Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood
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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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Excessive prenatal AMH exposure could promote the aberrant neuroendocrine function typical of PCOS and AMH can modulate GnRH neuron function.
“These data suggest that excessive prenatal AMH exposure could promote the aberrant neuroendocrine function typical of PCOS and that AMH can modulate GnRH neuron function [37, 38].”
From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [38]
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“Although further studies are needed to assess the effect on humans, higher serum levels of dehydroepiandrosterone (DHEAS) and testosterone in the first years after menarche have been found in daughters of PCOS women than in controls in several studies [21,22].”
Result
- Authors
- Tata, B., Mimouni, N. E. H., Barbotin, A.-L., Malone, S. A., Loyens, A., Pigny, P., Dewailly, D., Catteau-Jonard, S., Sundström-Poromaa, I., Piltonen, T. T., Dal Bello, F., Medana, C., Prevot, V., Clasadonte, J., & Giacobini, P.
- Affiliations
- Inserm (FR)
- Université de Lille (FR)
- Oulu University Hospital (FI)
- University of Turin (IT)
- Corresponding author
- Giacobini, Paolo
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-05-14
- Volume
- 24
- Issue
- 6
- Pages
- 834-846
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6098696
- OpenAlex
- W2803052640
- Cited by
- 434
- References
- 76
- Citations by year
- 2026: 33 · 2025: 49 · 2024: 53 · 2023: 53 · 2022: 65 · 2021: 57 · 2020: 59 · 2019: 47 · 2018: 18
- FWCI
- 48.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-14-CE12-0015)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- polycystic ovary syndrome, anti-Müllerian hormone, prenatal hormone exposure, fetal programming, GnRH neurons, neuroendocrine dysfunction, female infertility, mouse model
- MeSH terms
- Adult, Animals, Brain, Female, Fertility, Fetus, Humans, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Mice, Inbred C57BL, Neurons, Neurosecretory Systems, Ovary, Phenotype, Placenta, Polycystic Ovary Syndrome, Pregnancy, Pregnancy Trimester, Second, Case-Control Studies, Estrous Cycle, Green Fluorescent Proteins, Anti-Mullerian Hormone
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