Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis

Abstract

The hypothalamic peptide kisspeptin (metastin), the endogenous ligand of the G protein-coupled receptor KISS1R, plays a critical role in controlling GnRH release from hypothalamic GnRH neurons and thereby regulates hypothalamic-pituitary-gonadal functions. Although the therapeutic potential of kisspeptin is attractive, its susceptibility to proteolytic degradation limits its utility. To overcome this, KISS1R agonists or antagonists as peptide analogs or small molecules have been investigated. Kisspeptin analogs have been most extensively studied by reducing the length of the peptide from the original 54 amino acids to 10 amino acids or less and by substituting key amino acid residues. Also, 2 investigational kisspeptin agonist analogs have been evaluated in clinical studies in men; in agreement with animal studies, abrupt elevations in gonadotropin and testosterone levels were observed as an acute effect, followed by rapid reductions in these hormones as a chronic effect. Some studies of small-molecule KISS1R antagonists have also been published. In this review, we present a brief overview on kisspeptin/KISS1R physiology in reproductive functions and summarize the available knowledge of both agonists and antagonists. We also focus on the kisspeptin agonist analogs by summarizing key pharmacological findings from both clinical and preclinical studies, and discuss their potential therapeutic utility.

The Role of Neurokinin B Signalling in Reproductive Neuroendocrinology

“…The mechanisms whereby kisspeptin influences the HPG axis seem relatively straightforward: GnRH neurones express kisspeptin receptors (GPR54) [17,22], are exquisitely sensitive to kisspeptin originating from neurones of the ARC [23] and the anteroventral periventricular nucleus [17,24,25], as well as exogenous kisspeptin [26,27,28,29,30], and are consistently driven to secrete GnRH in either a phasic or continuous fashion apparently dependent on the frequency of kisspeptinergic stimulation [31,32]. However, the kisspeptin-dependent nature of the HPG axis is challenged by a report that mice lacking kisspeptin neurones exhibited normal reproductive development, whereas kisspeptin neurone ablation in adulthood rendered mice infertile, suggesting the development of compensatory mechanisms [33].…”

Kisspeptin system in female reproduction: A next-generation target in the manipulation of sex hormones

“…4 Therefore, it is well known that the use of GnRH analogues to control HPG functions via stimulatory or inhibitory mechanisms of action 9,10 might also be reproducible by kisspeptin analogues, suggesting that Kiss1r agonists and antagonists might provide another option to control HPG functions. 11 Additionally, the kisspeptin/neurokinin B/dynorphin system in the arcuate nucleus has provided important clues to the neural mechanisms of GnRH pulse-generation systems. 12 A recent review by Matsui and Asami 11 summarized the available knowledge of both agonist and antagonist.…”

The Effects of Chronic Subcutaneous Administration of an Investigational Kisspeptin Analog, TAK-683, on Gonadotropin-Releasing Hormone Pulse Generator Activity in Goats

“…Recently, a series of investigational kisspeptin analogs, including TAK-448, TAK-683 and KiSS1-305 [28,29,30,31,32], have been developed. These analogs possess agonistic activity at Kiss1r and are protease resistant.…”