GnRH and GnRHR exhibit critical extrapituitary roles in female reproductive health and cancers

Gonadotropin-releasing hormone (GnRH) is a crucial peptide hormone, forming the central axis of the hypothalamic-pituitary-gonadal (HPG) axis and orchestrating reproductive functions. Dysregulation of GnRH is implicated in numerous steroid hormone-dependent diseases, making its receptor, GnRHR, a well-established therapeutic target. While its central role is clear, a growing body of evidence suggests GnRH and GnRHR are also expressed in various peripheral reproductive and non-reproductive tissues, where their local autocrine and paracrine actions are less understood, representing a significant gap in therapeutic strategy.

This comprehensive review synthesizes current knowledge on GnRH and GnRHR signaling, specifically focusing on their extrapituitary autocrine and paracrine functions in female reproductive health. It examines molecular and cellular mechanisms, including G-protein coupling profiles and alternative cell-specific signaling pathways distinct from pituitary actions. The review highlights recent data concerning local GnRH systems in tissues like the endometrium, ovary, placenta, and breast, and their implications for hormone-dependent gynecological conditions and cancers. Finally, it explores future translational avenues for therapeutic innovation.

The review elucidates that extrapituitary GnRH and GnRHR systems operate via distinct molecular and cellular mechanisms compared to their pituitary counterparts, often involving alternative G-protein coupling profiles and cell-specific signaling pathways. These local systems exert significant (patho)physiological functions across various female reproductive tissues. In the endometrium, GnRH influences proliferation and differentiation, impacting conditions like endometriosis. In the ovary, it modulates follicular development and steroidogenesis, while in the placenta, it plays roles in implantation and pregnancy maintenance. Crucially, peripheral GnRH systems are implicated in the progression of hormone-dependent gynecological cancers, including ovarian and breast cancers, where they can influence tumor growth and metastasis. > This comprehensive synthesis underscores that peripheral GnRH/GnRHR signaling is not merely an 'off-target' effect but a distinct, functionally relevant system with unique therapeutic potential.