Abstract
The kisspeptins are a family of neuropeptides which act as upstream stimulators of gonadotrophin releasing hormone (GnRH) neurons. Kisspeptin signalling is prerequisite to establishing the normal human reproductive phenotype; loss of function mutations in the KISS1 or KISS1R gene produces normosmic hypogonadotrophic hypogonadism in humans and mice, whilst increased activation of KISS1R causes precocious puberty. Administration of exogenous kisspeptin to human subjects stimulates an acute gonadotrophin rise. Serum kisspeptin levels also markedly increase during pregnancy. The identification of kisspeptin has been one of the biggest discoveries in the field of reproductive endocrinology, since the isolation and sequencing of GnRH in 1977, and has generated a novel research avenue which has received much attention over the past decade. This research has delineated many properties of the KISS1-KISS1R system, but there is still further work to do. Understanding kisspeptin’s role throughout our reproductive lifetime should help us better understand—and therefore treat—disorders of reproductive function. Promisingly, the current data supports the potential to develop kisspeptin based therapies. As an outlook article this paper focusses predominantly on our groups recent investigations into the effects of kisspeptin administration to humans and the potential therapeutic role of kisspeptin.
Highlights
A seminal report from de Roux et al [24] utilized genetic microarray and linkage analysis techniques to identify a large deletion in KISS1 receptor (KISS1R) on chromosome 19p13, leading to production of truncated and nonfunctional G-protein coupled transmembrane kisspeptin receptors in five individuals affected by idiopathic hypogonadotrophic hypogonadism (IHH) in a consanguineous family in France
This was continued for a total of 8 weeks. During this period a pattern of initial, partial desensitization of the gonadotrophin response was observed, followed by a plateau response, with HA patients remaining partially responsive to KP-54 during this dosing regimen from day 14 until the end of the 8-week study period. This data suggests that kisspeptin may be useful in the treatment of HA in humans; it must be noted that in both studies investigating the effects of KP-54 in women with hypothalamic amenorrhoea, even in light of significantly raised levels of gonadotrophins using the twice weekly protocol, changes were not reflected at the ovarian level; that is, no woman demonstrated any significant follicular growth on serial ultrasound scanning
Kisspeptin has been shown in continuous intravenous infusion to restore pulsatile LH secretion in individuals with genetic dysfunction of the neurokinin B (NKB) signalling pathway, as previously discussed [15]. These findings suggest that it is not necessary for kisspeptin to be released in a pulsatile fashion and that gonadotrophin releasing hormone (GnRH) neurons have autonomous pulse-generating activity which is induced under conditions of continuous exposure to kisspeptin
Summary
Kisspeptin is produced by neurones in the infundibular (arcuate) nucleus of the hypothalamus These neurons have been shown to have direct afferent connections onto GnRH neurons of the mediobasal hypothalamus in humans, and kisspeptin activity has been shown to induce upregulation of KISS1R within these GnRH neurons. The effects of both kisspeptin-10 (KP-10) and kisspeptin (KP-54) have been investigated in animal studies [4] and both have been administered to humans [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Disorders of reproduction which lead to reduced GnRH signalling result in hypogonadotrophic hypogonadism They include idiopathic hypogonadotrophic hypogonadism (IHH) and hypothalamic amenorrhoea (HA). These findings have identified kisspeptin as a possible new therapeutic agent for the treatment of reproductive disorders in the future
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
