Neurokinin B and Kisspeptin: Sexual Partners or Single Agents?

Abstract

Despite recent progress in our understanding of reproductive physiology, the precise mechanisms controlling puberty still remainelusive.Patientswith idiopathichypogonadotrophic hypogonadism (IHH) have pubertal failure as a result of insufficient gonadotrophin release, which is usually caused by a defect in GnRH synthesis, secretion, or activity. Inactivatingmutations inanumberofgeneshavebeen found to cause IHH, but the underlying genetic defect in many patients with IHH remains unidentified (1). Two novel neuropeptides, kisspeptin and neurokinin B, have emerged recently as “new kids on the block” and caused an explosion of research in reproductive endocrinology. Their similar anatomical and functional characteristics have prompted speculation whether a “sexual partnership” exists between them to control reproductive maturation. Kisspeptin emerged as an important new player in reproductivephysiology in2003whendeRouxetal. (2)andSeminara et al. (3) discovered that humans with inactivating mutations of the kisspeptin receptor had a phenotype of hypogonadotrophic hypogonadism. Furthermore, animals lacking kisspeptin (4, 5) or its receptor (3) have a similar phenotype. Over the past 7 yr, more than 400 subsequent publications have elucidated the effects of kisspeptin (comprehensively reviewed in Ref. 6). Notably, administration of kisspeptin potently stimulates reproductive hormone release in all species studied (6), including humans (7–9). The stimulatory action of kisspeptin on gonadotrophin release is abolished by pharmacological antagonism of GnRH, thus suggesting a hypothalamic site of action (6). Kisspeptin is expressed in specific hypothalamic nuclei, such as the anteroventral periventricular and arcuate nuclei, which each have important roles in its physiological action (6). Recently, it has emerged that neurokinin B is also vital for normal pubertal function. Topaloglu et al. (10) discovered that inactivating mutations of neurokinin B or its receptor caused hypogonadotrophic hypogonadism in humans. Recent data show that neurokinin B and kisspeptin are colocalized in the arcuate nucleus in sheep (11), mice (12), rats (13), and humans (14). However, in contrast to the robust stimulatory action of kisspeptin on gonadotrophin release demonstrated in numerous species, the effects of administering neurokinin B to animals are less clear. Neurokinin B administration has been shown stimulate LH release in sheep (15) but have no effect (16, 17) or inhibit (12, 18) LH release in rodents. It is also interesting that mice with targeted deletion of neurokinin B receptor are fertile (19), in contrast to kisspeptin or kisspeptin receptor knockout mice (3–5). It is therefore timely that, in this issue of Endocrinology, Ramaswamy et al. (20) demonstrate in elegant primate studies that a single i.v. injection of neurokinin B robustly stimulatesLHrelease.Thiswork follows fromstudiesofkisspeptin administration to primates, performed by the same researchers. As observed previously with kisspeptin administration (21), the effect of neurokinin B on LH release was abolished by GnRH receptor antagonism (20), thus suggesting a hypothalamic site of action. Ramaswamy et al. also show that neurokinin B and kisspeptin are colocalized in the arcuate nucleus of primates (20), which is consistent with the findings inrodents, sheep,andhumans(11–14).However, in contrast to previous results with kisspeptin (22), repeated hourly injection of a neurokinin B agonist did not result in sustainedLHrelease(20). Interestingly,repeatedadministrationof the neurokinin B did not affect the ability of kisspeptin to stimulate GnRH release (20). The precise animal model chosen by Ramaswamy et al. in the current study may be important; ago-