Repurposing drugs with AMHR2 agonist activity as contraceptives

In a manuscript published in PNAS, Li et al. screened a repurposed drug library and identify small molecule agonists of the AMHR2 receptor, the first step in the development of an entirely new class of female contraceptives.

Women are born with a fixed number of oocytes encased in a single layer of pregranulosa cells forming primordial follicles. They constitute the ovarian reserve. Once activated, primordial follicles grow until they reach ovulation or die through apoptosis. The depletion of the primordial follicle pool triggers menopause.

Most existing hormonal contraceptives block ovulation of large antral follicles by acting on the hypothalamic-pituitary-gonadal axis, and share side-effects such as migraine, weight gain, diminished libido, breast tenderness, nausea, and increased cardiovascular and cancer risks. Since the developmental progression from a primordial follicle to an ovulated egg takes several months, and their activation and early growth is independent of gonadotropins and steroids, controlling primordial follicles activation could represent a new mechanism of contraception.

Anti-Mullerian hormone (AMH) is the only known paracrine factor capable of inhibiting the activation of primordial follicles. We have previously demonstrated complete contraception of adult female mice following the administration of an AAV9 gene therapy inducing superphysiological concentrations of AMH. Treatment with AMH resulted in a significant decrease in the number of activated follicles population and suppression of cycling.

Nevertheless, the use of recombinant AMH for long term contraception in women remains impractical. To address this concern, and accelerate the development of a new class of contraceptives based on this mechanism of action, we developed a screening methodology to identify small molecules that can recapitulate the contraceptive properties of AMH, by agonizing its receptor AMHR2. In this manuscript, we show that Sp600125, CYC-116, gandotinib, and ruxolitinib can function as AMHR2 agonists in vitro, and can inhibit primordial follicle activation and preantral follicle maturation in vivo. These findings open the way to use or modify these molecules to develop new contraceptives, with unique attributes, such as suppression of cycling with maintenance of estrogens, and potential applications in maintenance of the ovarian reserve during chemotherapy or aging.