The hypothalamic GnRH pulse generator: multiple regulatory mechanisms

Abstract

The pulsatile secretion of gonadotropin-releasing hormone (GnRH) release is an intrinsic property of hypothalamic GnRH neurons and attributed to several specific mechanisms. These include the 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, expression of G protein-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 provided insights into the basic cellular and molecular mechanisms involved in GnRH neuronal function. Hypothalamic control of reproductive functionThe episodic mode of GnRH secretion from the hypothalamus and of GnRH receptor (GnRH-R) activation in pituitary gonadotrophs are essential for optimal gonadotropin synthesis and secretion and ultimately for normal reproductive function [1][2][3][4][5]. The genesis of GnRH pulse generation in the hypothalamus is still incompletely understood. However, episodic neuropeptide secretion is an intrinsic property of the GnRH neuron and dependent on intracellular signaling and mechanism(s) leading to coordinated bursts of GnRH release [5][6][7][8][9][10][11][12]. Seminal studies by Ernst Knobil et al. in rhesus monkeys defined the importance of episodic pituitary stimulation for optimal gonadotropin secretion, as well as the relationship of GnRH release to electrical activity in the hypothalamus and the essential role of estrogen in promoting the mid-cycle 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, produced by a network of peptidergic neurons in the hypothalamus [11,[15][16][17][18][19][20]. The characteristic pulsatile secretion of GnRH from hypothalamic neurons is dependent on an autocrine interaction between GnRH and its receptors expressed in GnRHproducing neurons. It is noteworthy that GnRH-R expression, GnRH-dependent activation of Ca 2+ signaling, and autocrine regulation of GnRH release are evident in early fetal GnRH neurons. It is probable that such activity provides a mechanism for gene expression and regulated GnRH secretion during embryonic migration [21][22][23].Crown

Hypothalamic Regulation of Anterior Pituitary Function

“…In humans and non-human primates, small GnRH-I neuronal cell bodies are not localized to a specific nucleus, but are scattered mostly in the medio-basal hypothalamus, infundibular and periventricular regions, and form a diffuse neural network that coordinates the GnRH pulse generator [115,116]. GnRH-I neurons project to the median eminence and infundibular stalk and terminate on the hypophysealeportal circulation and also in the neurohypophysis.…”

“…This GnRH pulse generator is controlled by both intrinsic [123] and external regulators [116]. Pulse frequency determines the rate of pulsatile FSH/LH release from gonadotrophs, the ratio between FSH and LH, and the degree to which FSH and LH are glycosylated, which determines their stability and potency.…”

“…Theoretically, linking two autocrine-controlled GnRH systems provides an additional regulatory mechanism, a short-loop feedback, that controls LH and GnRH secretion [116].…”

Electrical synapses connect a network of gonadotropin releasing hormone neurons in a cichlid fish

“…It has long been known that this release depends on coordinated, pulsatile GnRH1 release, not simply elevated levels (7,8), requiring some level of synchronization in the output of these neurons. Episodic activation of the pituitary gonadotropes has been observed in multiple vertebrate taxa, including mammals and fish (9)(10)(11)(12), however, mechanisms that underlie this required coordinated activity of GnRH1 neurons are unknown. Synchrony could in principle derive from coincident input from a "pacemaker" neural population, from direct coupling of GnRH1 neurons, or from a combination of mechanisms.…”

Use of androgen deprivation therapy in prostate cancer: indications and prevalence

“…3 LH targets the testicular Leydig cell receptors, thereby promoting the synthesis of testosterone. 4 FSH interacts with the testicular Sertoli cells to promote the conversion of testosterone to estrogen.…”