Mechanism of the Direct Action of Gonadotropin-Releasing Hormone and Its Antagonist on Androgen Biosynthesis by Cultured Rat Testicular Cells*

Hsueh, Aaron J. W.; Bambino, Thomas; Zhuang, Lin-Zhi; Welsh, T. H.; Ling, Nicholas

doi:10.1210/endo-112-5-1653

Cited by 54 publications

(17 citation statements)

References 32 publications

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“…As previously demonstrated in cultured testicular cells, GnRH agonists exert an inhibitory effect on the steroidogenesis in Leydig cells (Hsueh et al 1983); however, we have found that testosterone had no effect on the GnRH mRNA levels. Thus the decrease in these levels under GnRH agonist treatment may involve other paracrine factors which remain to be elucidated.…”

Section: Discussionsupporting

confidence: 55%

LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis

Botte¹,

Lerrant²,

Bérault³

et al. 1999

Journal of Endocrinology

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The demonstration of an inhibitory effect of gonadotropinreleasing hormone (GnRH) agonists upon steroidogenesis in hypophysectomized rats and the presence of mRNA coding for GnRH and GnRH receptors (GnRH-R) in rat gonads suggests that GnRH can act locally in the gonads. To assess this hypothesis, we investigated the effects of GnRH analogs, gonadotropins and testosterone on the levels of both GnRH and GnRH-R mRNA in the rat testis. Using dot blot hybridization, we measured the mRNA levels 2 to 120 h after the administration of the GnRH agonist, triptorelin. We observed an acute reduction of both GnRH and GnRH-R mRNAs 24 h after the injection (about 38% of control). However, the kinetics for testis GnRH-R mRNA were different from those previously found for pituitary GnRH-R mRNA under the same conditions. Initially, the concentrations of serum LH and FSH peaked, then declined, probably due to the desensitization of the gonadotrope cells. In contrast, the GnRH antagonist, antarelix, after 8 h induced a 2·5-fold increase in GnRH-R mRNA, but not in GnRH mRNA, while gonadotropins levels were reduced. Human recombinant FSH had no significant effect on either GnRH or GnRH-R mRNA levels. Inversely, GnRH-R mRNA levels markedly decreased by 21% of that of control 24 h after hCG injection. Finally, 24 h after testosterone injection, a significant increase in GnRH-R mRNA levels (2·3 fold vs control) was found, but a reduction in the concentration of serum LH, probably by negative feedback on the pituitary, was observed. In contrast, GnRH mRNA levels were not significantly altered following testosterone treatment.Since LH receptors, GnRH-R and testosterone synthesis are colocalized in Leydig cells, our data suggest that LH could inhibit the GnRH-R gene expression or decrease the GnRH-R mRNA stability in the testis. However, this does not exclude the possibility that GnRH analogs could also affect the GnRH-R mRNA levels via direct binding to testicular GnRH-R. In contrast, the regulation of GnRH mRNA levels appeared to be independent of gonadotropins. Taken together, our results suggest a regulation of GnRH and GnRH-R mRNA specific for the testis.

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Section: Discussionsupporting

confidence: 55%

LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis

Botte¹,

Lerrant²,

Bérault³

et al. 1999

Journal of Endocrinology

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“…GnRH has been reported to directly inhibit steroidogenesis in the testis [21], but the mechanism by which GnRH reduces testosterone production is unknown. GnRH suppresses the stimulatory action of LH on testosterone production [2,22].…”

Section: Discussionmentioning

confidence: 99%

“…Because both GnRH and GnRH receptor are expressed in the testis [18,20], GnRH has been thought to act as a paracrine or an autocrine regulator of testis function. We speculate that annexin A5 participates in this function of GnRH in the testes.GnRH has been reported to directly inhibit steroidogenesis in the testis [21], but the mechanism by which GnRH reduces testosterone production is unknown. GnRH suppresses the stimulatory action of LH on testosterone production [2,22].…”

mentioning

confidence: 99%

Stimulation of Annexin A5 Expression by Gonadotropin Releasing Hormone (GnRH) in the Leydig Cells of Rats

Yao

Kawaminami

2008

Journal of Reproduction and Development

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Abstract. The distribution and regulation of annexin A5 expression, a gonadotropin releasing hormone (GnRH) receptor regulated protein in gonadotropes and luteal cells, in the testes of rats were examined. Immunocytochemical staining revealed high levels of annexin A5 in the Leydig and endothelial cells and lower levels in the primary spermatocytes and sperm. Hemicastration significantly increased the annexin A5 content of the remaining testis within 24 h. Annexin A5 immunoreactivity was increased mainly in interstitial tissues including the peritubular cells, while some spermatocytes also showed higher intensity of annexin A5 in the remaining testis. Administration of hCG (50 IU) enhanced the testicular content of annexin A5 after 24 h. This treatment expanded the area of interstitial tissue in the testis and increased annexin A5 immunoreactivity, but the area of the of endothelial cells was unchanged. Similarly, human chorionic gonadotropin (hCG) enhanced annexin A5 expression in a primary culture of testis cells that consisted of mainly interstitial cells. Because GnRH stimulates the expression of annexin A5 in the gonadotropes and luteal cells, we examined the effect of GnRH on annexin A5 expression in the testes. We found that des-Gly10 [Pro9]-GnRH ethylamide (100 nM), a GnRH agonist, increased annexin A5 expression in cultured testis cells and that Cetrorelix (100 nM), a GnRH antagonist, inhibited the effect of hCG on annexin A5 expression. These results suggest that pituitary luteinizing hormone promotes annexin A5 synthesis in Leydig cells and that this effect could be mediated by local GnRH in the testis. Key words: Annexin A5, Gonadotropin releasing hormone (GnRH), Human chorionic gonadotropin (hCG), Leydig cell, Rat (J. Reprod. Dev. 54: [259][260][261][262][263][264] 2008) onadotropin releasing hormone (GnRH) is a hypothalamic decapeptide that is primarily responsible for humoral control of reproduction. GnRH is secreted by GnRH neurons at the median eminence of the hypothalamus and is transported by the pituitary portal system to the gonadotropes of the anterior pituitary gland. GnRH binds to a specific G protein-coupled receptor and stimulates gonadotropin secretion. GnRH and its receptor are also reported to be expressed in tissues outside of the hypothalamus and pituitary gland, including the testis [1].Although the physiological role of GnRH in reproduction is well established, the functions of extrahypothalamic GnRH remain unclear. GnRH is known to directly inhibit testosterone production by unknown mechanisms [2,3]. It also inhibits the proliferation of some tumor cell lines [4,5], suggesting that it is also involved in specific cellular functions other than hormone secretion. For example, GnRH receptors in granulosa cells are thought to participate in follicular atresia [6]. So, it is interesting to know how GnRH works in the testis.We previously demonstrated that expression of annexin A5 is specifically stimulated by GnRH in pituitary gonadotropes [7]. Annexin A5 is a member of the annexin...

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“…The decrease in 17a-hydroxylase activities and C17_20 lyase activities in the regressed testes could be due to a reduced level of cytochrome P-450 which is known to be essential for the function of these enzymes or to a selective decrease in subpopulations of Leydig cells rich in C17_20 lyase activity (Rosentrauch, Bedrak & Friedlander, 1978; Payne, O'Shaughnessy, Chase, Dixon & Christensen, 1982;Bedrak et ai, 1983;Menard & Purvis, 1973;Nozu et ai, 1982). Evidence has also accumulated that in addition to LH other substances such as an intratesticularly produced LHRH-like peptide, arginine vasotocin (a potential pineal antigonadotrophic factor), as well as glucocorticoids and oestrogen, modulate, through a receptor-mediated process, 17a-hydroxylase and C17_20 lyase activities in the Leydig cell (Purvis, Clausen & Hansson, 1978;Nozu et ai, 1981 ; Adashi & Hsueh, 1982;Welsh, Bambino & Hsueh, 1982;Sharpe et ai, 1982;Hsueh, Bambino, Zhuang, Welsh & Ling, 1983). The regulatory interactions taking place at the testicular level therefore seem to be far more complicated than was initially envisaged.…”

Section: Discussionmentioning

confidence: 99%

Photoperiod-induced changes in the testicular metabolism of [14-14C]17 -hydroxyprogesterone in the bank vole (Clethrionomys glareolus)

Teräväinen¹,

Tähkä²

1985

Reproduction

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Summary. Minces of the testes of bank voles, born and reared in a long (18L:6D) photoperiod until weaning (18\p=n-\22days of age) and subjected thereafter to a short (6L: 18D, Group S) or a long (18L:6D, Group L) photoperiod for 6\p=n-\9weeks, were incubated with [4-14C]17\g=a\-hydroxyprogesterone in the presence of cofactors (NADP/ NADPH, 1\m=.\3 mmol/l) for 1 h at 37\s=deg\C.The radioactive metabolites were characterized and identified by thin-layer chromatography with derivative formation and chromatography to constant specific activity and isotope ratio. In Group L virtually all of the substrate was utilized and it was readily converted to androgens (48% of the radioactivity recovered) such as androstenedione and testosterone. The only pregnane metabolite identified was 17\g=a\-hydroxy,20\g=a\-dihydroxyprogesterone(43\m=.\3%). In Group S there was a decreased production of 1 7 \ g = a \ -h y d r o x y , 2 0 \ g = a \ -d i h y d r o p r o g e s t e r o n e and androgens (25\m=.\4% and 10\m=.\4%respectively) and a substantial portion of the substrate was not metabolized (38\m=.\8%). The main androgen metabolites identified, androst-4\x=req-\ ene-3\g=b\,17\g=b\-diol and 5\g=a\-androstane-3,17-dione are hormonally quite inert steroids. No androstenedione or testosterone was found. The results indicate that exposure to short photoperiod induces a decrease in the testicular C17-C20 lyase and 20\g=a\-hydroxysteroid dehydrogenase.

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Mechanism of the Direct Action of Gonadotropin-Releasing Hormone and Its Antagonist on Androgen Biosynthesis by Cultured Rat Testicular Cells*

Cited by 54 publications

References 32 publications

LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis

LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis

Stimulation of Annexin A5 Expression by Gonadotropin Releasing Hormone (GnRH) in the Leydig Cells of Rats

Photoperiod-induced changes in the testicular metabolism of [14-14C]17 -hydroxyprogesterone in the bank vole (Clethrionomys glareolus)

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