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

Abstract

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.

FUNDING:

European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).

• Authors: Mauro S B Silva, Laurine Decoster, Gaspard Delpouve, Tori Lhomme, Gaetan Ternier, Vincent Prevot, Paolo Giacobini
• Journal: EBioMedicine (EBioMedicine) Vol. 97 Pg. 104850 (Nov 2023) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 37898094 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Luteinizing Hormone
• Gonadotropin-Releasing Hormone

Topics

• Humans
• Female
• Mice
• Animals
• Polycystic Ovary Syndrome
• Luteinizing Hormone
• Gonadotropin-Releasing Hormone
• Neurons