Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms

Abstract

Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Extensive experimental studies in various species have demonstrated that kisspeptin-producing neurons are major afferents to GnRH neurons and are essential for different aspects of GnRH function, ranging from the tonic feedback control of GnRH and/or gonadotropin secretion to generation of the pre-ovulatory surge responsible for ovulation. 43 Interestingly, although kisspeptins do not seem to be mandatory for proper GnRH neuron migration, compelling experimental work has documented that populations of kisspeptin neurons undergo a dynamic process of prenatal and postnatal maturation that enables them to establish connections with GnRH neurons early in development 44 (under the control of steroid hormones [45][46][47] ). Similarly, identification of mutations in TAC3 (encoding tachykinin-3, which is cleaved to form neurokinin-B) and TACR3 (encoding tachykinin receptor 3; also known as neuromedin-K receptor [NKR]) [48][49][50] in patients with CHH highlights the important role of members of the tachykinin family in the control of GnRH neurons.…”

“…58 Exactly how the effects of leptin are transmitted to GnRH neurons is unknown, as this neuro nal population does not express the leptin receptor. 59 Experimental data suggest that kisspeptin neurons are sensitive to changes in leptin concentrations and metabolic conditions, 43 yet they apparently do not express functional leptin receptor, which indicates the mode of action is indirect. 60 Primary leptin targets for conduction of its reproductive effects probably include nitric oxideproducing neurons in the pre-optic hypothalamus 61 and neuronal circuits in the ventral premammillary nucleus, 60 which might transmit metabolic information to GnRH neurons through kiss peptin dependent and/or independent pathways.…”

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…In fact, identification of Kp is now considered as one of the major breakthroughs in reproductive biology since the isolation of GnRH back in the early 1970s (7,11). As extensively revewed elsewhere, kisspeptins, which include Kp-54 and Kp-10, are a family of structurally related peptides, encoded by the Kiss1 gene, that act via the G protein-coupled receptor Gpr54 (also termed Kiss1R) (7,8,10). The first evidence about the reproductive roles of kisspeptins and Gpr54 dates back to late 2003, when inactivating mutations of the receptor were described in patients with hypogonadotropic hypogonadism (HH), a pathological condition of impuberism and infertility of central origin (13,14).…”

“…Without any doubt, a major development in the field came with the identification of kisspeptins (Kp) as essential gatekeepers of puberty, a role that has drawn considerable attention in recent years (7,8,9,10), and will be discussed herein, especially in light of recent developments that seem to challenge the dogma of an indispensable role of kisspeptins in puberty. In addition, attention will be paid in this review to summarize some illustrative examples of the identification of additional central transmitters and regulatory mechanisms (putatively) involved in the control of puberty and its modulation by the metabolic status.…”

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

“…Metabolic effects on reproduction in humans which may involve KP dysregulation, include hypothalamic amenorrhea, (anorexia nervosa being an extreme example), and PCOS, which is characterized by increased LH pulse frequency and is often associated with obesity 68 . For detailed reference to the diverse physiological and pathophysiological regulation of KP the reader is referred to comprehensive reviews 76,105,106 .…”