune risk factors that lead to immune-mediated biliary epithelial cell damage, resulting in increased cholestasis, biliary proliferation, fibrosis, inflammation, and eventually cirrhosis. Sex-dependent differences in clinical presentation/outcomes may be attributed to estrogen-signaling aberrations, particularly the estrogen-induced mast cell activation, estrogen receptor (ER)-α activation, farnesoid X receptor (FXR) modulation by estrogen, or estrogen-related receptor (ERR) regulation (left panel). Estrogen-damaging effects can also be predominantly found in female patients and may be regulated by long noncoding RNA H19 (H19), bile acid (BA) synthesis, junction disruption and loss of membrane barrier, and FXR inhibition. Furthermore, oxidative stress may increase induction of cellular damage (right panel). Figure made using BioRender.com (Toronto, ON, Canada).