New Developments in Kisspeptin, Neurokinin B and Dynorphin A Regulation of Gonadotropin-Releasing Hormone Pulsatile Secretion

Abstract

corporating the mechanisms by which KNDy neuropeptides modulate the reproductive axis (see [1] and the cover of this issue). The second article, by Goodman et al. [2] , reviews the roles of kisspeptin, NKB and Dyn in GnRH pulse generation as gathered from a comprehensive series of excellent studies in sheep from their laboratory as well as from equally detailed and incisive experiments in goats [for a review, see 3 ], which led to the promulgation of a model proposing a role for the KNDy neuron NKB in stimulating kisspeptin to initiate a GnRH pulse. NKB also stimulated Dyn release from KNDy neurons to inhibit their activity and terminate the GnRH pulse. Further studies using a range of agonists and antagonists of kisspeptin, NKB and Dyn led to the development of a modified model which invokes an action for kisspeptin in activating unidentified KNDy neurons which reinforce the stimulatory actions of NKB on KNDy neurons [see 2 , fig. 11]. The third article reviews the sexually dimorphic distribution of kisspeptin, NKB and Dyn in the male and female human brain and changes that occur with aging. Hrabovszky [4] points out that in various mammalian species, the majority of kisspeptin-synthesizing neurons are concentrated in two distinct cell populations in the The KNDy neuropeptides kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn), play a pivotal role in regulating pulsatile gonadotropin-releasing hormone (GnRH) secretion. There are, however, relatively few studies attempting to integrate the interactions between KNDy-signalling systems. This special issue assembles three articles on this topic from studies on laboratory rats, sheep and humans. These reports go some way to clarifying kisspeptin, NKB and Dyn interactions in regulating pulsatile GnRH secretion and highlight species differences in the interplay and roles of these upstream regulators. In their article, Grachev et al. [1] point out that although the stimulatory effect of kisspeptin and the inhibitory effect of Dyn on the GnRH pulse generator are widely accepted, the effects of NKB in rodents are variable and sometimes controversial. Literature describing increased secretion of luteinizing hormone (LH) in response to NKB receptor agonism predominates and is in line with human physiology as well as with the pathophysiology of pubertal failure associated with disruption of NKB signalling. However, under hypoestrogenic conditions NKB exhibits a robust suppression of LH, which may shed light on the mechanisms of reproductive inhibition under pathological conditions such as anorexia nervosa. The article provides a revised working model inPublished online: April 1, 2014