Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood

• Published in: Nature Medicine Vol. 24; no. 6; pp. 834 - 846
• Main Authors: Tata, Brooke, Mimouni, Nour El Houda, Barbotin, Anne-Laure, Malone, Samuel A., Loyens, Anne, Pigny, Pascal, Dewailly, Didier, Catteau-Jonard, Sophie, Sundström-Poromaa, Inger, Piltonen, Terhi T., Dal Bello, Federica, Medana, Claudio, Prevot, Vincent, Clasadonte, Jerome, Giacobini, Paolo
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2018; Nature Publishing Group
• Subjects: 17β-Estradiol; 692/163/2743/2742; 692/699/2732/1577; Adult; Analysis; Animals; Anti-Mullerian Hormone - administration & dosage; Anti-Mullerian Hormone - blood; Biomedical and Life Sciences; Biomedicine; Brain - pathology; Cancer Research; Case-Control Studies; Comorbidity; Development and progression; Estradiol; Estrogens; Estrous Cycle; Female; Female infertility; Females; Fertility; Fetus - metabolism; Fetuses; Genetic aspects; Genotype & phenotype; Glycoproteins; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - metabolism; Gonadotropins; Green Fluorescent Proteins - metabolism; Health aspects; Hormone antagonists; Hormones; Humans; Infectious Diseases; Infertility; Life Sciences; Luteinizing hormone; Luteinizing Hormone - metabolism; Medical research; Metabolic Diseases; Metabolism; Mice, Inbred C57BL; Molecular Medicine; Neurons; Neurons - metabolism; Neurosciences; Neurosecretory Systems - metabolism; Offspring; Ovary - pathology; Phenols (Class of compounds); Phenotype; Phenotypes; Pituitary (anterior); Pituitary hormones; Placenta; Placenta - pathology; Polycystic ovary syndrome; Polycystic Ovary Syndrome - blood; Polycystic Ovary Syndrome - pathology; Polycystic Ovary Syndrome - physiopathology; Pregnancy; Pregnancy Trimester, Second - blood; Pregnant women; Prenatal experience; Progeny; Reproductive Biology; Risk factors; Sex hormones; Testosterone; Women; Women's health
• ISSN: 1078-8956; 1546-170X; 1546-170X; 1744-7933
• DOI: 10.1038/s41591-018-0035-5

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood. Excess anti-Müllerian hormone during pregnancy results in polycystic ovary syndrome-like phenotypes in female offspring, possibly explaining its pathogenesis as well as suggesting a possible therapy.