biostudies-literatureMcCarthy EAEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD NIH HHSNational Cancer Institute Cancer CenterNHLBI NIH HHSNCI NIH HHSNational Institutes of HealthNIH HHSe328-e347https://www.ebi.ac.uk/biostudies/studies/S-EPMC8684497biostudies-literatureUnknown107(1)<h4>Context</h4>Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons).<h4>Objective</h4>We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood-brain barrier) and impedes their downstream effects.<h4>Design</h4>Case/control.<h4>Setting</h4>Academic medical center.<h4>Participants</h4>Mice.<h4>Interventions</h4>Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature.<h4>Main outcome measures</h4>LH pulse parameters and body temperature.<h4>Results</h4>First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals' elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity.<h4>Conclusion</h4>The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.The Journal of clinical endocrinology and metabolismInhibiting Kiss1 Neurons With Kappa Opioid Receptor Agonists to Treat Polycystic Ovary Syndrome and Vasomotor Symptoms.PMC8684497R24 HD102061R01 HD099084R21 HD095383F32HD097963P30 CA006516F32 HD097963T32HL007609-31# NIH 5 P30 CA06516R01 HD090151T32 HL007609R24HD102061McCarthy EAMaguire CNavarro VMRiviere PJMSteiner RACheung ESchteingart CDLeon STalbi RReed SDDischino DfalseInhibiting Kiss1 Neurons With Kappa Opioid Receptor Agonists to Treat Polycystic Ovary Syndrome and Vasomotor Symptoms.<h4>Context</h4>Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons).<h4>Objective</h4>We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood-brain barrier) and impedes their downstream effects.<h4>Design</h4>Case/control.<h4>Setting</h4>Academic medical center.<h4>Participants</h4>Mice.<h4>Interventions</h4>Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature.<h4>Main outcome measures</h4>LH pulse parameters and body temperature.<h4>Results</h4>First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals' elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity.<h4>Conclusion</h4>The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.2022-01-01T00:00:00Z2022 Jan2025-04-04T07:51:06.334Z2025-04-04T07:51:06.334ZS-EPMC86844973438731910.1210/clinem/dgab602