Reproductive Deficits Induced by Prenatal Antimüllerian Hormone Exposure Require Androgen Receptor in Kisspeptin Cells

Author:

Ho Emily V1ORCID,Shi Chengxian1ORCID,Cassin Jessica1ORCID,He Michelle Y1ORCID,Nguyen Ryan D1ORCID,Ryan Genevieve E1ORCID,Tonsfeldt Karen J1ORCID,Mellon Pamela L1ORCID

Affiliation:

1. Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093, USA

Abstract

Abstract Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by elevated androgens and antimüllerian hormone (AMH). These hormones remain elevated throughout pregnancy, and potential effects of hormone exposure on offspring from women with PCOS remain largely unexplored. Expanding on recent reports of prenatal AMH exposure in mice, we have fully characterized the reproductive consequences of prenatal AMH (pAMH) exposure throughout the lifespan of first- and second-generation offspring of both sexes. We also sought to elucidate mechanisms underlying pAMH-induced reproductive effects. There is a known reciprocal relationship between AMH and androgens, and in PCOS and PCOS-like animal models, androgen feedback is dysregulated at the level of the hypothalamus. Kisspeptin neurons express androgen receptors and play a critical role in sexual development and function. We therefore hypothesized that pAMH-induced reproductive phenotypes would be mediated by androgen signaling at the level of kisspeptin cells. We tested the pAMH model in kisspeptin-specific androgen receptor knockout (KARKO) mice and found that virtually all pAMH-induced phenotypes assayed are eliminated in KARKO offspring compared to littermate controls. By demonstrating the necessity of androgen receptor in kisspeptin cells to induce pAMH phenotypes, we have advanced understanding of the interactions between AMH and androgens in the context of prenatal exposure, which could have significant implications for children of women with PCOS.

Funder

National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

National Centers for Translational Research in Reproduction and Infertility

Doris A. Howell Research Scholarship for Women’s Health

National Institute of Neurological Disorders and Stroke

Publisher

The Endocrine Society

Subject

Endocrinology

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