Softening tough tissue in aging ovaries may help fight infertility


Would-be parents hoping to get pregnant face a ticking clock: The older potential mothers get, the more their fertility drops. A new study in mice may help explain why. Ovaries accumulate “stiff” tissue as they age, and researchers have found that reducing the amount of this tissue—“softening” the ovaries, as it were—restored fertility in the animals, raising the possibility that the same approach could work in humans.

The study “is a huge advance,” says ovarian biologist Francesca Duncan of the Northwestern University Feinberg School of Medicine, who wasn’t connected to the research. The results, she says, suggest treatment for the age-related decline in fertility is “not a pipe dream.”

Female fertility ends at menopause, but it begins to decline around age 30. Scientists still don’t know why. One recently uncovered suspect is fibrosis, an abnormal proliferation of tough, supporting material known as connective tissue. As we get older, fibrosis can stiffen the heart, lungs, liver, and, as Duncan and her colleagues revealed in 2016, the ovaries.

Takashi Umehara, then a postdoc at the University of Adelaide, and colleagues wanted to determine whether ovarian fibrosis was responsible for falling fertility. Although female mice don’t undergo menopause, their ability to reproduce wanes as they get older.

The researchers first gave 15-month-old mice (roughly equivalent to humans in their early 50s) an approved drug for reducing fibrosis. These rodents are normally too old to reproduce, but the medication enabled more than half of them to ovulate, the team reports today in Science Advances. When the researchers fertilized the resulting eggs in a lab dish, apparently healthy embryos developed, suggesting the eggs were sound.

The mice were past their reproductive age, unlike most patients at fertility clinics. So the scientists also tested the drug on 12-month-old rodents, which are comparable to 35-year-old people. “That’s where the clinical need is,” says reproductive biologist and study senior author Rebecca Robker, also of the University of Adelaide. Again, the drug provided a reproductive jolt, nearly doubling the number of eggs the animals ovulated. The eggs appeared to be healthy, giving rise to embryos after in vitro fertilization. Even younger mice, however, did not benefit from the drug.

Despite these successes, the researchers weren’t sure whether reduced fibrosis drove the improved fertility, Robker says. “We didn’t know if [fibrosis] would be reversible,” she says, because it involves the accumulation of tough collagen strands. But when the scientists scrutinized the animals’ ovaries under the microscope, they found the amount of fibrosis was much lower in both groups of mice that received the drug than in the controls.

Faulty mitochondria, the organelles that supply energy to cells, may foster ovarian fibrosis. As mice and humans get older, these structures begin to malfunction, producing less of the energy-rich molecules that cells need and generating more destructive metabolic byproducts.

To probe the role of mitochondria in infertility, Robker and colleagues dosed 14-month-old mice with a different drug, BGP-15, which tunes up the organelles. Compared with untreated mice of the same age, the rodents ovulated more than twice as many eggs and showed less fibrosis in their ovaries.

The team also tested two other molecules that bolster mitochondria—metformin, an antidiabetes drug sometimes prescribed for infertility, and MitoQ, which is often touted as an antiaging supplement. Both molecules lessened ovarian fibrosis in old mice but did not stimulate ovulation.

Obesity suppresses fertility in humans, but whether ovarian fibrosis is connected to this decline was unknown. The researchers discovered fibrosis was prevalent in the ovaries of young, obese mice. They also found that BGP-15, metformin, and MitoQ curtailed the fiber buildup and spurred ovulation in these animals.

“This is the first evidence that links age-associated ovarian fibrosis with a reduction in fertility and shows that reducing it in any way can extend reproduction,” says Barbara Vanderhyden, an ovarian cancer researcher at the Ottawa Hospital Research Institute who also wasn’t connected to the research. She cautions, however, that diminishing fibrosis did not rejuvenate the mice’s ovaries. “It’s helpful, but it’s not a reversal.”

How fibrosis undermines fertility remains uncertain, but it may make ovarian tissue rigid, Robker says. An egg matures inside a cradle known as a follicle, which balloons to about 1 million times its original size before bursting to release the egg. The buildup of connective tissue might imprison follicles, preventing them from enlarging and thus thwarting egg development. The researchers found that BGP-15 spurs mice to produce an enzyme that dissolves the collagen fibers in connective tissue, which may liberate the follicles.

Researchers may be able to launch clinical trials to test BGP-15 or other fibrosis-quashing molecules. One hurdle is that the ovaries are tucked away deep in the abdomen, making it hard to determine who has developed fibrosis— the condition is usually diagnosed after surgical removal of the ovaries. “We need to find a noninvasive [way],” Robker says.

Science, 17 June 2022