Critical Roles of Kisspeptins in Female Puberty and Preovulatory Gonadotropin Surges as Revealed by a Novel Antagonist

Abstract

Kisspeptins (Kp) have recently emerged as master regulators of the reproductive axis and among the most potent elicitors of GnRH-gonadotropin secretion. Despite their paramount importance in reproductive physiology and their potential therapeutic implications, development of Kp antagonists has remained elusive, and only recently has the first compound with the ability to block Kp actions in vitro and in vivo, namely p234, been reported. However, previous in vivo studies all used acute central injections, whereas characterization of the effects of the antagonist after continuous or systemic administration, which poses pharmacological challenges, is still pending. We report herein a comprehensive series of analyses on the impact of continuous intracerebroventricular infusion of p234 on puberty onset and the preovulatory surge of gonadotropins in the female rat. In addition, the effects of systemic (ip) administration of a tagged p234-penetratin, with a predicted higher permeability at the blood-brain barrier, on Kp-10 induced gonadotropin secretion were evaluated. Central infusion of p234 to pubertal females delayed vaginal opening and decreased uterine and ovarian weights at the expected time of puberty, without affecting body weight. Likewise, chronic intracerebroventricular administration of p234 for 4 d prevented the preovulatory surges of LH and FSH. In addition, systemic (ip) administration of p234-penetratin significantly attenuated acute LH and FSH responses to Kp-10, either after intracerebroventricular or ip injection of Kp. Our data document the validity of p234 for antagonizing Kp actions in vivo and provide direct experimental evidence for the important role of Kp signaling in the key events of female reproduction, such as puberty onset and the preovulatory surge of gonadotropins.

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

“…Peptide 234 also delayed puberty in female rats 116 which together with the effects on GnRH pulse frequency in pubertal and prepubertal monkeys confirms a role for KP in puberty which had been suggested by the failure to progress through puberty in patients with GPR 54 and KP mutations 6,7 .…”

“…The positive feedback of estrogen in the LH ovulatory surge in female rats was also shown directly to be KP dependent as peptide 234 inhibited this surge 116 , as was also demonstrated with KP antiserum 115 .…”

“…Similarly, peptide 271, which has a penetratin sequence attached to convey brain penetration, was able to inhibit the LH stimulation by i.c.v. KP when it was administered systemically to rats 116 …”

“…In these treatments steroid hormones are lowered to castrate levels resulting in side effects such as hot flushes, reduced lean body mass, loss of libido and bone loss. The demonstration that KP antagonists reduce LH pulsatility 109,120 and inhibit the ovulatory LH surge 116 , but do not appear to affect basal LH, suggests that they may find clinical utility in conditions where maximal suppression of sex steroids is contra-indicated. Examples are benign prostatic hyperplasia, endometriosis and uterine fibroids where lowering of gonadal steroids could improve the conditions without the side effects of reducing steroid hormones to castrate levels.…”

Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons

“…Ablation of the GPR54 (12, 13) or the Kiss1 (13, 14) gene renders mice of either sex hypogonadotropic and infertile. Kisspeptin is a powerful GnRH secretagogue (15,16), and kisspeptin administration advances puberty onset (17,18), whereas GPR54 antagonists delay puberty onset (19). These data provide compelling support for the idea that activation of kisspeptin neurons precipitates the pubertal stimulation of GnRH neurosecretion.…”