Fisio Seminario GNRH

The hypothalamic GnRH pulsegenerator: multiple regulatory mechanisms

Lazar Z. Krsmanovic, Lian Hu, Po-Ki Leung, Hao Feng and Kevin J. Catt

Section on Hormonal Regulation, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA

Pulsatile secretion of gonadotropin-releasing hormone(GnRH) release is an intrinsic property of hypothalamic GnRH neurons. Pulse generation has been attributed to multiple specific mechanisms, including spontaneous electrical activity of GnRH neurons, calcium and cAMP signaling, a GnRH receptor autocrine regulatory component, a GnRH concentration-dependent switch in GnRH receptor (GnRH-R) coupling to specific G proteins, the expression of Gprotein-coupled receptors (GPCRs) and steroid receptors, and homologous and heterologous interactions between cell membrane receptors expressed in GnRH neurons. The coexistence of multiple regulatory mechanisms for pulsatile GnRH secretion provides a high degree of redundancy in maintaining this crucial component of the mammalian reproductive process. These studies provide insights into the basic cellular andmolecular mechanisms involved in GnRH neuronal function.

Hypothalamic control of reproductive function

The episodic mode of GnRH secretion from the hypothalamus, and pulsatile GnRH receptor (GnRH-R) activation in pituitary gonadotrophs, are essential for optimal gonadotropin synthesis and secretion and ultimately for normal reproductive function [1–5]. The genesis of GnRH pulse generation inthe hypothalamus is still incompletely understood. However, episodic neuropeptide secretion is an intrinsic property of the GnRH neuron, and is dependent on intracellular signaling mechanism(s) that lead to coordinated bursts of GnRH release [5–12]. Seminal studies by Ernst Knobil et al. in rhesus monkeys defined the importance of episodic pituitary stimulation for optimal gonadotropin secretion, aswell as the relationship of GnRH release to electrical activity in the hypothalamus and the essential role of estrogen in promoting the midcycle LH surge [13,14].

The neuroendocrine control of reproductive function is expressed through the episodic secretion of gonadotropic hormones from the anterior pituitary gland in response to pulsatile stimulation by GnRH, itself produced by a network ofpeptidergic neurons in the hypothalamus [11,15–20]. The characteristic pulsatile secretion of GnRH from hypothalamic neurons is dependent on an autocrine interaction between GnRH and its receptors expressed in GnRH-producing neurons. It is noteworthy that GnRH-R expression, GnRH-dependent activation of Ca2+ signaling, and autocrine regulation of GnRH release are already evident in early fetal GnRHneurons. Such activity is likely to provide a mechanism for regulated gene expression and GnRH secretion during embryonic migration [21–23].

The GnRH neuronal system

Mammalian reproduction is controlled by integrated sets of interactions between the hypothalamus, pituitary gland, and gonads. Each component of the reproductive system is regulated by feedback mechanisms that coordinate theprocesses leading to gonadotropin secretion, gamete prouction, and maintenance of the species [1,24–26]. GnRH neurons in most mammalian species are distributed in the preoptic area and adjacent sites in the rostral region of the hypothalamus, rather than being concentrated in a discrete nucleus. These scattered neurons are believed to form a diffuse neural network that functions coordinately as a GnRHpulse generator [27]. The generation of pulsatile GnRH release at the median eminence is the central and essential element governing reproductive function, and depends on the coordinated activities of the 1500 or so GnRH neurons that are located in the hypothalamus [28]. Of these, about 34% are required to control the ovarian cycle in the mouse [29]. Studies using intrahypothalamic injection of...