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GLP-1RA Ameliorates Polycystic Ovary Syndrome via Hypothalamic RASA1/AKT: A Novel pathway Linking Hyperandrogenism to GnRH Dysregulation

ABSTRACT: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia and hypothalamic-pituitary-gonadal (HPG) axis dysregulation involving gonadotropin-releasing hormone (GnRH) hyperactivity. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) show therapeutic promise in PCOS, their central regulation mechanisms remain unknown. Here, we demonstrate that GLP-1RA improves follicular maturation in PCOS via hypothalamic RASA1-dependent modulation of GnRH secretion. Based on our letrozole-induced PCOS rats, GLP-1RA was shown to restore hormonal homeostasis by normalizing testosterone, suppressing luteinizing hormone, and reinstating estrous cyclicity alongside ovarian recovery. Proteomics analysis revealed a substantial recovery from hyperandrogenism-induced hypothalamic dysregulation after GLP-1RA therapy. Landscapes of PCOS and GLP-1RA hypothalamic perturbations were systematically drawn. Crucially, subsequent network analysis identified RASA1-GnRH axis as a core axis underpins GLP-1RA related pharmacological rescue of PCOS hypothalamus. Bidirectional genetic perturbations of RASA1 in GnRH neurons rigorously confirmed RASA1's regulation over GnRH synthesis, as well as the mediating role of Ras/AKT in this pathway. Notably, the modulation of both RASA1 and Akt effectively counteracted testosterone-induced GnRH hypersecretion and reversed GLP-1RA treatment-mediated GnRH suppression, thereby fully establishing GLP-1RA’s pharmacological mechanism through RASA1-Ras/Akt-GnRH signaling axis. Our study represented the first investigation into the hypothalamic molecular mechanism by which GLP-1RA improves PCOS, highlighting RASA1 as a critical mediator of HPG axis in the female reproductive systems. The discovery of novel target in central control would serve as a promising therapeutic strategy for PCOS reproductive improvement beyond metabolic treatment.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Linlin Yang

PROVIDER: PXD064291 | iProX | Mon May 26 00:00:00 BST 2025

REPOSITORIES: iProX

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GLP-1RA Ameliorates Polycystic Ovary Syndrome via Hypothalamic RASA1/AKT: A Novel pathway Linking Hyperandrogenism to GnRH Dysregulation

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