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Hypothalamic RASA1/Ras/AKT/GnRH axis reprogramming mediates GLP-1RA's central rescue of PCOS HPG dysfunction.

Linlin Yang¹, Na Guo¹, Xing Wang²

¹Endocrinology Department, Data Management Department, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Diabetes, Obesity & Metabolism

|November 10, 2025

Summary

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) centrally regulate the hypothalamic RASA1/Ras/AKT/GnRH axis to manage polycystic ovary syndrome (PCOS). This study reveals GLP-1RAs as a novel therapeutic for PCOS by targeting this key neuroendocrine pathway.

Area of Science:

Neuroendocrinology
Reproductive Biology
Molecular Medicine

Background:

Polycystic ovary syndrome (PCOS) involves hyperandrogenaemia and hypothalamic-pituitary-gonadal (HPG) axis dysregulation, driven by hyperactivity of gonadotropin-releasing hormone (GnRH) neurons.
Current therapies for PCOS are limited, and the central mechanisms underlying its reproductive dysfunction remain unclear.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show promise for PCOS, but their central actions are not well understood, with focus typically on peripheral metabolic effects.

Purpose of the Study:

To elucidate the central mechanism by which GLP-1 receptor agonists (GLP-1RAs) exert therapeutic effects in polycystic ovary syndrome (PCOS).
To identify key molecular players in the hypothalamus that mediate the neuroendocrine regulation of PCOS by GLP-1RAs.
To establish the causal role of identified pathways in HPG axis homeostasis and PCOS pathophysiology.

Main Methods:

Utilized liraglutide, a GLP-1RA, in a letrozole-induced PCOS rat model.
Performed systematic hypothalamic proteomic profiling to identify signaling perturbations.
Conducted pharmacology gain- and loss-of-function experiments, including AAV-mediated gene delivery, to investigate the role of RASA1 and Ras/AKT signaling in GnRH regulation.

Main Results:

GLP-1RA treatment in PCOS rats reduced testosterone and luteinizing hormone, improved estrous cyclicity, and normalized ovarian morphology.
Hypothalamic proteomic analysis identified RASA1 as a crucial hub, linking GLP-1RA treatment to GnRH regulation by modulating Ras/AKT signaling.
In vivo experiments confirmed RASA1's central role in regulating ovarian function and hormone homeostasis, with genetic and pharmacological manipulations confirming its causal relationship with GnRH secretion and GLP-1RA's suppressive effects.

Conclusions:

This study provides the first evidence for a central mechanism of GLP-1RA action in managing PCOS.
The hypothalamic RASA1/Ras/AKT/GnRH axis is identified as a master regulator of HPG axis homeostasis in the context of PCOS.
These findings reveal novel therapeutic targets for precision intervention in reproductive neuroendocrinology for PCOS management.

Keywords:

GLP‐1RA GnRH RASA1 hypothalamus polycystic ovary syndrome

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