Hypothalamic Epac2/AKT/GnRH signalling is associated with metformin-responsive neuroendocrine improvement in a PCOS model.

Authors

Na Guo, Hongyun Li, Jinhong He, Huanhuan Zhou, Xing Wang, Linlin Yang, Huijuan Ma

Published in

Journal of ovarian research. Volume 19. Issue 1. Jul 24, 2026. Epub Jul 24, 2026.

Abstract

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterised by hypothalamic-pituitary-gonadal (HPG) axis dysfunction and pathological gonadotropin-releasing hormone (GnRH) hypersecretion. While metformin demonstrates therapeutic efficacy in PCOS, its potential neuroendocrine mechanisms remain incompletely understood. This study aimed to investigate the involvement of hypothalamic signalling in metformin-responsive neuroendocrine regulation in PCOS.
Letrozole-induced PCOS rat models were treated with metformin to assess reproductive and metabolic outcomes. Data-independent acquisition (DIA) proteomics of hypothalamic tissue was performed to identify dysregulated pathways, followed by network analysis to explore candidate regulatory nodes. Mechanistic investigations were conducted in glucosamine-induced insulin-resistant GT1-7 GnRH neurons using pharmacological modulation and siRNA knockdown. In vivo functional relevance was examined using AAV-mediated Epac2 knockdown in the mouse arcuate nucleus.
Metformin improved metabolic and reproductive abnormalities in PCOS rats, including insulin resistance, GnRH/LH hypersecretion, estrous cyclicity disruption, and ovarian morphological alterations. Hypothalamic proteomic and network analyses suggested that metformin-responsive changes were associated with insulin and cAMP-related signalling pathways. In GT1-7 neurons, metformin increased Epac2 expression, restored AKT signalling, and reduced GnRH overproduction under insulin-resistant conditions. Hypothalamic Epac2 knockdown reduced AKT signalling and was associated with systemic insulin resistance, increased GnRH/LH secretion, and preliminary supportive ovarian morphological observations, consistent with a functional contribution of Epac2 to reproductive-metabolic regulation.
These findings support the involvement of hypothalamic Epac2/AKT/GnRH signalling in metformin-responsive neuroendocrine regulation in PCOS. Further studies are required to determine the relative contributions of central and peripheral mechanisms.

PMID:
42760541
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

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