Invited review: Translating kisspeptin and neurokinin B biology into new therapies for reproductive health

Abstract

The reproductive neuropeptide kisspeptin has emerged as the master regulator of mammalian reproduction due to its key roles in the initiation of puberty and the control of fertility. Alongside the tachykinin neurokinin B and the endogenous opioid dynorphin, these peptides are central to the hormonal control of reproduction. Building on the expanding body of experimental animal models, interest has flourished with human studies revealing that kisspeptin administration stimulates physiological reproductive hormone secretion in both healthy men and women, as well as patients with common reproductive disorders. In addition, emerging therapeutic roles based on neurokinin B for the management of menopausal flushing, endometriosis and uterine fibroids are increasingly recognised. In this review, we focus on kisspeptin and neurokinin B and their potential application as novel clinical strategies for the management of reproductive disorders.

Neurokinin 1/3 receptor antagonists for menopausal women: A current systematic review and insights into the investigational non-hormonal therapy

“…[62,80] The data provides insights into the potential hypothalamic effects of peripheral administration of NK3R antagonists to counteract heat dissipation responses seen among women experiencing hot flushes. [81–85] Clinically, NT-814 can reduce nighttime awakenings among women by 81% as reported by Trower et al in their 2020 trial. [44] There are variabilities in the first appearance of symptomatic benefit, where Trower reported benefits after the first dose and persistence for up to 2 weeks.…”

Dissecting the KNDy hypothesis: KNDy neuron-derived kisspeptins are dispensable for puberty but essential for preserved female fertility and gonadotropin pulsatility

“…Notwithstanding, our data provide novel physiological evidence for the differential contribution of KNDy-vs. non KNDykisspeptins in the control of reproduction, and conclusively document that, while dispensable/compensable for pubertal maturation, KNDyborn kisspeptins are required for maintenance of gonadotropin pulsatility and fertility, specifically in the female. In-depth characterization of such functional diversity has become specially relevant, considering the promising potential of kisspeptin-and NKB-based therapies for management of some reproductive (and eventually metabolic) disorders in humans [68][69][70].…”

Polycystic ovary syndrome: pathophysiology and therapeutic opportunities

“…102 A bolus dose of KP54 induces oocyte maturation in patients with polycystic ovary syndrome without causing clinically significant ovarian hyperstimulation syndrome. 100 101 Administration of a subcutaneous bolus injection of native kisspeptin is safe and well tolerated 103 and also results in higher expression of gonadotrophin receptors (follicle stimulating hormone receptor and luteinising hormone receptor) and steroidogenic enzymes (including aromatase CYP19A1, steroidogenic acute regulatory protein, and 3β-hydroxysteroid dehydrogenase type II) in ovarian granulosa cells, potentially promoting an ovarian environment favouring progesterone synthesis and ovarian implantation. 104 Use of KP54 as an ovulation induction agent, however, might be limited by tachyphylaxis.…”