Bile Acid Metabolism Regulates Ovarian Function: Networks and Reproductive Health Applications.

BAs are a structurally diverse group of amphipathic molecules, with over 60 distinct species identified in mammals to date. Their primary function is to facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins in the small intestine. Synthesized in the liver and stored in the gallbladder, BAs are released into the intestinal lumen upon food intake. While most undergo enterohepatic re-circulation for re-use, a small fraction is excreted as waste (Ref. 1 ). Traditionally viewed as mere digestive agents, emerging research has revealed their critical role as signalling molecules that mediate finely tuned inter-organ communication – from the liver (their site of synthesis) to the gut (where they are modified by microbiota) and then via the circulatory system to nearly all organs, where they exert pleiotropic physiological effects (Ref. 2 ). The structural diversity of BAs not only reflects the complexity of their synthesis and metabolism (e.g., classic vs. alternative pathways, microbial modification), but also suggests that distinct BA species may possess unique bioactivities. For instance, specific BAs can modulate metabolism, immunity and inflammatory responses by activating nuclear receptors (e.g., FXR) or membrane receptors (e.g., TGR5) (Ref. 2 ). These multifaceted properties underlie their significant alterations – and even pivotal roles – in various diseases, including metabolic disorders (Ref. 3 ), neurodegenerative diseases (Ref. 1 ), kidney diseases (Ref. 4 ) and inflammatory bowel disease (Ref. 5 ), positioning them as potential diagnostic markers or therapeutic targets (Ref. 6 ). Notably, the regulatory effects of BAs on the reproductive system are increasingly recognized, particularly their roles in the follicular microenvironment. Recent studies have shown that follicular fluid (FF) contains BA concentrations higher than those in serum, with a predominance of primary BAs, indicating that BA homeostasis within the follicle is not solely determined by passive diffusion (Ref. 7 ). These observations raise important questions regarding the origin and regulatory mechanisms of BAs in the ovarian follicular environment. This phenomenon may influence follicular development, oocyte maturation and luteal function, closely linking BAs to female reproductive health. This review summarizes the sources, regulatory mechanisms and potential roles of BAs in FF, offering novel perspectives for research on reproductive physiology and related disorders.

In recent years, the role of BAs in ovarian physiological and pathological processes has gained increasing attention. The understanding of BA sources in the ovary has evolved from initial hypotheses of local ovarian synthesis to the current consensus that follicular fluid BAs predominantly originate from systemic circulation, where they are actively transported into the follicular microenvironment via specific transporters such as NTCP, ASBT and ABCC3. This transporter-mediated uptake mechanism plays a pivotal role in regulating ovarian function. Pathological disruption of BA homeostasis profoundly affects ovarian physiological function. During follicular atresia, abnormal accumulation of toxic BAs including GCDCA accelerates granulosa cell apoptosis and follicular degeneration by up-regulating pro-apoptotic factors (BAX/CASPASE3) while down-regulating the anti-apoptotic protein BCL2. Follicular fluid from PCOS patients exhibits characteristic BA disorder, manifested by elevated levels of glycocholic acid (GCDCA) and TCA, and this metabolic alteration has a causal relationship with abnormally activated ER stress. BAs regulate ovarian function through diverse molecular mechanisms. They mediate direct genomic effects via nuclear receptors (FXR and TGR5) and the membrane receptor GPBAR1, while also indirectly modulating ovarian function through regulation of ER stress, redox homeostasis and vitamin D metabolism. This is exemplified by UDCA, which improves ovarian morphology and corrects endocrine abnormalities in PCOS through ER stress suppression. Furthermore, BA metabolism demonstrates regulatory effects on the ovarian microenvironment. Beyond directly influencing granulosa cell function, BAs participate in angiogenesis regulation, as demonstrated by TUDCA’s ability to counteract the aberrant VEGFA signalling pathway in ovarian hyperstimulation syndrome (OHSS), thereby suppressing pathological angiogenesis while alleviating oxidative stress. These findings collectively establish BAs as crucial modulators of ovarian physiology. They coordinate follicular development through synergistic regulation of granulosa cell viability, steroidogenesis and oocyte quality, demonstrating their systemic influence on reproductive function. In assisted reproductive technology, the composition of follicular fluid BAs, including UDCA derivatives, has shown significant correlation with embryo quality, suggesting their potential utility as biomarkers for assessing oocyte developmental competence. Clinical studies have demonstrated that serum or follicular fluid BA profiles may serve as valuable diagnostic tools for various ovarian dysfunctions, ranging from precocious puberty to diminished ovarian reserve. Environmental factors including air pollutant NO 2 and exogenous chemicals like bisphenol A have been shown to impair oocyte quality through disruption of BA metabolic pathways, whereas specific dietary patterns such as fertility-promoting diets can optimize intra-follicular BA profiles to improve reproductive outcomes. Emerging evidence indicates that gut dysbiosis-induced alterations in BA metabolism, such as reduced GDCA/THDCA levels, can disrupt FXR/TGR5 signalling and exacerbate PCOS-associated hyperandrogenism and insulin resistance, thereby establishing the gut–BAs–ovary axis as a promising novel therapeutic target. Therapeutic interventions targeting this axis, including synbiotics or BA-based therapies, have shown promise in concurrently addressing both metabolic and reproductive abnormalities in PCOS. These provide a solid theoretical foundation for the clinical application of BAs. Despite significant progress, critical questions remained unresolved. Future research should focus on elucidating the precise mechanisms of BA dynamic transport in the ovary, including how transporters such as FABP6 and ASBT were hormonally regulated and whether they exhibited stage-specific expression patterns during folliculogenesis. Secondly, deciphering the interconversion and regulatory mechanisms among BA subtypes in follicular fluid to inform drug development. Thirdly, Optimization of clinical translation requires standardization of BA detection protocols, development of personalized therapeutic regimens (including precision modulation of the gut–BAs–ovary axis via microbiome transplantation or FXR/TGR5-targeted agents), and determination of optimal clinical indications and intervention timing for UDCA/TUDCA administration in assisted reproductive technologies. In conclusion, BAs have transcended their traditional role as digestive adjuncts to emerge as key regulators of ovarian function modulation. Future research should focus on elucidating their underlying mechanisms and facilitating clinical translation, which would not only provide innovative diagnostic and therapeutic approaches for various reproductive disorders including PCOS, precocious puberty and premature ovarian failure, but also potentially enable development of targeted therapeutic agents based on BA metabolism to achieve precise regulation throughout a woman’s reproductive lifespan – from pubertal development through perimenopausal functional maintenance.