Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders

Abstract

BACKGROUND. 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 KISS1Rmediated inositol monophosphate (IP 1) and Ca 2+ 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 IP 1 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.

A review of the pathophysiology of functional hypothalamic amenorrhoea in women subject to psychological stress, disordered eating, excessive exercise or a combination of these factors

“…Further studies are required, with the aim of developing treatment protocols enabling persistent gonadotrophin stimulation. 45 An alternative potential future therapeutic option to restore LH pulsatility in some women with FHA is recombinant leptin treatment, 22 but further studies are needed to assess whether this is only beneficial in the context of relative leptin deficiency. Subcutaneous recombinant human leptin was associated with increased mean LH level and pulse frequency after two weeks treatment, when studied in 8 women with FHA.…”

“…Endogenous kisspeptins are cleaved from a 145 amino acid precursor and encoded by the KISS1 gene. The biological actions of kisspeptin occur through its interaction with the G protein coupled kisspeptin receptor (KISS1R), resulting in stimulation of phospholipase C, and intracellular second messengers diacylglycerol and inositol 1,4,5‐trisphosphate (IP3), with intracellular stored calcium release 45 . Expression of KISS‐1 and KISS1R are developmentally and hormonally regulated.…”

“…Scientists have created synthetic nonapeptides for use therapeutically; KP‐112‐121 (KP‐10), Tak‐448 and Tak‐683 are kisspeptin analogues proven in vitro and in vivo to be potent agonists of KISS1R 64‐66 . MVT‐602 (previously known as TAK‐448) is a KISS1R agonist with a longer duration of action than KP‐54, via increased firing rate at GnRH neurons for a prolonged duration; median 115 minutes, relative to 55 minutes after KP‐54 administration 45 …”

“…These results are promising to enable less frequent therapeutic kisspeptin administration, with the potential to avoid tachyphylaxis. Further studies are required, with the aim of developing treatment protocols enabling persistent gonadotrophin stimulation 45 …”

Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as a GnRH Pulse Generator Controlling Mammalian Reproduction

“…Further, peripheral (not only central) administration of kisspeptin successfully induced GnRH/gonadotropin release in mammals including rodents (53,62,64,94), ruminants (46,95), and primates (63,96). This may be an advantage for therapeutic use of kisspeptin or its analogs in humans and domestic animals (97)(98)(99). Furthermore, GnRH neuronal cell bodies also seem to be an action site of ARC kisspeptin neurons because a retrograde tracing study revealed the projection of ARC kisspeptin neurons to the POA in mice (100) and confocal microscopy revealed contacts of kisspeptin fibers from the ARC population to GnRH neurons in ewes (101).…”