Evidence from the Agonadal Juvenile Male Rhesus Monkey (Macaca mulatta) for the View that the Action of Neurokinin B to Trigger Gonadotropin-Releasing Hormone Release Is Upstream from the Kisspeptin Receptor

Human genetics have revealed that kisspeptin signaling and neurokinin B (NKB) signaling are both required for robust pulsatile gonadotropin-releasing hormone (GnRH) release, and therefore for puberty and maintenance of adult gonadal function. How these two peptides interact to affect GnRH pulse generation remains a mystery. To address the hierarchy of the NKB and kisspeptin signaling pathways that are essential for GnRH release, two experiments were conducted using agonadal, juvenile male monkeys. Pituitary responsiveness to GnRH was first heightened by a pulsatile GnRH infusion to use the in situ pituitary as a bioassay for GnRH release. In the first experiment (n = 3), the kisspeptin receptor (KISS1R) was desensitized by a continuous 99-hour i.v. infusion of kisspeptin-10 (100  g/h). During the last 4 h of continuous kisspeptin-10 infusion, desensitization of KISS1R was confirmed by failure of an i.v. bolus of kisspeptin-10 to elicit GnRH release. Desensitization of KISS1R was associated with a markedly blunted GnRH response to senktide. The response to senktide was progressively restored during the Received: February 11, 2011 Accepted after revision: May 5, 2011 Published online: August 10, 2011 Tony M. Plant Department of Obstetrics, Gynecology and Reproductive Sciences B331 Magee-Womens Research Institute, University of Pittsburgh School of Medicine Pittsburgh, PA 15213 (USA) Tel. +1 412 641 7663, E-Mail planttm @ mwri.magee.edu © 2011 S. Karger AG, Basel Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /7 /2 01 7 12 :5 2: 37 P M