Neurokinin 3 receptor agonist senktide stimulates GnRH release in isolated hypogonadotropic hypogonadism mice

Isolated hypogonadotropic hypogonadism (IHH) is caused by defective gonadotropin-releasing hormone (GnRH) secretion or action, resulting in absent or incomplete pubertal development and infertility. However, the pathogenesis mechanism of IHH is not fully understood. This study utilized PROK2/PROKR2 knockdown mice and GT1-7 cells to investigate the effects and potential mechanismsof the NK3R agonist senktide on GnRH deficiency and related syndromes. In this investigation, PROK2/PROKR2 knockdown resulted in a deficiency of GnRH neurons, reduced levels of LSH, FSH, and E2, and the inhibition of the MAPK/ERK and PI3K/AKT pathways in mice. However, this effect was reversed by senktide. Furthermore, the inhibition of MAPK/ERK or PI3K/AKT signaling pathways counteracted the remission of the GnRH insufficiency and associated syndrome by senktide in mice with PROK2/PROKR2 knockdown. In summary, NK3R agonist senktide alleviated the GnRH insufficiency and related syndromes caused by PROK2/PROKR2 knockdown via the MAPK/ERK pathway and the PI3K/AKT pathway.