Jean-Pierre Aubert Research Center (JPArc), Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm UMR-S 1172, Lille, France.
University of Lille, FHU 1000 Days for Health, Lille, France.
CHU Lille, Institut de Biologie de la Reproduction-Spermiologie-CECOS, Lille, France.
Lille, Laboratoire de Biochimie & Hormonologie, Centre de Biologie Pathologie, Lille, France.
CHU Lille, Service de Gynécologie Endocrinienne et Médecine
de la Reproduction, Hôpital Jeanne de Flandre, Lille, France.
Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland; University of Oulu and Medical Research Center Oulu, Oulu, Finland.
Department of Molecular Biotechnology and Health Science, University of Torino, Torino, Italy.
These authors contributed equally: Brooke Tata, Nour El
These authors jointly supervised this work: Jerome Clasadonte, Paolo Giacobini. *e-mail: firstname.lastname@example.org
COS is the most common female reproductive disorder, affect-
ing 10–18% of women of reproductive age worldwide
syndrome is underpinned by excessive ovarian and/or adrenal
androgen secretion, oligo-anovulation and, in many cases, insulin
resistance and associated metabolic derangements
. In nonpreg-
nant women with PCOS, serum levels of AMH are two- to threefold
higher than in women without polycystic ovaries or PCOS
the severity of the reproductive dysfunction is positively correlated
with AMH levels
. The pathophysiology of PCOS also extends
to hypothalamic neuronal dysregulation, as most PCOS individu
als exhibit increased luteinizing hormone (LH) levels suggestive of
high-frequency GnRH secretion
. Whether this defect is pri-
mary or secondary to other changes in PCOS remains unclear, but
recent evidence has shown that GnRH-positive neurons express
AMH receptors and that exogenous AMH potently increases GnRH
neuron firing and GnRH release in murine living tissue explants
Familial clustering and twin studies have shown that PCOS has
a strong heritable component
. However, the mutations that have
been identified so far do not account for its high prevalence in the
population, implying that fetal environmental factors might play
important roles in the onset of this disease
Here we showed that AMH concentrations during pregnancy are
significantly higher in women with PCOS as compared to women
with no reproductive defects (unpaired two-tailed Mann–Whitney
U test, P ≤ 0.0001). Using mouse models, we showed that exposure
to excess AMH during gestation engaged a series of events in the
dams leading to a fetal programming of the exposed offspring into
exhibiting a PCOS-like reproductive and neuroendocrine pheno
type in adulthood. GnRH antagonist treatment of these offspring
during adulthood normalized their neuroendocrine phenotype.
AMH levels during pregnancy are higher in women with PCOS
than in controls. AMH levels were previously found to be low dur
ing pregnancy in women with normal fertility
; however, whether
this is also the case for pregnant women with PCOS has never
Elevated prenatal anti-Müllerian hormone
reprograms the fetus and induces polycystic ovary
syndrome in adulthood
, Nour El Houda Mimouni
, Anne-Laure Barbotin
, Samuel A. Malone
, Pascal Pigny
, Didier Dewailly
, Sophie Catteau-Jonard
, Inger Sundström-Poromaa
Terhi T. Piltonen
, Federica Dal Bello
, Claudio Medana
, Vincent Prevot
, Jerome Clasadonte
and Paolo Giacobini
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 devel-
opmental 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.
NATURE MEDICINE | VOL 24 | JUNE 2018 | 834–846 | www.nature.com/naturemedicine
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.