Newly identified protein function may reveal understanding of lifetime fertility

UNIVERSITY PARK, Pa. — A protein in mouse ovaries regulates the formation of the ovarian follicle reserve, which comprises a mammal’s lifetime supply of egg cells and surrounding support cells, according to new study conducted by a U.S.-Canadian team. The discovery provides a foundation for further research on premature ovarian insufficiency and menopause in women and reproductive problems in dairy cows.

The researchers published their findings in the Proceedings of the National Academy of Sciences.

According to Camilla Hughes, who led the research as a postdoctoral scholar at the University of Montreal and is now an assistant professor of reproductive biology in Penn State’s College of Agricultural Sciences, finding the protein — called Steroidogenic factor 1 (SF-1) — and identifying its role has substantial implications for human and cattle reproductive health and success.

“First, it helps us to know how the stage is set for lifetime fertility,” said Hughes, who is also an affiliate of the Center for Reproductive Biology and Health in the Huck Institutes of the Life Sciences. “Understanding how many eggs the ovary is going to have at a given time will help us, perhaps, to develop technologies to influence the ovarian follicle reserve. If it is amenable to drug modulation, it becomes an attractive target for the development of therapeutic interventions to address conditions where follicle depletion is the cause of infertility.”

The ovarian reserve — established prior to or around the time of birth in mammals — comprises the nonrenewing pool of immature eggs and supporting cells (referred to together as follicles), representing the lifetime fertility potential of the ovary. Follicle depletion accompanies the natural aging process and is a primary cause of menopause in humans.

The frequency of infertility in humans has increased in recent decades, primarily due to couples choosing to delay childbearing, Hughes noted. It affects some 15% of couples, and approximately 40% of these cases are attributable to ovarian dysfunction, she added. A major cause of infertility is aging and consequent depletion of the ovarian follicle reserve.

The ovarian disorder known as premature ovarian insufficiency manifests as early infertility, Hughes explained. This condition is characterized by loss of ovarian function and the onset of menopause prior to the age of 40. This is due to a decline in the population of follicles, but the underlying cause of premature ovarian insufficiency is known in only about half of cases.

In this paper, the researchers reported that in the absence of SF-1, the number of eggs in the ovarian reserve was dramatically reduced, and the ovaries themselves were much smaller. This was due to increased egg death and impaired formation of follicles. The few follicles that formed were dysfunctional, with impaired communication between eggs and other cells in the ovary, disruptions of key ovarian cellular signaling pathways and incorrect formation of structural components of the ovary.

This indicates that SF-1 is necessary to support egg survival, ovarian cell-cell communication and structural formation of the ovary, the researchers suggested. While this study was conducted in mice — which reach can be generated quickly and researchers can easily modify to lack specific proteins and study resulting function —Hughes explained the findings can be applied to inform research on fertility problems in cows or to better understand menopause and age-related infertility in humans.  

“Understanding how this reserve of eggs is formed in the first place can perhaps help us to understand why we have these later-in-life problems with fertility when the reserve is depleted,” Hughes said. “Perhaps therapies can be devised to slow down or somehow counteract that depletion.”

Contributing to the research were Bruce Murphy and Olivia Smith, Centre for Research in Reproduction and Fertility, University of Montreal; Marie-Charlotte Meinsohn, Pediatric Surgical Research Laboratories, Massachusetts General Hospital; and Mylène Brunelle and Nicolas Gévry, Department of Biology, University of Sherbrooke.

“The credit for these findings goes to the whole interdisciplinary team that includes researchers from University of Montreal, University of Sherbrooke and Massachusetts General Hospital,” Hughes said. “Without the team, and most especially my postdoc mentor, Dr. Bruce Murphy at University of Montreal, the work would not have been possible.”

The Canadian Institutes of Health Research and the Lalor Foundation funded this research.