L'exposition prénatale à l'hormone Anti-Müllerienne (AMH) agit sur la reprogrammation fœtale et induit l'apparition du syndrome des ovaires polykystiques à l'âge adulte

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide with high comorbidity and economic burden. It is mainly characterized by hyperandrogenism, oligo/anovulation and polycystic appearing ovaries. Moreover, most women with PCOS exhibit higher levels of circulating luteinizing hormone (LH), suggestive of heightened gonadotropin-releasing hormone (GnRH) release. Additionally, PCOS patients also exhibit 2-3x higher levels of Anti-Müllerian Hormone (AMH) as compared to healthy controls.While the exact origin of PCOS is unknown, familiar clustering and twin studies of PCOS patients and their relatives suggest a strong heritable component in PCOS. However, the candidate genes identified account for only <10% of the estimated 70% heritability of PCOS, implying that it may originate during intrauterine development and that environmental factors, such as hormonal imbalances during fetal life, could be involved in the onset of PCOS.In this study, we first measured AMH levels in a cohort of pregnant women with PCOS and control women which revealed that AMH is significantly more elevated in the former group versus the latter, we then modelized our clinical findings by exposing pregnant mice to high concentration of AMH during a specific temporal window and showed that this fetal exposure leads to a cascade of alterations impacting the maternal brain, the ovaries, and the placenta, which consequently reprogram the fetal brain and induce the acquisition of the major PCOS cardinal neuroendocrine reproductive features, namely hyperandrogenism, elevation in LH pulse frequency and oligo-anovulation, and a persistent rise in the GnRH neuronal firing activity in adulthood. Moreover, our results show that the long-term consequences of a short exposure to elevated AMH levels during gestation expand beyond the first generation exposed and that PCOS-like manifestations seem to be transmitted across subsequent generations of females.Intrestingly, using a pharmacological approach, we demonstrate that tempering GnRH signaling pathway rescues the neuroendocrine phenotype of PCOS-like animals, restoring their normal hormonal levels, estrus cyclicity and ovarian morphology.Lastly, we sought to understand how early exposure to AMH excess would affect the neuroendocrine and reproductive features of the male offspring. Here, we demonstrate that prenatal AMH treatment profoundly impacts the Hypothalamic-Pituitary-Gonadal (HPG) axis function in males, which fail to engage the testosterone surge at birth observed in control newborns, leading to a feminization of sexually dimorphic circuitries of their brains, an increase in LH, a drastic decrease in testosterone levels, severe alterations in the testicular steroidogenesis and morphology as well as a higher risk of developing cryptorchidism in adulthood. Thus, it could be of clinical interest to relate findings from this study to the reproductive phenotype of sons of PCOS women, who are exposed during gestation but not systematically investigated in adulthood.Collectively, our results challenge the concept of PCOS originating in utero and appear to consolidate the role of AMH as a trigger of the pathogenesis, suggesting that an altered hormonal milieu during early life associated with PCOS may not only affect the female fetus but also the male fetus exposed and that these alterations could be transmitted across multiple generations.These findings point to PAMH mouse model as an excellent preclinical tool to investigate both neuroendocrine disturbances of PCOS and how developmental programming effects are transmitted, while offering a therapeutic avenue for the treatment of the disease.Le syndrome des ovaires polykystiques (SOPK) est la principale cause d’infertilité feminine à travers le monde, associé à un risqué élevé de comorbidités avec des conséquences économiques non négligeables. Ce syndrome est caractérisé par une oligo-anovulation, une hyperandrogénie, et un aspect échographique d’ovaires polykystiques. De plus, la plupart des femmes atteintes de SOPK présentent des concentrations élevées de LH suggérant une libération accrue de GnRH. De plus, les patientes SOPK ont habituellement des concentrations en Hormone Anti Müllerienne (AMH) 2 à 3 fois plus élevés que les femmes non atteintes.Alors que l’origine exacte du SOPK demeure inconnue, des études de clustering familial et portant sur des jumeaux ou des ascendants de femmes atteintes du SOPK ont mis en évidence une forte composante héréditaire. Cependant, les gènes candidats identifiés n’expliquent qu’à peine 10% des cas de SOPK suggérant qu’une origine développementale et que des facteurs environnementaux tels que des modifications hormonales durant la vie foetale pourrait être à l’origine du SOPK.Dans cette étude, nous avons d'abord comparé les concentrations d'AMH dans un groupe de femmes atteintes de SOPK et chez des femmes témoins pendant la grossesse. Les concentrations d’AMH se sont révélées significativement plus élevées chez les SOPK par rapport aux témoins. Nous avons ensuite utilisé ces résultats cliniques pour développer un modèle animal murin de SOPK en exposant les souris gestantes à une concentration élevée d’AMH au cours d'une fenêtre temporelle spécifique. Nous avons montré que cette exposition foetale conduisait à une cascade d'altérations affectant le cerveau maternel, les ovaires et le placenta, entrainant une reprogrammation du cerveau foetal et induisant l'acquisition des principaux critères diagnostiques retrouvés dans le SOPK, à savoir l'hyperandrogénie, l'augmentation de la pulsalitié de la LH et de l'oligo-anovulation, ainsi qu’une augmentation persistante de l'activité électrique de la GnRH à l'âge adulte. De plus, nos résultats montrent que les conséquences à long terme d'une exposition courte à des niveaux élevés d'AMH pendant la gestation s'étendent au-delà de la première génération exposée et que les manifestations de type SOPK semblent être transmises d’une génération à l’autre chez les femelles.De manière intéressante, en utilisant une approche pharmacologique, nous avons démontré que l’inhibition partielle de la voie de signalisation de la GnRH permettait de restaurer chez les animaux SOPK un phénotype neuroendocrinien normal, en rétablissant des concentrations hormonales normales, la cyclicité oestrale et leur morphologie ovarienne.Enfin, nous avons cherché à comprendre comment une exposition précoce à un excès d'AMH affecterait les caractéristiques neuroendocriennes et reproductives de la progéniture mâle. Ici, nous avons démontré que le traitement par AMH en période prénatale modifiait la fonction de l'axe hypothalamo-hypophyso-gonadique (HPG) chez les mâles, qui ne parviennent pas à engager le pic de testostérone néonatal normalement observé chez les nouveau-nés mâles témoins, conduisant à une féminisation des circuits sexuellement dimorphiques cérébraux, à une augmentation de la LH, et finalement à une diminution drastique des niveaux de testostérone à l’âge adulte, à des altérations sévères de la stéroïdogenèse et de la spermatogenèse ainsi qu'à un risque plus élevé de développer une cryptorchidie à l'âge adulte. Ainsi, il pourrait être intéressant de relier les résultats de cette étude au phénotype reproductif des garçons de femmes atteintes du SOPK, qui ont été exposés pendant la grossesse mais qui ne sont habituellement pas suivis plus tard à l'âge adulte [...

Fertilization, but Not Post-Implantation Development, Can Occur in the Absence of Sperm and Oocyte Beta1 Integrin in Mice

Fertilization is a complex process that requires successive stages and culminates in the adhesion/fusion of gamete membranes. If the question of the involvement of oocyte integrins has been swept away by deletion experiments, that of the involvement of sperm integrins remains to be further characterized. In the present study, we addressed the question of the feasibility of sperm&ndash;oocyte adhesion/fusion and early implantation in the absence of sperm &beta;1 integrin. Males and females with &beta;1 integrin-depleted sperm and oocytes were mated, and fertilization outcome was monitored by a gestational ultrasound analysis. Results suggest that although the sperm &beta;1 integrin participates in gamete adhesion/fusion, it is dispensable for fertilization in mice. However, sperm- and/or oocyte-originated integrin &beta;1 is essential for post-implantation development. Redundancy phenomena could be at the origin of a compensatory expression or alternative dimerization pattern

Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process

International audiencePolycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects. These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy

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

International audiencePolycystic 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