Dissecting the Roles of Gonadotropin-Inhibitory Hormone in Mammals: Studies Using Pharmacological Tools and Genetically Modified Mouse Models.

Silvia Leon,Manuel Tena-Sempere

doi:10.3389/fendo.2015.00189

Abstract

Reproduction is essential for perpetuation of the species and, hence, is controlled by a sophisticated network of regulatory factors of central and peripheral origin that integrate at the hypothalamic–pituitary–gonadal (HPG) axis. Among the central regulators of reproduction, kisspeptins, as major stimulatory drivers of gonadotropin-releasing hormone (GnRH) neurosecretion, have drawn considerable interest in the last decade. However, the dynamic, if not cyclic (in the female), nature of reproductive function and the potency of kisspeptins and other stimulatory signals of the HPG axis make tenable the existence of counterbalance inhibitory mechanisms, which may keep stimulation at check and would allow adaptation of reproductive maturation and function to different endogenous and environmental conditions. In this context, discovery of the gonadotropin-inhibitory hormone (GnIH) in birds, and its mammalian homolog, RFRP, opened up the exciting possibility that this inhibitory signal might operate centrally to suppress, directly or indirectly, GnRH/gonadotropin secretion, thus reciprocally cooperating with other stimulatory inputs in the dynamic regulation of the reproductive hypothalamic–pituitary unit. After more than 15 years of active research, the role of GnIH/RFRP in the control of the HPG axis has been documented in different species. Yet, important aspects of the physiology of this system, especially regarding its relative importance and actual roles in the control of key facets of reproductive function, remain controversial. In the present work, we aim to provide a critical review of recent developments in this area, with special attention to studies in rodent models, using pharmacological tools and functional genomics. In doing so, we intend to endow the reader with an updated view of what is known (and what is not known) about the physiological role of GnIH/RFRP signaling in the control of mammalian reproduction.

Highlights

Reproductive maturation and function are indispensable for perpetuation of the species and, are controlled by a sophisticated network of regulatory signals, which impact at the so-called hypothalamic–pituitary–gonadal (HPG) axis (1)
Less progress has been made in the identification of inhibitory signals, which may counterbalance the effects of kisspeptins and other potent elicitors of gonadotropin-releasing hormone (GnRH)/ gonadotropin secretion, thereby playing an essential role in the precise and dynamic control of the HPG axis
This study suggested that the inhibitory effect of RFRP-3 in the testis might be mediated through local production of GnRH

Summary

INTRODUCTION

Reproductive maturation (including puberty) and function are indispensable for perpetuation of the species and, are controlled by a sophisticated network of regulatory signals, which impact at the so-called hypothalamic–pituitary–gonadal (HPG) axis (1). Less progress has been made in the identification of inhibitory signals, which may counterbalance the effects of kisspeptins and other potent elicitors of GnRH/ gonadotropin secretion, thereby playing an essential role in the precise and dynamic control of the HPG axis In this context, identification in 2000 of a novel peptide of the RF-amide superfamily, named gonadotropin-inhibitory hormone (GnIH) on the basis of its action as GonadotropinInhibitory Hormone, raised considerable interest (3). The first isolation of a RF-amide peptide occurred in an invertebrate species (11), and led to the discovery of a large series of peptides with a similar carboxyl-terminal RF-amide motif in different invertebrate and vertebrate species (9, 10) In this context, in 2000, Tsutsui and colleagues discovered in birds a 12 amino acid hypothalamic neuropeptide, with a Ser-Ile-Lys-Pro-Ser-AlaTyrLeu-Pro-Leu-Arg-Phe-NH2 sequence, with the distinct capacity to inhibit gonadotropin release by cultured quail pituitaries (3). NPFF1R mRNA is expressed in central nervous system, in the hypothalamus, spinal cord, amygdala, hippocampus, and substantia nigra, and in peripheral

VPHSAANLPLRFa NMEAGTRSHFPSLPQRFa

Peripheral administration of GnIH decreased the

LH responses in ORX mice getting a fixed dose of

Findings

CONCLUDING REMARKS