Antifibrotic drug finerenone restores fertility in premature ovarian insufficiency.

Currently, no effective treatment exists for infertility associated with premature ovarian insufficiency (POI) because affected patients lack hormone-responsive antral follicles. By screening a Food and Drug Administration (FDA)–approved drug library, we identified finerenone, a kidney disease medication, as a promising drug for restoring fertility in POI. Finerenone stimulated follicle development in aged mice and restored antral follicle development in patients with POI following oral administration, resulting in mature oocytes and embryos. Mechanistically, finerenone reduced fibrotic deposition in the ovarian stroma, alleviating collagen-mediated suppression of follicular development. Building on this insight, we identified additional FDA-approved oral antifibrotic drugs as potential treatments for POI-related infertility. Our findings highlight the ovarian stroma—rather than the follicles themselves—as the key therapeutic target and offer potential therapeutic leads for POI-related infertility. Editor's summary: Premature ovarian insufficiency is associated with decreased numbers of ovarian follicles and decreased frequency of menstrual periods before age 40. This occurs in more than 1% of women and leads to what is generally considered to be irreversible infertility. By screening a library of approved drugs, Lin et al. identified a promising candidate in finerenone, a mineralocorticoid receptor antagonist used for kidney disease (see the Perspective by Duncan and Babayev). The authors demonstrated that finerenone decreased ovarian fibrosis in mouse models, facilitating follicular development and improving fertility, and other antifibrotic drugs showed similar effects. In a pilot clinical trial, patients treated with finerenone showed improvement in ovarian function and follicle maturation, some getting as far as in vitro fertilization, all without major side effects or risk of fetal exposure. —Yevgeniya Nusinovich INTRODUCTION: Premature ovarian insufficiency (POI) affects approximately 1 to 3% of women under the age of 40. It is characterized by symptoms such as oligomenorrhea or amenorrhea, sex steroid deficiency, elevated follicle-stimulating hormone levels, and infertility. Currently, no effective treatments exist to restore fertility in patients with POI. This is because ovarian follicular development in these patients is insufficient, typically lacking ultrasound-detectable antral follicles that are hormone-responsive. The limited residual small follicles, if present, fail to respond to exogenous gonadotropin stimulation during in vitro fertilization (IVF). However, these small ovarian follicles represent the most promising resource for restoring fertility in these patients. RATIONALE: There are no clinically approved oral drugs for restoring fertility in patients with POI. Drug repurposing leverages existing drugs with established safety profiles to accelerate clinical translation for new indications. Therefore, based on our previous research findings on the regulation of small ovarian follicle development, we established a platform and systematically screened 1297 compounds from an FDA-approved drug library and identified finerenone as a safe and potentially effective candidate for treating POI-associated infertility. RESULTS: We first revealed that finerenone promoted ovarian follicular development in mice, with no observed adverse effects on oocyte quality, early embryonic development, or offspring health. Furthermore, our pilot clinical trial showed that oral finerenone administration (20 mg, twice weekly) promoted the development of follicles in patients with POI, yielding mature eggs (oocytes) and viable embryos. Mechanistically, we found that finerenone reduced collagen deposition (fibrosis) within aged ovaries, thus reducing the stromal fibrosis-mediated restriction of follicular development and creating a more permissive microenvironment for follicle activation and growth. Based on these findings, we further identified a series of FDA-approved oral antifibrotic drugs, including nintedanib, ruxolitinib, and other drugs with established antifibrotic activity but based on distinct antifibrotic mechanisms, which were effective in promoting ovarian follicle growth. This underscores the clinical potential of these drugs being repurposed for the treatment of POI-related infertility. This broader validation across antifibrotic drugs with different mechanisms of action supports the notion that ovarian stromal fibrosis is a central, druggable, pathological condition that suppresses follicle growth in POI. CONCLUSION: Our findings provide a starting point showing that targeting the ovarian stroma—rather than the follicles themselves—represents an effective therapeutic strategy for POI-related infertility. We propose that alleviating ovarian stromal fibrosis through repurposed antifibrotic drugs, such as finerenone, nintedanib, ruxolitinib, or other FDA-approved oral agents, offers a possible promising intervention for restoring fertility in patients with POI. Schematic model of finerenone-mediated follicle growth.: Ovarian stromal collagen suppresses the development of small follicles (left), whereas finerenone reduces the fibrotic deposits (right), relieving stromal constraints and thus enabling follicle activation and development. [ABSTRACT FROM AUTHOR]