Regulation of Luteinizing Hormone Receptor Messenger Ribonucleic Acid Levels by Gonadotropins, Growth Factors, and Gonadotropin-Releasing Hormone in Cultured Rat Granulosa Cells*

Piquette, Gary N.; LaPolt, Philip S.; Oikawa, Mamoru; Hsueh, Aaron J. W.

doi:10.1210/endo-128-5-2449

Cited by 98 publications

(29 citation statements)

References 36 publications

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“…It has been reported that an intrinsic GnRH system, with endogenous GnRH, GnRH receptor, and biological response, exists in rodent (2, 24, 52) and human (8, 11, 22, 30, 36, 37, 59) ovaries. It is well documented that GnRH-I possesses antigo- nadotropic effect in the rat ovary, downregulating the expression of FSH and LH receptors (67,60), inhibiting gonadotropin-stimulated cAMP production (54,41), and suppressing steroidogenic enzymes (32,63). In addition, we demonstrated that GnRH-I-treatment interferes with follicular recruitment, growth, and luteinization induced by gonadotropins (1,25,30).…”

Section: Discussionmentioning

confidence: 57%

Inhibition of cytochromeP-450 C17 enzyme by a GnRH agonist in ovarian follicles from gonadotropin-stimulated rats

Irusta

Parborell²,

Tesone³

2007

American Journal of Physiology-Endocrinology and Metabolism

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Irusta G, Parborell F, Tesone M. Inhibition of cytochrome P-450 C17 enzyme by a GnRH agonist in ovarian follicles from gonadotropin-stimulated rats. Am J Physiol Endocrinol Metab 292: E1456 -E1464, 2007; doi:10.1152/ajpendo.00226.2006.-Our objective was to study the direct action of a GnRH-I agonist, leuprolide acetate (LA), on ovarian steroidogenesis in preovulatory follicles obtained from equine chorionic gonadotropin (eCG)-treated rats. Previously, we have demonstrated an inhibitory effect of LA on steroidogenesis and follicular development. In this study, we tested the hypothesis that gonadotropin-releasing hormone (GnRH) exerts its negative effect on follicular development by inhibiting thecal cytochrome P-450 C17 (P450C17) ␣-hydroxylase expression and, consequently, androgen synthesis. Studies were carried out in prepubertal female rats injected with either eCG (control) or eCG plus LA (LA) and killed at different time points. Immunohistochemical studies indicated that LA induced steroidogenic acute regulatory protein (StAR) expression mainly in theca cells of preantral and antral follicles. In addition, serum progesterone levels increased significantly (P Ͻ 0.05), whereas those of androsterone decreased (P Ͻ 0.05) after 8 h of LA treatment. This inhibition caused by LA seemed to be a consequence of the decreased expression of follicular P450C17 ␣-hydroxylase, as demonstrated by Western blot and RT-PCR techniques. In vitro studies using follicles isolated from 48-h-eCG-treated rats and cultured with LA showed a significant (P Ͻ 0.05) inhibition of FSH-induced androsterone follicular content as well as P450C17 ␣-hydroxylase protein levels, as determined by Western analysis. However, LA increased StAR protein expression in these follicles without significant changes in P450scc enzyme levels. Taking all these findings into account, we suggest that GnRH-I exerts a direct inhibitory action on gonadotropininduced follicular development by decreasing the temporal expression of the P450C17 enzyme and, consequently, androgen production, thus reducing the supply of estrogens available to developing follicles. ovary; follicle; gonadotropin-releasing hormone agonist; steroidogenesis THE SUPPRESSION OF GONADOTROPINS exerted by the administration of gonadotropin-releasing hormone (GnRH) analogs on the pituitary-gonadal axis is well known. The agonists initially stimulate the secretion of large amounts of gonadotropins, followed by a desensitization of the pituitary and the subsequent inhibition of gonadal steroid production (33, 62). However, in the last several years there has been increasing evidence that GnRH is an intraovarian regulatory factor. A GnRH-like peptide, GnRH receptors, and transcription products from their genes have been found in ovarian tissue (3,7,31,65), and a direct inhibitory effect of this decapeptide has been observed on steroidogenesis in both granulosa cells (Gc) (31,32,35,38,40,43,58) and in corpus luteum (1,62,64). In addition, we (57) have demonstrated that in vitro treatment with a GnRH-I ...

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Section: Discussionmentioning

confidence: 57%

Inhibition of cytochromeP-450 C17 enzyme by a GnRH agonist in ovarian follicles from gonadotropin-stimulated rats

Irusta

Parborell²,

Tesone³

2007

American Journal of Physiology-Endocrinology and Metabolism

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“…An association between phosphorylated histone H3 and the inhibin-␣ promoter is detected by 1 h post FSH (5), and increased inhibin-␣ mRNA is detected by 10 h post FSH (80). Although we do not know whether FSH stimulates a similarly rapid association of phospho-histone H3 and the LHR promoter, increased LHR mRNA is not detected until 36 h post FSH (81). These results indicate, as discussed above, that distinct factors must be involved in producing the discrete chronological expression pattern observed for these two genes.…”

Section: Discussionmentioning

confidence: 58%

Follicle-stimulating Hormone Activation of Hypoxia-inducible Factor-1 by the Phosphatidylinositol 3-Kinase/AKT/Ras Homolog Enriched in Brain (Rheb)/Mammalian Target of Rapamycin (mTOR) Pathway Is Necessary for Induction of Select Protein Markers of Follicular Differentiation

Alam

Maizels

Park

et al. 2004

Journal of Biological Chemistry

229

185

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We sought to elucidate the role of AKT in folliclestimulating hormone (FSH)-mediated granulosa cell (GC) differentiation. Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol (PI) 3-kinase/AKT activity leads to Rheb (Ras homolog enriched in brain) and subsequent mTOR (mammalian target of rapamycin) activation. mTOR then stimulates translation by phosphorylating p70 S6 kinase and, consequently, the 40 S ribosomal protein S6. Activation of this pathway is required for FSH-mediated induction of several follicular differentiation markers, including luteinizing-hormone receptor (LHR), inhibin-␣, microtubuleassociated protein 2D, and the PKA type II␤ regulatory subunit. FSH also promotes activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). FSHstimulated HIF-1 activity is inhibited by the PI 3-kinase inhibitor LY294002, the Rheb inhibitor FTI-277 (farnesyltransferase inhibitor-277), and the mTOR inhibitor rapamycin. Finally, we find that the FSH-mediated upregulation of reporter activities for LHR, inhibin-␣, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1␣ interferes with the up-regulation of these genes. These results show that FSH enhances HIF-1 activity downstream of the PI 3-kinase/AKT/Rheb/mTOR pathway in GCs and that HIF-1 activity is necessary for FSH to induce multiple follicular differentiation markers.The anterior pituitary hormone follicle-stimulating hormone (FSH) 1 provides the key stimulus that promotes proliferation and differentiation of the ovarian follicle to the pre-ovulatory phenotype (1, 2 FSH signaling results in increased transcription of a number of characteristic follicular differentiation markers, including the steroidogenic enzymes side-chain cleavage cytochrome P-450 and aromatase cytochrome P-450 (12), the luteinizing hormone receptor (LHR) (3), inhibin-␣ (13), the signaling intermediates microtubule-associated protein 2D (MAP2D) (14), and the PKA type II␤ regulatory subunit (RII␤) (15). FSH also stimulates antrum formation and angiogenesis in the peripheral follicle thecal cells mediated in part by the vascular endothelial growth factor (VEGF) (16,17). Our investigation into the mechanisms by which two of these FSH targets, MAP2D and RII␤, are up-regulated in response to FSH revealed that their up-regulation at the protein level is blocked by the PI 3-kinase inhibitors LY294002 and wortmannin. FSH-mediated PI 3-kinase activation is also necessary for the expression of the cartilage link protein (8) in GCs and for optimal transferrin secretion and lactate production by Sertoli cells (9). In support of a role for PI 3-kinase/AKT activity in GC differentiation, insulin-like growth factor-1 (IGF-1), which activates the PI 3-kinase/AKT pathway via the IGF-1 receptor (18), synergizes with FSH in GCs to increase the expression of LHR (19), inhibin-␣ (20), and side-chain cleavage cytochrome P-450 and is sufficient for the expres...

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“…The LHR and FSHR activate this signaling system [41,42] and that addition of cAMP analogs, or the receptor-independent activation of the cAMP signaling system, can induce the expression of aromatase in granulosa cells [43][44][45]. However, LHR activation on aromatase expression in granulosa cells are highly dependent on receptor density.…”

Section: Discussionmentioning

confidence: 99%

Effect of triptolide on estradiol release from cultured rat granulosa cells

Zhang

Liu

et al. 2012

Endocr J

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Regulation of Luteinizing Hormone Receptor Messenger Ribonucleic Acid Levels by Gonadotropins, Growth Factors, and Gonadotropin-Releasing Hormone in Cultured Rat Granulosa Cells*

Cited by 98 publications

References 36 publications

Inhibition of cytochromeP-450 C17 enzyme by a GnRH agonist in ovarian follicles from gonadotropin-stimulated rats

Inhibition of cytochromeP-450 C17 enzyme by a GnRH agonist in ovarian follicles from gonadotropin-stimulated rats

Follicle-stimulating Hormone Activation of Hypoxia-inducible Factor-1 by the Phosphatidylinositol 3-Kinase/AKT/Ras Homolog Enriched in Brain (Rheb)/Mammalian Target of Rapamycin (mTOR) Pathway Is Necessary for Induction of Select Protein Markers of Follicular Differentiation

Effect of triptolide on estradiol release from cultured rat granulosa cells

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