Failure to ovulate and release mature oocytes is one of the most common female infertility problems. With increasing age or conditions like obesity, no oocytes are released even on 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 wounding and repair.
In a recent study, a team of scientists from Australia have 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 published its findings in the June 17, 2022, online issue of Science Advances.
The team was led by Rebecca Robker from the University of Adelaide, where she is a professor at the School of Biomedicine, Faculty of Health and Medical Sciences. Speaking to BioWorld Science, Robker said that "one challenge we faced was convincing our clinical colleagues that ovarian fibrosis (the excess inflammation and collagen) could actually be preventing egg release from ovaries and causing anovulation. Currently, clinical treatments for triggering ovulation in women involve administering very high doses of hormones to make the egg-containing follicles grow and mature, and the search for new therapies has been all about finding new hormones or treatment protocols to stimulate these follicles."
The results from Robker's study indicate that removing the excess collagen surrounding the follicles could allow any remaining eggs to be released in response to hormones.
The authors investigated the origins of ovarian fibrosis onset 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 old female mice exhibited altered metabolism, oxidative stress, heightened inflammation and collagen deposition. Robker added that "it was very surprising that the ovary defects we observed in obese mice were identical to those of the older 'middle-age' mice. This suggests that obesity causes damage to the ovary similar to perimenopause and may explain some types of infertility that are common in obese women." The authors found that mitochondrial dysfunction seen with both aging and/or obesity is linked to a cascade of intracellular stress pathways within the ovarian stroma, particularly oxidative stress, and triggered both proinflammatory and anti-inflammatory responses, resulting in fibrotic collagen deposition.
Treatment of obese or reproductively old female mice with BGP-15 (a PARP-1 inhibitor) improved mitochondrial activity in ovarian stromal cells, reduced oxidative stress, and dampened inflammation. BGP-15 treatment also resulted in matrix metalloprotease 13 (MMP-13) induction, collagen removal, and improved oocyte release.
Mice treated with pirfenidone, metformin or MitoQ (mitoquinone mesylate) also exhibited reduced ovarian fibrosis, thus providing proof-of-concept evidence that ovarian fibrosis is reversible, and using currently available drugs. In terms of translation, Robker hopes that the drugs the study has identified can now be tested in clinical trials for efficacy to improve fertility.
Robker also hopes that the published results indicate "there is likely to be a treatment for ovarian fibrosis in the foreseeable future that could be used in conjunction with current assistive reproductive technology (ART) protocols to improve pregnancy success rates in women who have very few eggs.Next, Robker and her team intend to investigate "what types of immune cells reside in the ovary and what triggers them to transition towards causing damage." According to her, "if we can further optimize methods to prolong the functioning of the ovary it will have major flow-on effects of not only extending a woman's fertile years but greatly improving her overall health by facilitating natural hormone production later in life."