Effects of Gonadotrophin‐Releasing Hormone Outside the Hypothalamic‐Pituitary‐Reproductive Axis

Skinner, Donal C.; Albertson, Asher J.; Navratil, Amy M.; Smith, Alyson S.; Mignot, Mallory; Talbott, Heather; Scanlan-Blake, Niamh

doi:10.1111/j.1365-2826.2009.01842.x

Cited by 96 publications

(81 citation statements)

References 188 publications

(264 reference statements)

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“…However, the results of the present study may indicate that LA had a different effect in ovariectomized rats, as a downregulation in ghrelin and LPL mRNA expression to levels similar to those in the LA group were observed at the end of the experiment, which was probably associated with a decrease in food consumption and less FM deposition, which in fact corresponded to the results on body composition. It may be hypothesized that by LA administration stimulates a replacement of steroidal secretion in ovariectomized rats in other specialized tissues, which was supported by previous reports on the GnRH receptor outside of the hypothalamic-pituitary-reproductive axis (42).…”

Section: Discussionsupporting

confidence: 64%

Changes in body composition and mRNA expression of ghrelin and lipoprotein lipase in rats treated with leuprolide acetate, a GnRH agonist

et al. 2017

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Abstract. Leuprolide acetate (LA), a gonadotropin-releasing hormone (GnRH) agonist, was identified to cause changes in body weight in experimental and clinical trials; however, to date, the effect of LA on the body composition has not been properly assessed. The aim of the present study was to evaluate the long-term effect of LA administration on body composition and the mRNA expression of ghrelin and lipoprotein lipase (LPL) in rats. Ovariectomized (OVX), ovariectomized and LA-treated (OVX+LA), non-ovariectomized (CTRL) and non-ovariectomized but LA-treated (LA) rats were used. LA treatment was performed by intramuscular injection at 5 µg/kg every 72 h over 120 days. Analysis of body composition and mRNA expression of ghrelin and lipoprotein lipase were performed. The results indicated significant changes in body composition after treatment; in the OVX, LA, OVX+LA and CTRL group, the body weight was increased by 216.1, 183.7, 175.4 and 150.1%, respectively, compared with baseline. The fat mass in the LA group was 14% higher than that in the CTRL group, while that in the OVX group was 19% higher than that in the OVX+LA, and the fat-free mass was similar between the LA and CTRL as well as the OVX and OVX+LA groups. Following 120 days of treatment, the mRNA expression of ghrelin and LPL in the LA group was ~20% higher than that in the CTRL group, while that in the OVX+LA was downregulated in comparison with that in the OVX group. The results of the present study confirmed changes in body composition and mRNA expression of ghrelin and LPL caused by long-term administration of LA. LA may contribute to regulate food consumption and exert control over adipogenesis.

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Section: Discussionsupporting

confidence: 64%

Changes in body composition and mRNA expression of ghrelin and lipoprotein lipase in rats treated with leuprolide acetate, a GnRH agonist

et al. 2017

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“…10 In fact, GnRH/ GnRHR systems were also found to be expressed in peripheral organs, in particular in the female reproductive tract, 11 and in several tumors, 12 where their activation is associated with a strong antiproliferative/antimetastatic activity.…”

Section: Discussionmentioning

confidence: 99%

“…29 This observation also suggests that estrus cycle -dependent synaptogenesis, occurring in the rat female hippocampus, may be regulated by the cyclic release of hypothalamic GnRH. However, GnRH projections may be widespread in the brain 10 and GnRH might reach the hippocampal region from cerebrospinal fluid or from neurons located in other brain regions; GnRH fibers have been found in the hippocampus and a population of septal GnRH neurons were found to project axons through a septo hippocampal tract. …”

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confidence: 99%

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

Maggi¹

2016

MOJAP

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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...

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“…GnRH pathways have been shown to be involved in cell growth, invasion and angiogenesis of peripheral tumors, to varying extent (Skinner et al, 2009). GnRH receptor ligands have been shown to act differently on the GnRH receptor positive peripheral tissues at different doses (Mezo and Manea, 2010); a dose-dependent increase in cell proliferation at low (nanomolar) concentrations and inhibitory action at higher (micromolar) concentrations (Chen et al, 2007).…”

Section: Tumor Cell Proliferation Assay (Mtt Assay)mentioning

confidence: 99%

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

Varamini

Mansfeld

Giddam

et al. 2017

International Journal of Pharmaceutics

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Graphical abstractGonadotropin-releasing hormone (GnRH) is an endogenous peptide with a short biological half-life. Although GnRH analogs (eg. triptorelin) are developed with enhanced stability compared to the native peptide, they still suffer from poor biological stability and pharmacokinetic properties. Furthermore, they are only effective in the treatment of hormone-dependent reproductive cancers. In this study we applied lipidation and glycosylation along with D-amino acid substitution at position 6 (D-Trp 6 ) to improve the stability, permeability, and consequently the potency of the GnRH peptide and triptorelin. We showed that the conjugation of GnRH with a lipid moiety and carbohydrates made all modified constructs (1-8) more stable than the parent peptide against enzymatic degradation (5.5 to 6.5 times). Two of the lactose-modified glycolipopeptides, 3 and 6, showed 27 and 16 times higher membrane permeability than the parent GnRH, respectively. All analogs with D-Trp 6 -substitution (4-6) exerted GnRH receptor-mediated antiproliferative activity in prostate and ovarian GnRH-receptor positive cell lines. They were more potent than triptorelin in the hormone-independent prostate cancer cell line: DU145. Compound 6 (lactose-modified) was the most potent analog for stimulating the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) gonadotropins from rat pituitary cells in vitro. The same glycolipopeptide exhibited a higher efficacy and duration of action in stimulating the release of LH than triptorelin in a preclinical mouse model. The superior activity 2 of lipid-and carbohydrate-substituted triptorelin analog 6 made it a promising candidate for the development of new GnRH agonists to treat both hormone-dependent and hormone-refractory prostate cancer..LIST OF ABBREVIATIONS

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Effects of Gonadotrophin‐Releasing Hormone Outside the Hypothalamic‐Pituitary‐Reproductive Axis

Cited by 96 publications

References 188 publications

Changes in body composition and mRNA expression of ghrelin and lipoprotein lipase in rats treated with leuprolide acetate, a GnRH agonist

Changes in body composition and mRNA expression of ghrelin and lipoprotein lipase in rats treated with leuprolide acetate, a GnRH agonist

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

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

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