February 2026

OB-GYN

THE OVARIAN STROMA AS A THERAPEUTIC TARGET: ANTIFIBROTIC STRATEGIES TO RESTORE FOLLICULOGENESIS AND IMPROVE FERTILITY

In disorders such as premature ovarian insufficiency (POI), ovarian function is lost before age 40, leading to infertility and long-term health consequences. POI affects up to 3% of women, and current treatments cannot restore ovarian reserve because new functional follicles cannot be generated.
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Recent commentary from Francesca E. Duncan, PhD, and Elnur Babayev, MD, highlight emerging evidence that suggests that the ovarian stroma, rather than the follicle alone, represents a promising therapeutic target for restoring ovarian function. This reframes ovarian dysfunction as a disease of the tissue microenvironment and opens new opportunities for clinical intervention.
 
The Ovarian Microenvironment and Fibrosis
Follicle development depends not only on the oocyte and surrounding granulosa cells but also on the mechanical and biochemical cues provided by the ovarian stroma. The stroma is composed of endothelial, immune, neural and smooth muscle cells embedded in a collagen-rich extracellular matrix.

Increased stromal stiffness and collagen deposition restrict follicle activation. Conditions such as ovarian aging, PCOS, chemotherapy exposure and POI are all associated with increased ovarian fibrosis. Experimental models show that stiff ovarian environments impair follicle survival, alter hormone production and reduce oocyte quality. Conversely, loosening the extracellular matrix promotes follicle activation and growth.
 
Antifibrotic Drug Repurposing
Researchers developed an in vitro screening platform to identify FDA-approved drugs capable of promoting follicle activation by modulating the ovarian stroma. Using neonatal mouse ovaries, they screened nearly 1,300 compounds for induction of Kit ligand, a granulosa cell factor essential for initiating growth of dormant primordial follicles.

Among several candidates, finerenone was selected due to its oral availability, safety profile and known antifibrotic properties. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently used in chronic kidney disease. In mouse models, finerenone promoted follicle activation ex vivo and improved follicle number, ovulation and fecundity when administered systemically in reproductively aged animals. Even a single targeted intraovarian injection stimulated follicle development.

Mechanistic studies demonstrated that finerenone acts through the ovarian mineralocorticoid receptor to reduce expression of collagen proteins within the extracellular matrix. Similar results were observed with direct suppression of collagen expression or treatment with other antifibrotic agents, confirming that reducing stromal stiffness creates a permissive niche for folliculogenesis.
Translation to Patients With POI
The research team extended these findings in a small exploratory clinical study of 11 women with POI-associated infertility. At baseline, most participants had no detectable antral follicles on ultrasound. Patients received oral finerenone for two to seven months and were monitored with serial ultrasound and hormone measurements.
Antral follicle development was observed in all participants during the study period. Ten women proceeded with ovarian stimulation and IVF, resulting in eight mature oocytes retrieved from six patients and early cleavage-stage embryos in three. Pregnancy and live birth outcomes have not yet been reported.
 
Clinical Implications and Next Steps
These early clinical observations must be interpreted cautiously given the small sample size, lack of a control group and potential confounding from hormone therapy and intensive monitoring. Spontaneous follicle development can occur in women with POI, highlighting the need for controlled trials to establish clinical benefit.
Nevertheless, this work represents a significant advance in reproductive medicine by demonstrating that targeting the ovarian stroma may restore follicle responsiveness even in severely diminished ovarian reserve. Ovarian fibrosis is implicated not only in POI but also in PCOS, ovarian aging, endometriosis, and treatment related gonadotoxicity.
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Future efforts must focus on rigorous clinical trials, development of noninvasive methods to assess ovarian fibrosis, and identification of ovarian specific drug targets. By integrating basic ovarian biology with translational and clinical research, Northwestern Medicine continues to advance innovative strategies aimed at extending ovarian longevity and improving reproductive outcomes.

Based on research published in Science (Duncan & Babayev, 2026)
 
See the full publication.

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