Anti-Mullerian hormone actions to control primate folliculogenesis

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 DESCRIPTION (provided by applicant): The goal of this research is to understand the mechanisms whereby anti-Müllerian hormone (AMH) either directly, or indirectly via other locally synthesized factors, regulates preantral follicle growth and antral follicle maturation in the stag-dependent manner in primates during the menstrual cycle. Increasing evidence suggests that AMH alters preantral follicle growth; and the discovery that AMH reduces aromatase and luteinizing hormone receptor expression in cultured granulosa cells adds another dimension to possible AMH actions in antral follicles. Likewise, the PI's evidence that AMH is heterogeneously and dynamically expressed in the macaque follicles reinforces the concept of stage-dependent AMH actions during primate folliculogeneisis. Finally, the recent "in vitro follicl maturation" (IFM) technique provides a feasible model for manipulative studies to unravel local factors and signaling pathways that are critical to the follicular development and oocyte maturation in the primate ovary. Therefore, translational studies are proposed in the adult, female rhesus monkeys, to test the hypotheses that: (Aim 1) AMH promotes preantral follicle growth, but inhibits antral follicle maturation in vitro and (Aim 2) AMH promotes preantral-to-antral follicle growth, but prevents further maturation and selection of the dominant follicle durig the follicular phase of the menstrual cycle in vivo. AMH addition (recombinant human AMH protein) and ablation (anti-human AMH antibody) experiments will be conducted through IFM in vitro and intraovarian infusion in vivo. Follicular morphology and histology, as well as function i steroidogenesis and local factor production, oocyte maturation and competence in fertilization and preimplantation development, plus genome-wide mRNA levels and selected AMH-regulated genes (Aim 3) will be analyzed with the assistance of the Assisted Reproductive Technologies Support Core and Massively Parallel Sequencing Shared Resource. AMH will also be examined as a noninvasive biomarker for further follicle growth and oocyte maturation during IFM. Finally, data generated from the nonhuman primate research will be applied to human IFM with the hypothesis that AMH manipulation improves the coordinated development and maturation of human follicles and their enclosed oocytes (Aim 4). These experiments will provide valuable information on the heterogeneous expression and stage- dependent actions of AMH in ovarian follicles, as well as mechanisms of AMH controlling follicular development, in primates. New insight will emerge on the potential of AMH to serve as a biomarker for follicle growth and oocyte competence during IFM. Emerging concepts should refine clinical paradigms, e.g., local AMH action or value as a biomarker of ovarian reserve in infertility, including primary ovarian insufficiency, polycystic ovarian syndrome, endometriosis, in vitro fertilization, reproductive aging and cancer.