Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice.
GnRH
Hyperandrogenism
Luteinizing hormone
Ovarian dysfunction
PCOS
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
03
08
2023
revised:
18
09
2023
accepted:
12
10
2023
medline:
13
11
2023
pubmed:
29
10
2023
entrez:
28
10
2023
Statut:
ppublish
Résumé
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. We used adult Gnrh1 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. 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. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).
Sections du résumé
BACKGROUND
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
METHODS
We used adult Gnrh1
FINDINGS
RESULTS
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
CONCLUSIONS
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
BACKGROUND
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).
Identifiants
pubmed: 37898094
pii: S2352-3964(23)00416-4
doi: 10.1016/j.ebiom.2023.104850
pmc: PMC10630624
pii:
doi:
Substances chimiques
Luteinizing Hormone
9002-67-9
Gonadotropin-Releasing Hormone
33515-09-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104850Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests P.G. and V.P. disclose that they are inventors of a patent application by the INSERM (Institut National de la Santé et de la Recherche Médicale) covering the use of GnRH antagonists for the treatment of women affected with PCOS (N° of publication: WO2018177746). All other authors do not have competing interests.