Gestational progesterone restores menstrual cycle in PCOS patients via enhancing ovary estrogen production

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, typically characterized by irregular menstrual cycles. Our study found that postpartum menstrual cycles were largely restored in PCOS patients following assisted reproductive technology (ART) therapy. However, this recovery in menstrual cycles was not -associated with any specific ART procedures. Using a PCOS mouse model, we demonstrated that elevated progesterone levels during pregnancy were responsible for normalizing estrous cyclicity. Elevated levels of progesterone induced granulosa cell apoptosis and depleted large follicles, which potentially contributed to ovarian function suppression during pregnancy. Mechanistic studies indicated that progesterone decreased follicle-stimulating hormone receptor (FSHR) expression in a GATA binding protein 2 (GATA2)-dependent manner. Interestingly, the capacity of granulosa cells to convert androgens to estrogens significantly increased after progesterone withdrawal, as evidenced by elevated expression of cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) in granulosa cells when stimulated with follicle-stimulating hormone. In addition, we found that progesterone administration reduced the thickness of the uterine endometrium in PCOS mice. Our findings suggest that sustained high levels of progesterone during pregnancy can enhance ovarian reproductive endocrine capacity and improve endometrial function, thereby facilitating the recovery of postpartum menstrual cycles.