Understanding GnRH : local systems, signalling mechanisms, and implications in female health

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Tosh, Lily and Tinto, Kirsty and Cunningham, Margaret and Mulheran, Paul and Ferro, Valerie (2026) Understanding GnRH : local systems, signalling mechanisms, and implications in female health. Open Biology, 16 (7). 260006. ISSN 2046-2441 (https://doi.org/10.1098/rsob.260006)

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Abstract

Gonadotropin-releasing hormone (GnRH) is a peptide hormone forming a central component of the hypothalamic–pituitary–gonadal axis and is critical for controlling reproductive functions. Dysregulated GnRH is implicated in many steroid hormone-dependent diseases, and its receptor, GnRHR, is an attractive and clinically exploited therapeutic target. Mounting evidence suggests that beyond the hypothalamus and pituitary, GnRH and GnRHR are expressed in reproductive and non-reproductive, healthy and malignant peripheral tissues, where they act in an autocrine and paracrine manner. This review provides an updated overview of GnRH and GnRHR signalling with a focus on extrapituitary autocrine and paracrine roles in female reproductive health. We examine the molecular and cellular mechanisms of extrapituitary GnRHR signalling, including G-protein coupling profiles, and alternative cell-specific mechanisms that differ from pituitary signalling. We highlight recent data surrounding the (patho) physiological functions of local GnRH systems, including in the endometrium, ovary, placenta and breast, and their implications for hormone-dependent gynaecological conditions and cancers. Finally, we consider implications of peripheral GnRH/GnRHR systems for therapeutic innovation, including avenues for targeted or biased GnRH-based therapeutics, GnRH/GnRHR-mediated ‘off target’ effects of GnRH analogues, and explore future translational avenues for the treatment of both hormone-dependent and hormone-refractory diseases.

ORCID iDs

Tosh, Lily ORCID logoORCID: https://orcid.org/0009-0003-8414-5935, Tinto, Kirsty ORCID logoORCID: https://orcid.org/0009-0008-7954-0742, Cunningham, Margaret ORCID logoORCID: https://orcid.org/0000-0001-6454-8671, Mulheran, Paul ORCID logoORCID: https://orcid.org/0000-0002-9469-8010 and Ferro, Valerie ORCID logoORCID: https://orcid.org/0000-0003-1967-3603;
CORE (COnnecting REpositories)