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  • Gonadotropin-Releasing Hormone Antagonist: INTRODUCTION


In the mammalian ovary, only a small fraction of oocytes ovulate during reproductive life, whereas the majority of ovarian follicles undergo atresia by a hormonally regulated apoptotic mechanism.

Gonadotropin-releasing hormone (GnRH) and its analogs have been widely used to prevent the spontaneous LH surge in assisted reproduction techniques. Suppression of gonadotropin secretion can be achieved with either GnRH-agonist (GnRH-a) or GnRH-antagonist (GnRH-ant). Chronic administration of GnRH-a leads to pituitary desensitization and inhibition of gonadotropin and sex steroid levels by reducing the number of GnRH receptors on the cell membrane. Conversely, GnRH-ant achieves suppression of gonadotropin secretion by the competitive blockade of the GnRH receptors. canadian healthcare mall

Aside from the effects of GnRH analogs on the pituitary-gonadal axis, studies have shown that GnRH and its analogs have extrapituitary effects, particularly on the ovaries of rats and humans. However, there is some controversy about the physiological relevance of an endogenous GnRH-like molecule during folliculogenesis.

We have previously demonstrated, in prepubertal rats, that GnRH-a treatment produces an increase in ovarian follicle DNA fragmentation by interfering with the pathways of FSH, cAMP, or growth factors, or a combination of theses. In addition, several studies performed in rats have demonstrated the antigonadal effect of GnRH analogs administered in vivo or in vitro. There is also evidence of the presence of GnRH mRNA and GnRH receptor mRNA in ovarian cells. These findings support the concept that a GnRH-like peptide may play an autocrine or paracrine regulatory role in the ovary. In addition, in the rat ovary, GnRH has been identified as an atretogenic factor capable of inducing granulosa cell apoptosis. Moreover, Birnbaumer et al. demonstrated that administration of GnRH-ant together with FSH leads to a significant increase in the number of follicles susceptible to ovulation, suggesting that GnRH or GnRH-like substances are present and active under normal physiological conditions.

The molecular mechanism of apoptosis is a matter of an active debate. However, it is accepted that morphological changes observed during programmed cell death are the consequence of an activation of caspase cascades. At least two main signaling pathways have been postulated to participate in this process. The first involves membrane receptors called ‘‘death receptors’’, and the second relies on a cell’s ability to sense changes in the ratios and numbers between members of the BCL-2 family of proteins. BCL-2 prevents apoptosis induction by a wide range of stimuli, suggesting that different pathways of transduction signals converge at this point. Several authors have identified a variety of proteins related to BCL-2, such as BAX, BAK, BID, and the different BCL-X isoforms, that can either promote or prevent apoptosis. Mitochondria play a key role in the apoptotic pathway through the release of several factors, such as cytochrome C, from the intermembrane space to the cytoplasm. It has been suggested that this pathway could be regulated by the relative levels and subcellular distribution of BCL-2 family proteins. The antiapoptotic members (i.e., BCL-2 or BCL-Xl) are mostly associated with the outer membrane of mitochondria and inhibit cytochrome C release, whereas the proapoptotic molecules such as BAX, BAD, or BID are cytosolic proteins. They translocate to the mitochondria and trigger cytochrome C release upon apoptosis induction. Several studies have demonstrated that apoptotic cell death is associated with follicular atresia in chicken, porcine, and rodent ovaries. FSH and LH are the primary survival factors for ovarian follicles; the antiapoptotic effects of these gonadotropins are probably mediated by the production of ovarian growth factors. On the other hand, androgens, GnRH, tumor necrosis factor a, and FAS/FAS ligand (FASL) are factors that have been involved as potential inducers of granulosa cell apoptosis. In a previous work, we described that the apoptotic action of GnRH-a correlates with an imbalance in the ratio of antiapoptotic:proapoptotic proteins (BCL-Xl:BCL-Xs) in rat follicles, suggesting that members of the BCL-2 gene family are involved in GnRH cell death induction in ovarian tissue.

Those observations led us to postulate that an endogenous GnRH ovarian molecule has some inhibitory function during folliculogenesis in the rat, and that this effect could be elucidated by the administration of GnRH analogs to gonadotropin-treated rats. Therefore, the aim of the present study is to examine the in vivo effects of GnRH analogs on follicular development and apoptosis in ovarian follicles obtained from prepubertal eCG-treated rats. In particular, we examine whether the action of GnRH-a leuprolide acetate (LA) and the GnRH-ant antide (Ant) is associated with BAX and cytochrome C subcellular redistribution.

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