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

Abstract

Reproductive hormones impact on all stages of life from gamete production, fertilisation, fetal development and parturition, neonatal development and puberty through to adulthood and senescence.The reproductive hormone cascade has therefore been the target for the development of numerous drugs which modulate its activity at many levels. As the central regulator of the cascade, gonadotropinreleasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent deseases such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilisation (IVF) protocols. Recently-discovered neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), have also been identified as therapeutic targets and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade, GnRH, KP and NKB.

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

“…Furthermore, the precise effect of NK3R antagonists to lower plasma LH without affecting FSH in intact females suggests that NK3R antagonists may be uniquely suited for the treatment of hyperandrogenism, a key aspect of polycystic ovary syndrome (PCOS) (1). PCOS patients express a persistently high LH pulse frequency (indicative of a high GnRH pulse frequency) and consequently a high plasma LH to FSH ratio (49,50).…”

“…odulation of the hypothalamic-pituitary-gonadal (HPG) axis is a clinically validated therapeutic approach for the treatment of disorders of the reproductive system, as proven by the established medical use of GnRH modulators (1). However, the approved duration of use of GnRH modulators is restricted due to their castrating effects and consequent menopausal-like adverse events, including loss of bone mineral density and incidences of hot flashes (2).…”

Control of puberty onset and fertility by gonadotropin-releasing hormone neurons

“…Indeed, having been first identified in the clinic, kisspeptin has been the subject of intense investigation by the biomedical community and has now progressed back to the clinic. Kisspeptin agonists and antagonists are undergoing clinical trials and being considered as treatments for multiple reproductive disorders, including hypothalamic amenorrhoea and PCOS, as well as for contraception and ovulation induction as part of in vitro fertilization regimens 90,223,224 .…”

The significance of Ciona intestinalis as a stem organism in integrative studies of functional evolution of the chordate endocrine, neuroendocrine, and nervous systems

“…Tachykinins (TKs) are 9-14-amino acid multi-functional vertebrate brain/gut peptides involved in a wide variety of biological functions (Millar and Newton, 2013;Steinhoff et al, 2014). The mammalian TK family consists of four major peptides, substance P, neurokinin A, neurokinin B, and homeokinin-1/endokinins, and three subtypes of TK receptors, NK1, NK2, and NK3, have been identified in vertebrates (Steinhoff et al, 2014).…”