A kidney drug helped women with premature ovarian failure produce mature eggs

Between 1 and 3% of women of childbearing age develop premature ovarian insufficiency (POI), a condition in which the ovaries stop functioning normally well before menopause. Their follicle-stimulating hormone levels are already elevated, so the standard fertility approach -- giving more hormones -- does not work. Many of these women still have dormant primordial follicles in their ovaries. The follicles are there; they simply will not grow.

A collaboration between Juntendo University in Tokyo and the University of Hong Kong has identified a possible reason why -- and a drug that appears to fix it. The findings, published in Science, suggest that excess collagen in ovarian tissue physically constrains dormant follicles, preventing them from developing. An antifibrotic drug already approved for kidney disease reduced that collagen and restarted follicle growth in both mice and a small group of women with POI.

The scar tissue hypothesis

Prof. Kazuhiro Kawamura at Juntendo previously developed a surgical technique called in-vitro activation (IVA), which removes ovarian tissue, treats it with drugs that activate growth pathways, and transplants it back into the patient. The technique has produced pregnancies and live births, but it requires surgery and is technically demanding.

Working with Prof. Kui Liu's team at HKU, the researchers asked whether the problem could be approached differently. If dormant follicles are being held in place by stiff, fibrotic ovarian tissue, could softening that tissue allow them to grow on their own?

The team identified finerenone as a candidate. Finerenone is a mineralocorticoid receptor antagonist known for its antifibrotic properties and an established safety profile in patients with chronic kidney disease. It is already FDA-approved and taken orally -- a far simpler intervention than surgery.

What happened in mice

When ovaries from immature mice were cultured in vitro with finerenone, they developed follicles and eventually produced mature oocytes. The researchers then tested oral dosing in adult mice over an 18-week period. Mice receiving finerenone gave birth to more offspring than those on placebo.

The drug also worked in older mice that had become infertile due to age-related ovarian insufficiency, inducing follicle formation where none had been occurring spontaneously.

Gene expression analysis revealed the mechanism: finerenone suppressed collagen production in the ovarian cortex, the outer layer of the ovary where primordial follicles reside. Excess collagen deposition causes tissue stiffening (fibrosis), which the researchers propose physically restricts small follicle growth. By reducing that mechanical constraint, finerenone allowed dormant follicles to activate.

To confirm that the effect was specifically about fibrosis rather than some other property of finerenone, the team tested two additional antifibrotic drugs -- nintedanib and ruxolitinib -- which work through entirely different mechanisms. Both also induced follicle formation in mouse ovaries, supporting the hypothesis that the barrier is mechanical rather than chemical.

Early results in women

The researchers enrolled 14 women with POI at HKU Shenzhen Hospital in an experimental study. Participants received oral finerenone for three to seven months. Follicle development was observed in all 14 participants. Seven produced mature oocytes suitable for in-vitro fertilization. The quality of those oocytes was comparable to eggs from same-age women without POI undergoing IVF.

"Finerenone's antifibrotic effect alleviates ECM-mediated constraints on small follicle growth, thereby allowing follicles to develop," said Prof. Kawamura. "Furthermore, we identified the stromal collagen-granulosa signaling as an important negative regulator of follicular development."

Important caveats

The human data, while encouraging, comes from just 14 participants in an open-label study with no control group. Without a placebo arm, it is impossible to know how many of these women might have produced follicles spontaneously -- a phenomenon that occurs occasionally in POI. Larger, randomized, controlled trials are essential before any clinical conclusions can be drawn.

The mouse studies used young animals for the in-vitro experiments and adult but not elderly mice for the fertility trials. Whether the approach works similarly across the full spectrum of human POI -- which can result from autoimmune, genetic, iatrogenic, or idiopathic causes -- remains unclear. Different causes of POI may produce different degrees and types of ovarian fibrosis.

Finerenone also has known effects beyond its antifibrotic properties, including on blood pressure and potassium levels, which would need monitoring in any fertility application. The drug is not currently approved for reproductive indications.

A less invasive path

If validated in larger trials, antifibrotic therapy could offer a substantially less invasive alternative to the surgical IVA technique for some women with POI. Taking a pill rather than undergoing laparoscopic surgery and tissue transplantation would expand access to treatment, particularly in settings where surgical expertise is limited.

"Further clinical characterization of FDA-approved oral antifibrotic drugs for their abilities in activating small ovarian follicles in patients offers a promising path to repurposing therapies for POI-related infertility," Prof. Kawamura said.

The conceptual insight -- that physical tissue stiffness can prevent follicle development -- also opens new research directions. If ovarian fibrosis is a modifiable barrier, interventions that prevent collagen accumulation in the first place could potentially delay or reduce the severity of ovarian aging more broadly.