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

Abstract

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.

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Fig. 1: AMH levels during the second trimester of gestation are higher in women with PCOS than controls.
Fig. 2: Prenatal AMH treatment disrupts estrous cyclicity, ovarian morphology, and fertility in adult offspring.
Fig. 3: Prenatal AMH treatment leads to hyperandrogenism and elevation in LH secretion and pulsatility.
Fig. 4: Prenatal AMH treatment increases perinatal T levels in females and masculinizes their brains.
Fig. 5: PAMH GnRH-GFP mice exhibit higher GnRH dendritic spine density, increased GABAergic appositions to GnRH neurons, and elevated firing frequency of GnRH neurons in adulthood.
Fig. 6: Postnatal GnRH antagonist treatment of PAMH mice restores the PCOS-like neuroendocrine phenotype.

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Acknowledgements

We thank M. Tardivel (microscopy core facility), M.-H. Gevaert (histology core facility), D. Taillieu and J. Devassine (animal core facility), and the BICeL core facility of the Lille University School of Medicine for expert technical assistance. We are deeply indebted to P. Ciofi (U1215, Neurocentre Magendie, Institut National de la Santé et de la Recherche Médicale, Bordeaux, France) for his helpful feedback and discussion of the data. This work was supported by: the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC-2016-CoG to P.G. grant agreement n° 725149/REPRODAMH); the Institut National de la Santé et de la Recherche Médicale (INSERM), France (grant number U1172); the Centre Hospitalier Régional Universitaire, CHU de Lille, France (Bonus H to P.G. and Ph.D. fellowship to N.E.H.M.); Agence Nationale de la Recherche (ANR), France (ANR-14-CE12-0015-01 RoSes and GnRH to P.G.); Bourse France L’Oréal-UNESCO Pour les Femmes et la Science to B.K.T; Horizon 2020 Marie Sklodowska-Curie actions – European Research Fellowship (H2020-MSCA-IF-2014) to J.C.

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P.G. designed the study, analyzed data, prepared the figures, and wrote the manuscript. J.C. performed electrophysiological recordings and was involved in all aspects of study design, interpretation of results, and manuscript preparation; B.T., N.E.H.M., and A.-L.B. designed and performed the experiments and analyzed the data; A.L., assisted with experiments; P.P. performed the AMH measurements in blood human samples; S.A.M. performed tissue-clearing experiments; D.D., S.C.-J., and T.T.P. helped with several aspects of interpretation of clinical and preclinical results and manuscript preparation; I.S.-P. provided biological samples and clinical information for the human study; C.M and F.D.B. performed nano-HPLC-HRMS experiments; and V.P. was involved in the study design, interpretation of the results, and preparation of the manuscript.

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Correspondence to Paolo Giacobini.

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Tata, B., Mimouni, N., Barbotin, AL. et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med 24, 834–846 (2018). https://doi.org/10.1038/s41591-018-0035-5

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