The estrogen-gallstone connection: uncovering the pathways

Gallstones are a common health concern, particularly in women. Estrogen is suspected to play a role, potentially altering bile composition and promoting gallstone development. This review explores the link between estrogen exposure and gallstone formation in various contexts, including pregnancy, postmenopausal hormone replacement therapy (HRT), and gender-affirming hormone therapy (GAHT). Two independent authors systematically searched PubMed, Cochrane, and Embase for literature relevant to estrogen-induced gallstones. Studies were included if they discussed the role of estrogen in the induction of gallstones by different conditions such as HRT, GAHT, prostatic carcinoma, and pregnancy. A scoping review identified 18 studies (1979–2021) encompassing over 211,000 patients and healthy controls. We investigated the risk of gallstones in postmenopausal HT users, pregnant women, oral contraceptive users, men receiving estrogen therapy for prostate cancer, and individuals on GAHT. Our findings suggest an increased risk of gallstones with prolonged HT use (> 45 years). Estrogen therapy elevated biliary cholesterol saturation in both men and women taking oral contraceptives. A low incidence (2%) of gallstones was observed in the third trimester of pregnancy. Interestingly, a case of GAHT-associated gallstone development in a transgender woman emerged. Estrogen exposure, both natural and through various therapies, appears to be associated with an increased risk of gallstones. Further research is needed to elucidate the specific mechanisms in different contexts. Notably, estrogen therapy for specific conditions like hypogonadism or surgical menopause seems unrelated to gallstone formation.