Evaluation of the effect of exogenous AMH on ovarian function and fertility

/Abstract: AMH functions as a master regulator of ovarian function, capable of inhibiting primordial follicle activation, suppressing early preantral follicle growth, modulating antral follicle maturation, and producing contraception when given at supraphysiological doses in mice, rats, and cats. Given these potent and pleiotropic effects, and its distinct mechanism of action uniquely affecting follicles before they become responsive to gonadotropins and sex steroids, AMH has shown substantial promise as a treatment for various indications in women's health. Indeed, treatment with AMH may be used for contraception, synchronization of follicles for stimulation, and protection from accelerated ovarian aging in chemotherapy-induced ovarian failure models. Yet most of what we know about the role of AMH in the ovary is derived from rodent models whose reproductive physiology is dissimilar to humans, being poly-ovulatory with shorter cycles, and no menses. To better understand the function of AMH in humans, we propose to use non-human primates (NHPs) as a model. Our long-term goal is to understand how AMH affects ovarian function in primates, and if supraphysiological levels are safe, and have beneficial effects on fertility. These discoveries could expand our understanding of this hormone in mono-ovulatory species and facilitate the development of novel treatments based on AMH for humans. We hypothesize that supraphysiological AMH can induce contraception without disrupting estradiol homeostasis, reduce the rate of attrition of the ovarian reserve and ovarian aging, and when given at sub- contraceptive levels improve oocyte and embryo quality. Our rationale, for testing these hypotheses in NHP is that AMH function is highly context- and dose-dependent and that the use of these models is necessary to better understand the biology of AMH, and the risks and opportunities of AMH as a treatment, in humans. Our specific aims will be to test the following hypotheses: 1) that AMH prevents ovulation but maintains reproductive hormones and cyclicity and is safe when administered chronically at supraphysiological doses; 2) that AMH modulates follicle dynamics and reduces the rate of activation of primordial follicles by affecting follicle maturation and development thereby reducing ovarian aging; and 3) that chronic AMH treatment does not adversely affect oocyte or embryo quality, and in some context may even improve oocyte quality, and pre-implantation embryo development. The proposed studies would represent a significant contribution to our understanding of the mechanisms of action of AMH in female fertility, with the potential to produce proof of concept of applications with significant clinical impact. Furthermore, it will provide novel insights into the gonadotropin- and sex-steroid-independent mechanisms of regulation of ovulation and ovarian aging, representing some of the greatest remaining mysteries of reproductive biology. These studies are highly innovative, by providing for the first time a comprehensive assessment of how AMH modulates ovarian biology and reproductive function in primates. Project Number: 1R01HD115719-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: David Pepin | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $724,714 | Activity Code: R01 | Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11571901A1