Gonadotropin-Releasing Hormone Antagonist Antide Inhibits Apoptosis of Preovulatory Follicle Cells in Rat Ovary1

Parborell, Fernanda; Irusta, Griselda; Vitale, Alejandra; González, Olga; Pecci, Adalı́; Tesone, Marta

doi:10.1095/biolreprod.104.034454

Cited by 39 publications

(37 citation statements)

References 62 publications

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“…These lines of evidence, together with our previous reports demonstrating that antral follicles from gonadotropin-treated rats are more sensitive toward undergoing an apoptotic process when they have been exposed to a GnRH-I-a treatment (55,56), suggest that GnRH could act as an intraovarian factor by interfering with gonadotropin induction of follicular development.…”

Section: Discussionsupporting

confidence: 61%

“…In addition, we demonstrated that GnRH-I-treatment interferes with follicular recruitment, growth, and luteinization induced by gonadotropins (1,25,30). Moreover, we demonstrated that the GnRH antagonist treatment of gonadotropin-treated rats improves follicular development, suggesting a binding impairment of the GnRH-like peptide synthesized in the ovary to its receptors (1,49,56,57).…”

Section: Discussionmentioning

confidence: 80%

“…One ovary from each rat (n ϭ 5) was used in immunohistochemical studies. From the contralateral ovary, individual ovarian follicles (60 -80 follicles/ovary) were dissected under a stereoscopic microscope, as previously described (1,49,56,57). Accordingly, healthy antral follicles (AF; Ͼ200 m in diameter) from five ovaries were isolated and divided into three pools, one for each of the different assays (RT-PCR, Western blot, or steroid extraction).…”

Section: Methodsmentioning

confidence: 99%

“…In particular, 48 h of chronic in vivo GnRH-I-a treatment increases follicular concentrations of progesterone due to the enhancement of StAR expression and causes a decrease in follicular and serum concentrations of androgens and estradiol (34). Because estradiol is essential for normal follicular growth and atresia rescue (29), the previously observed GnRH-induced inhibition of folliculogenesis and increase in apoptosis appear to take place through alterations in the ovarian steroid pathway (1,49,56,57).Cytochrome P-450 C17 (P450C17) is a key branch point enzyme in the pathways of steroid hormone biosynthesis. It is associated with the smooth endoplasmic reticulum (SER) and catalyzes two sequential reactions: the hydroxylation of the C21 steroids progesterone or pregnenolone (17␣-hydroxylase activity) and the cleavage of the two-carbon side chain (C17,20 lyase activity) to yield the C19 steroids androstenedione or dehydroepiandrosterone, respectively (19).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…It is hypothesized that GnRH plays a paracrine/autocrine role in the regulation of gonadal development and function. Several studies have shown that GnRH agonists induce apoptosis possibly via receotors on granulosa cells in mammalian ovaries (Billig et al 1994, Parborell et al 2005. GnRH directly affected oocyte meiosis and follicular steroidogenesis in the goldfish ovary (Pati & Habibi 2000).…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of the pituitary and ovarian GnRH systems in the leopard gecko: signaling crosstalk between multiple receptor subtypes in ovarian follicles

Ikemoto

Park

2007

Journal of Molecular Endocrinology

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GnRH regulates reproductive functions through interaction with its pituitary receptor in vertebrates. The present study demonstrated that the leopard gecko possessed two and three genes for GnRH ligands and receptors, respectively, though one of the three receptor subtypes had long been thought not to exist in reptiles. Each receptor subtype showed a distinct pharmacology. All types of ligands and receptors showed different expression patterns, and were widely expressed both inside and outside the brain. This report also shows a comparison of the pituitary and ovarian GnRH systems in the leopard gecko during and after the egg-laying season. All three receptor subtypes were expressed in both the whole pituitary and ovary; however, only one receptor subtype could be detected in the anterior pituitary gland. In situ hybridization showed spatial expression patterns of ovarian receptors, and suggested co-expression of multiple receptor subtypes in granulosa cells of larger follicles. Co-transfection of receptor subtypes showed a distinct pharmacology in COS-7 cells compared with those of single transfections. These results suggest that distinct signaling mechanisms are involved in the pituitary and ovarian GnRH systems. Seasonal and developmental variations in receptor expression in the anterior pituitary gland and ovarian follicles may contribute to the seasonal breeding of this animal.

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Regulation of ovarian angiogenesis and apoptosis by GnRH‐I analogs

Parborell

Irusta

Celin

et al. 2007

Molecular Reproduction Devel

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An adequate vascular supply is important to provide endocrine and paracrine signals during follicular development. We evaluated the direct in vivo effects of both the GnRH-agonist Leuprolide acetate (LA) and the GnRH-antagonist Antide (Ant) on the expression of VEGF-A and ANPT-1 and their receptors in ovarian follicles from prepubertal eCG-treated rats. We also examined whether the changes observed in apoptosis by GnRH-I analogs have an effect on the caspase cascade. LA significantly decreased the levels of VEGF-A, its receptor Flk-1, and ANPT-1 when compared to controls, while the co-injection of Ant interfered with this effect. No changes were observed in the levels of Tie-2 after treatment with these analogs. When we measured the follicular content of caspase-3 protein, we observed that LA significantly increased the level of the active form. The co-injection of Ant interfered with this effect and Ant alone significantly decreased caspase-3 cleavage. IHC analyses corroborated these data. Notably, while LA increased caspase-3 activity levels, Ant decreased them when compared to controls. In follicles obtained from LA-treated rats, cleavage of PARP (a substrate of caspase-3) from the intact 113-kDa protein showed a significant enhancement in an 85-kDa fragment. The co-injection of Ant interfered with this effect. Ant alone significantly decreased PARP cleavage as compared to controls. We conclude that the decrease in VEGF-A, its receptor Flk-1/KDR, and ANPT-1 produced by the administration of GnRH-I agonist is one of the mechanisms involved in ovarian cell apoptosis. This suggests an intraovarian role of an endogenous GnRH-like peptide in gonadotropin-induced follicular development.

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Gonadotropin-Releasing Hormone Antagonist Antide Inhibits Apoptosis of Preovulatory Follicle Cells in Rat Ovary1

Cited by 39 publications

References 62 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

Comparative analysis of the pituitary and ovarian GnRH systems in the leopard gecko: signaling crosstalk between multiple receptor subtypes in ovarian follicles

Regulation of ovarian angiogenesis and apoptosis by GnRH‐I analogs

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