Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice. - Université de Lille Accéder directement au contenu
Article Dans Une Revue EBioMedicine Année : 2023

Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice.

Résumé

Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments. Methods We used adult Gnrh1cre female mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in hypophysiotropic GnRH neurons. Chronic chemogenetic activation protocol was carried out with clozapine N-oxide (CNO) i.p. injections every 48 h over a month. We evaluated the reproductive and hormonal profile before, during, and two months after chemogenetic manipulations. Findings We discovered that the overactivation of GnRH neurons was sufficient to disrupt reproductive cycles, promote hyperandrogenism, and induce ovarian dysfunction. These PCOS features were detected with a long-lasting neuroendocrine dysfunction through abnormally high luteinizing hormone (LH) pulse secretion. Additionally, the GnRH-R blockade prevented the establishment of long-term neuroendocrine dysfunction and androgen excess in these animals. Interpretation Taken together, our results show that hyperactivity of hypothalamic GnRH neurons is a major driver of reproductive and hormonal impairments in PCOS and suggest that antagonizing the aberrant GnRH signaling could be an efficient therapeutic venue for the treatment of PCOS.
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hal-04586676 , version 1 (24-05-2024)

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Silva Mauro, Laurine Decoster, Gaspard Delpouve, Tori Lhomme, Gaetan Ternier, et al.. Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice.. EBioMedicine, 2023, EBioMedicine, 97, pp.104850. ⟨10.1016/j.ebiom.2023.104850⟩. ⟨hal-04586676⟩

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