David Pepin, PhD; Patricia Donahoe, MD
Competition Sponsor: US National Academy of Medicine
Fertility clinics around the world measure the levels of a hormone called Mullerian Inhibiting Substance (MIS) as a marker of ovarian “age”. Women are born with a set number of dormant follicles, the “ovarian reserve”, which gradually get used over time until they are depleted at menopause. MIS is produced by growing follicles in the ovary where it inhibits the activation of dormant follicles by negative feedback, thus regulating the rate of depletion of ovarian reserve during aging. We have recently demonstrated that treatment with high levels of MIS in mice can inhibit dormant follicle activation and prevent the growth of new follicles. Because MIS acts on the first step of follicle activation, unlike oral contraceptives inhibit the final step of ovulation, MIS has the potential of preserving follicles in their dormant state, and thus extend the ovarian lifespan. Furthermore, the persistence of estrogen production even during complete suppression by MIS suggest there may be a therapeutic window at which MIS can both extend ovarian lifespan and maintain hormonal health. We hypothesize that low-dose chronic administration of MIS by gene therapy could delay ovarian aging by reducing the rate of follicle activation while still maintaining sex steroid production. We propose to evaluate long-term treatment with MIS in female mice and assess their reproductive longevity and hormonal health. Thus, MIS may provide a novel paradigm of a natural hormone that combats ovarian aging and prevents or delays the negative consequences of menopause on bone, cardiovascular, neurological, and overall health.