Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

Abstract

Abbreviations: cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-triphosphate; HPG, hypothalamic-pituitary-gonadal; APP, amyloid precursor protein; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-3-kinase; EGR1, early growth response 1; PP, phosphotyrosine phosphatase; NF-Kb, nuclear factor kappa-light-chain-enhancer of activated b cells; DHCR24, 3-betahydroxysterol delta-24-reductase; St AR, steroidogenic acute regulatory protein; IKK-β, inhibitor of nuclear factor kappa-b kinase subunit beta; Aβ, amyloid beta peptide IntroductionGonadotropin releasing hormone (GnRH) is 35year-old neuropeptide recognized as the central regulator of reproductive functions.1 It was actually one of the earliest hypothalamic-releasing hormones sequenced and characterized and led its discoverer Andrew Schally to be awarded by the Nobel prize in 1977. 2 The peptide is a sequence of ten aminoacids ( Figure 1A) with a cyclized proline at the N-terminal and a glycine-amide residue at C-terminal, which confer some resistance to terminal peptidases.In mammals, GnRH is mainly produced by a limited number of hypothalamic neurons, which do not form a defined nucleus but show a dispersed organization in the mediobasal hypothalamus. Making axonal contacts with the hypothalamo-hypophyseal portal vessels, GnRH neurons release the decapeptide in the bloodstream directed to the adenohypophysis in a pulsatile manner. 3 At the pituitary level, the decapeptide interact with specific G protein-coupled receptors (GnRHR) present on gonadotrope cells inducing the release of the two gonadotropins (LH, luteinizing hormone and FSH, follicle stimulating hormones) which in turn coordinate male and female gonadal functions promoting the folliculogenesis and the ovulation in female, the spermatogenesis in male, and the production of sex steroid hormones (estrogen, progesterone and testosterone) ( Figure 1B). 4,5 GnRHR may be coupled either to Gaq/11 or Gas subunits which activate different intracellular responses including cAMP and DAG/IP3 pathways, as well as the mitogen-activated protein kinase (MAPK) cascades. 6 The separate activation of Gaq/11 or Gas subunits, by changes in the frequency of decapeptide pulsatile release, is the basis for the differential control of gonadotropin release. 7The actions of GnRH on reproductive functions cover the whole lifespan and characterize the maturation, the pubertal activation and the adult functions of the hormonal hypothalamo-pituitary-gonadal axis. Because of its importance on reproductive functions, a series of synthetic analogues, with agonist or antagonist activities have been developed soon after GnRH identification (Table 1). 8,9The pharmacological approach with GnRH analogues has been so far limited to the induction of puberty or, more in general, for recovery of fertility through a pulsatile administration; on the contrary, a continuous administration of GnRH agonists or antagonist is used to block the gonadotropin r...

GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile

“…Evaluation of the neurotransmitter levels was performed from hypothalamus, pituitary as well as from hippocampus and frontal cortex. The reasons for selecting these areas of brain mainly include i) presence of GnRHR in the described tissues, which contributes to regulation of reproduction and reproductive behaviour [ 8 , 9 ]; ii) active steroidogenesis occurring in these regions [ 10 , 11 ] and iii) them being important sites of neurotransmitter synthesis [ 12 ]. The rates of neurotransmitter synthesis and clearance were monitored by estimating the activities of neurotransmitter metabolizing enzymes.…”

Systematic review of hormone replacement therapy in the infertile man

“…Under the influence of neuropeptides (i.e. kisspeptin, noradrenaline and leptin with stimulatory effects, and prolactin, dopamine, serotonin, γ-aminobutyric acid (GABA) and interleukin 1 being inhibitory), the arcuate nucleus and preoptic area in the hypothalamus secrete GnRH in a pulsatile manner that in turn stimulates the gonadotrophs in the anterior pituitary gland to release the gonadotrophins; FSH and LH [11] .…”

First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor

“…The GnRH-R plays a crucial role in several diseases and it is located within and outside the brain [ 1 , 2 , 14 , 15 ]. Beside the CNS, the GnRH-R is also expressed in the Hypothalamus–pituitary–gonadal axis (HPG axis) (e.g.…”

“…Disturbance of gonadotropin releasing hormone (GnRH) signaling is implied in a variety of human diseases spanning from reproductive diseases, hormone dependent oncological diseases and neurodegenerative diseases. GnRH receptor (GnRH-R) play a central role in this context and have consequently attracted considerable interest as therapeutic targets [ 1 , 2 ].…”