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dc.contributor.authorAbbara, A
dc.contributor.authorEng, PC
dc.contributor.authorPhylactou, M
dc.contributor.authorClarke, SA
dc.contributor.authorRichardson, R
dc.contributor.authorSykes, CM
dc.contributor.authorPhumsatitpong, C
dc.contributor.authorMills, E
dc.contributor.authorModi, M
dc.contributor.authorIzzi-Engbeaya, C
dc.contributor.authorPapadopoulou, D
dc.contributor.authorPurugganan, K
dc.contributor.authorJayasena, CN
dc.contributor.authorWebber, L
dc.contributor.authorSalim, R
dc.contributor.authorOwen, B
dc.contributor.authorBech, P
dc.contributor.authorComninos, AN
dc.contributor.authorMcArdle, CA
dc.contributor.authorVoliotis, M
dc.contributor.authorTsaneva-Atanasova, K
dc.contributor.authorMoenter, S
dc.contributor.authorHanyaloglu, A
dc.contributor.authorDhillo, WS
dc.date.accessioned2020-11-17T15:36:31Z
dc.date.issued2020-11-16
dc.description.abstractBACKGROUND Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODS We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTS In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSION Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATION International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDING National Institute for Health Research and NIH.en_GB
dc.description.sponsorshipNational Institute for Health Research (NIHR)en_GB
dc.description.sponsorshipMedical Research Council (MRC)en_GB
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (BBSRC)en_GB
dc.description.sponsorshipEngineering and Physical Sciences Research Council (EPSRC)en_GB
dc.description.sponsorshipNIH/Eunice Kennedy Shriver National Institute of Child Health and Human Developmenten_GB
dc.identifier.citationPublished online 16 November 2020en_GB
dc.identifier.doi10.1172/JCI139681
dc.identifier.grantnumberEP/N014391/1en_GB
dc.identifier.grantnumberR37 HD34860en_GB
dc.identifier.urihttp://hdl.handle.net/10871/123652
dc.language.isoenen_GB
dc.publisherAmerican Society for Clinical Investigationen_GB
dc.rights.embargoreasonUnder indefinite embargo due to publisher policy  en_GB
dc.rights© 2020 American Society for Clinical Investigationen_GB
dc.titleKisspeptin receptor agonist has therapeutic potential for female reproductive disordersen_GB
dc.typeArticleen_GB
dc.date.available2020-11-17T15:36:31Z
dc.identifier.issn0021-9738
dc.descriptionThis is the final version. Available from the American Society for Clinical Investigation via the DOI in this recorden_GB
dc.identifier.journalJournal of Clinical Investigationen_GB
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_GB
dcterms.dateAccepted2020-09-03
rioxxterms.versionVoRen_GB
rioxxterms.licenseref.startdate2020-11-16
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2020-11-17T15:32:43Z
refterms.versionFCDVoR
refterms.panelBen_GB
refterms.accessExceptionpublicationDisallowsOA


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