Species differences in the sensitivity to GnRH analogs

Thau, Rosemarie B.; Limonta, Patrizia; Schmidt, Frederick H.; Sundaram, K.

doi:10.1016/s0022-4731(85)80020-0

Cited by 14 publications

(7 citation statements)

References 28 publications

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“…Earlier studies have shown that when administered to normal adult males, GnRH-analogues reduce the secretion of LH and FSH from the pituitary gland [4,5]. The reduction of gonadotropin secretion results in lower testosterone levels in testes, leading to the inhibition of spermatogenesis [40], particularly in postmeiotic phase [4,41,42]. In contrast, recent studies have shown that GnRH-analogues stimulate regeneration of spermatogenesis after testicular damage caused by irradia- tion or chemical toxins [3,6,8].…”

Section: Discussionmentioning

confidence: 99%

Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal1

Ohmura

Ogawa

Ono

et al. 2003

Biology of Reproduction

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Recent studies have demonstrated that GnRH-analogues can stimulate regeneration of spermatogenesis of rats when administered after testicular damages. Although the mechanism of this phenomenon has not been elucidated yet, stem cell factor (SCF) produced by Sertoli cells was proposed to mediate the effects of GnRH-analogues on spermatogonial proliferation and/or survival. In the present study, we quantitatively evaluated the proliferation of spermatogonia and addressed whether SCF mediates the effect of GnRH-analogue on spermatogonial proliferation, using a novel approach combining spermatogonial transplantation and laser confocal microscopic observation. In the first experiment, using wild-type mice as recipients for spermatogonial transplantation, the number of donor spermatogonia per 100 Sertoli cells in each spermatogenic colony was significantly higher in the experimental group of mice treated with leuprorelin, a GnRH-agonist, than that of the control group at 4 and 5 wk after transplantation. In the second experiment, Steel/Steeldickie (Sl/Sld) mutant mice, which lack expression of membrane bound form SCF, were used as recipients. As seen in the first experiment, the number of undifferentiated spermatogonia was significantly higher in leuprorelin-treated than in the control group. Since undifferentiated spermatogonia do not express the receptor of SCF, the present study clearly demonstrates that neither membrane-bound nor secreted forms of SCF are involved in the mechanism of GnRH-analogue's effect on spermatogonial proliferation and/or survival.

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Section: Discussionmentioning

confidence: 99%

Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal1

Ohmura

Ogawa

Ono

et al. 2003

Biology of Reproduction

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Section: Gonadotropin-releasing Hormone (Gnrh)mentioning

confidence: 92%

“…We have reported several nonpeptide antagonist series with remarkable selectivity for the human receptor compared with the rat receptor (10 -13). These observations are somewhat surprising given that, with one or two exceptions (14,15), similar degrees of species selectivity have not been reported for the thousands of peptide GnRH analogs that have been synthesized by numerous groups (16).The rat GnRH receptor is highly homologous (87%) to the human receptor, whereas the receptor cloned from the rhesus macaque (Macaca mulatta) contains only 8 substitutions of the 328 amino acids in the human sequence. Therefore, to identify the molecular basis of this species selectivity and identify residues involved in nonpeptide ligand binding to the GnRH receptor, we have investigated residues responsible for the selectivity of several nonpeptide GnRH antagonists for the human receptor over receptors from rat and macaque.…”

mentioning

confidence: 99%

Species Selectivity of Nonpeptide Antagonists of the Gonadotropinreleasing Hormone Receptor Is Determined by Residues in Extracellular Loops II and III and the Amino Terminus

Reinhart¹,

Xie²,

Liu³

et al. 2004

Journal of Biological Chemistry

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Efforts to develop orally available gonadotropin-releasing hormone (GnRH) receptor antagonists have led to the discovery of several classes of potent nonpeptide antagonists. Here we investigated molecular interactions of three classes of nonpeptide antagonists with human, rat, and macaque GnRH receptors. Although all are high affinity ligands of the human receptor (K i <5 nM), these compounds show reduced affinity for the macaque receptor and bind only weakly (K i >1 M) to the rat receptor. To identify residues responsible for this selectivity, a series of chimeric receptors and mutant receptors was constructed and evaluated for nonpeptide binding. Surprisingly, 4 key residues located in the amino terminus (Met-24) and extracellular loops II (Ser-203, Gln-208) and III (Leu-300) of the GnRH receptor appear to be primarily responsible for species-selective binding. Comparisons of reciprocal mutations suggest that these may not be direct contacts but rather may be involved in organizing extracellular portions of the receptor. These data are novel because most previous reports of residues involved in binding of nonpeptide ligands to peptide-activated G protein-coupled receptors, including the GnRH receptor as well as mono-amine receptors, have identified binding sites in the transmembrane regions. Gonadotropin-releasing hormone (GnRH)1 is a linear decapeptide amide, pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 , that regulates the reproductive endocrine axis in both male and female vertebrates (1, 2). The GnRH receptor (Gn-RHR) is a member of the G protein-coupled receptor superfamily (3). Its activation stimulates phospholipase C and phosphatidyl inositol turnover by coupling to the GTP-binding proteins G q and G 11 (4). Stimulation of pituitary GnRH receptors by hypothalamic GnRH released into the pituitary portal circulation results in secretion of the gonadotropins, luteinizing hormone, and follicle-stimulating hormone into the peripheral circulation. The gonadotropins in turn regulate the production of steroids and gametes by the gonads. Receptors for GnRH have been cloned from a wide range of species (5), and numerous studies have been reported elucidating key residues in the receptor responsible for peptide binding and signal transduction (5).Peptide drugs that inhibit the action of GnRH have proven useful in regulating the hypothalamic-pituitary-gonadal axis and are now routinely used for ablation of gonadal steroids. This approach has proven effective in the management of endometriosis, prostate cancer, uterine fibroids, breast cancer, and other conditions, including infertility (6). However, the requirement for daily injection or implantation of long acting depots has prompted a number of groups to attempt to develop orally active, nonpeptide antagonists (for a review, see Ref. 7). These efforts have been hindered in part by the species selectivity that is observed for most nonpeptide GnRH antagonists. Cho et al. (8) reported synthesis of T-98475, a nonpeptide GnRH antagonist with high affinity to the hu...

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“…The goal of adjuvant therapy is supposedly to produce atrophy of the spermatogenic epithelium. These authors could not dem onstrate any effects of leuprolide upon the testes of their mice, but it has been shown that the pituitary gonadal axis of the mouse is extremely insensitive to inhibition by the GnRH analogues [16]. Therefore it is not surprising that protection against the cisplatin was not achieved.…”

mentioning

confidence: 98%

Protection against Cytotoxic- Induced Testis Damage - Experimental Approaches

Id¹

1993

Eur Urol

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Species differences in the sensitivity to GnRH analogs

Cited by 14 publications

References 28 publications

Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal1

Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal1

Species Selectivity of Nonpeptide Antagonists of the Gonadotropinreleasing Hormone Receptor Is Determined by Residues in Extracellular Loops II and III and the Amino Terminus

Protection against Cytotoxic- Induced Testis Damage - Experimental Approaches

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