Failure to ovulate and release mature oocytes is one of the most common female infertility problems. With increasing age or conditions such as obesity, no oocytes are released, even upon ovulation induction with hormonal treatment.
Aging is known to be associated with increased ovarian fibrosis, characterized by excess collagen accumulation, and altered matrix degradation. Ovulation, the process by which an egg is released from the ovary, is one of the most dynamic cycles of tissue injury and repair.
In a recent study, a team of scientists from Australia found, using murine models, that inflammation-mediated excess collagen deposition within the ovarian stromal compartment causes impaired oocyte release. The study also showed promising results in reversing ovarian fibrosis in aged and obese mice using antifibrotic drugs. The team reported its findings in the June 17, 2022, online edition of Science advances.
The team was led by Rebecca Robker from the University of Adelaide, where she is a professor in the School of Biomedicine, Faculty of Health and Medical Sciences. Talk to BioWorld ScienceRobker said that “one challenge we faced was convincing our clinical colleagues that ovarian fibrosis (the excess inflammation and collagen) could actually prevent egg release from ovaries and cause anovulation. Currently, clinical treatments involve inducing ovulation at causing women to administer very high doses of hormones to make the egg-containing follicles grow and mature, and the search for new therapies has been about finding new hormones or treatment protocols to stimulate these follicles.”
The results of Robker’s study suggest that removing the excess collagen around the follicles may allow any remaining eggs to be released in response to hormones.
The authors investigated the origins of ovarian fibrosis by measuring cellular stress responses and inflammatory mediators that cause collagen deposition, in the context of reproductive aging and obesity/insulin resistance, which also causes anovulation.
They found that the ovarian stroma of obese and reproductively aged female mice showed altered metabolism, oxidative stress, increased inflammation and collagen deposition. Robker added that “it was very surprising that the ovarian defects we observed in obese mice were identical to those of the older ‘middle-aged’ mice. This suggests that obesity causes damage to the ovary similar to perimenopause and may explain some types of infertility . which is common in obese women.” The authors found that mitochondrial dysfunction seen with both aging and/or obesity was linked to a cascade of intracellular stress pathways within the ovarian stroma, particularly oxidative stress, and induced both pro-inflammatory and anti-inflammatory responses, which leading to fibrotic collagen deposition.
Treatment of obese or reproductively aged female mice with BGP-15 (a PARP-1 inhibitor) improved mitochondrial activity in ovarian stromal cells, reduced oxidative stress, and attenuated inflammation. BGP-15 treatment also resulted in matrix metalloprotease 13 (MMP-13) induction, collagen removal and enhanced oocyte release.
Mice treated with pirfenidone, metformin, or MitoQ (mitoquinone mesylate) also showed reduced ovarian fibrosis, thus providing proof of concept that ovarian fibrosis is reversible, using currently available drugs. In terms of translation, Robker hopes that the drugs the study identified can now be tested in clinical trials for effectiveness in improving fertility.
Robker also hopes that the published results indicate “there is likely to be a treatment for ovarian fibrosis in the foreseeable future that can be used in conjunction with current assisted reproductive technology (ART) protocols to improve pregnancy success rates in women who have very few eggs. .
Next, Robker and her team aim to investigate “which types of immune cells reside in the ovary and what prompts them to switch to causing damage.” According to her, “if we can further optimize methods to prolong the functioning of the ovary, it will have huge knock-on effects in not only extending a woman’s fertile years, but greatly improving her overall health through natural hormone production facilitate later in life.”