Sustained high progesterone during pregnancy can improve menstrual cyclicity in PCOS patients

Polycystic ovary syndrome (PCOS) affects 6%−20% of reproductive-aged women, and is commonly accompanied by irregular menstrual cycles and anovulatory infertility. The mechanisms underlying menstrual cycle irregularities associated with PCOS, and how they may change after pregnancy remain incompletely understood.

A recent study published in Life Metabolism, led by Prof. Chaojun Li from Nanjing Medical University, reveals that sustained high progesterone exposure during pregnancy can significantly improve menstrual cyclicity in PCOS patients and a PCOS-like mouse model, providing novel insights into the hormonal mechanisms underlying postpartum recovery.

In a retrospective cohort of 186 PCOS patients who delivered after assisted reproductive technology (ART), 60.60% of those with irregular cycles showed improved menstrual regularity postpartum. Importantly, improvement was not associated with baseline clinical characteristics or ART procedures, supporting an association with pregnancy-related endocrine dynamics rather than specific ART interventions.

To probe mechanism, the authors used a letrozole-induced PCOS-like mouse model, and administered progesterone for 3 weeks to mimic sustained gestational elevation. Progesterone treatment normalized estrous cyclicity, reduced ovarian weight/index, and improved circulating testosterone and LH. Histology showed fewer advanced follicles and a thinner endometrium during diestrus. Further investigation showed that progesterone depleted large follicles via granulosa cell apoptosis, facilitating a reset of ovarian function.

At the cellular level, progesterone induced granulosa-cell apoptosis and reduced follicle-stimulating hormone receptor (FSHR) expression in a GATA2-dependent manner. After progesterone withdrawal, progesterone pretreatment increased granulosa-cell steroidogenic responsiveness to FSH (e.g., upregulation of StAR, CYP11a1, HSD3B1, and CYP19a1), suggesting a dual role of progesterone: it transiently suppresses follicular activity during gestation-like exposure, and then enhances FSH-driven estrogen production after withdrawal, collectively supporting menstrual-cycle recovery.

Overall, these findings provide a mechanistic framework linking gestational progesterone dynamics to postpartum menstrual-cycle improvement in PCOS, highlighting progesterone's role as a potential therapeutic agent for PCOS-related menstrual dysfunction. While further studies are needed to address confounding factors like prolactin, this research paves the way for hormone-based strategies mimicking pregnancy effects.