Primary Ovarian Insufficiency (POI), in which the ovaries do not mature and release eggs properly, affects about 3% of women under age 40 and typically causes infertility. However, a drug already approved to treat kidney disease may one day help some of these people get pregnant, a research team reports today in Science.
In studies of mouse ovarian tissue and live mice, the drug, called finerenone, kick-started the growth of tiny egg-containing sacs, or follicles—a process that is often defunct in people with POI. In a small clinical trial, people with POI who were given the drug went on to produce mature eggs that could be harvested, and some of the eggs were then successfully fertilized in the lab. None of the resulting embryos have yet been implanted; however, POI specialists are still excited by the initial data. The researchers’ work so far “feels very comprehensive,” says Suzannah Williams, an Ovarian Physiologist at the University of Oxford.
In a normal menstrual cycle, hormones trigger follicles in the ovary to grow from tiny specks into larger sacs that help eggs mature for ovulation. However, people with POI typically do not have any larger, later stage follicles, only low numbers of the tiny specks. These much smaller follicles do not respond to fertility drugs, putting techniques such as In Vitro Fertilization (IVF), which requires mature eggs, out of reach for many POI patients.
Kui Liu, a Molecular Reproductive Biologist at the University of Hong Kong, has been trying to solve the problem by nudging smaller follicles to develop further. In the new study, his team screened more than 1,200 drugs already approved by the U.S. Food and Drug Administration (FDA) for their effects on mouse ovarian cells in a dish. A handful of compounds increased expression of KitL, a gene associated with follicle development.
The group prioritized finerenone because it can be taken orally as a tablet and has a good safety record. In people with chronic kidney disease, the drug is thought to work by reducing inflammation and fibrosis, a dangerous type of hardening or scarring of tissue.
To the team’s surprise, finerenone did not have any effect on isolated mouse follicles in a dish, suggesting it was promoting their development indirectly. Sure enough, culturing whole mouse ovaries with the drug did prod tiny follicles to develop into larger ones. Feeding or injecting the drug into aged female mice — which show poorer follicle development than younger animals — also boosted follicular growth. And younger mice given the drug had more pups than controls.
The researchers found the drug changed the activity of genes associated with the structure of ovarian tissue, specifically lowering expression of genes for collagen and other proteins that provide scaffolding for cells in the ovaries and other organs. Silencing genes that drive collagen production in cultured mouse ovaries improved follicle development, as did treating the organs with other known collagen-reducing drugs.
Liu thinks collagen reduction helps promote follicle development by physically loosening up ovarian tissue and may also alter molecular signaling in the organ. The idea gels with a now-well-known link between POI and fibrosis — excessive deposition of collagen that leads to tissue stiffening, he says. Some recent research also suggests alleviating fibrosis could slow ovarian aging.
Williams sees the study as part of a trend in POI research of studying follicles’ environment rather than follicles themselves. Testing the drug in older mice “was a nice idea,” she adds, because they naturally have more collagen and stiffer ovarian tissue and do not need to be created artificially through genetic engineering or chemical treatments that might alter the animals’ biology in other ways.
However, Rebecca Robker, a Biomedical Scientist and Reproductive Biologist at the University of Adelaide, remains cautious about the team’s fibrosis finding. “I think they’re measuring something very interesting,” she says, but notes that the researchers did not observe fibrosis directly in the animals’ ovaries, or prove the drug activated small follicles by reducing fibrosis.
To see whether the drug could help patients, Liu and colleagues recruited 14 women with POI-associated infertility, who took finerenone for up to 7 months. Ultrasound monitoring revealed that all developed late-stage follicles. Some then took fertility drugs and had clinicians harvest mature eggs for IVF or freezing. So far, researchers have obtained mature eggs from seven of the patients; three (3) subsequently obtained an embryo via IVF. Liu says the team does not yet have data on implantations, pregnancies, or births.
The trial did not have a control group, so it is difficult to disentangle how much finerenone helped — on rare occasions people with POI can become pregnant without any intervention. Still, the approach appears promising, Williams says. “The benefit of this is they’ve got a drug that is already past FDA, which I think is a huge bonus.”
Williams and Robker emphasize the need for longer term data on finerenone’s ovarian effects: If it activates lots of follicles, it could potentially lead to rapid egg depletion, as eggs in later stage follicles do not survive long. And although the team’s mouse experiments did not turn up negative impacts on egg quality, fertility, or pup development, researchers will need to rule out any harmful effects on pregnant people or fetuses.
Liu says the team is now planning a larger, multicenter clinical trial to investigate finerenone for POI-associated infertility. And the group is studying some of the other FDA-approved drugs that showed promise at in their initial screen. “We should … try to look for more treasure that we can repurpose,” Liu says.