Clinica de Reproduccion Asistida FIV-Madrid and Instituto de Bioquimica (CSIC-UCM), C/Alvarez de Baena 4, 28006 Madrid, Spain. E-mail: ehernandezm{at}meditex.es
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Abstract |
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Key words: embryo implantation/GnRH agonists/GnRH antagonists
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Introduction |
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Shortly after GnRH was discovered, the agonist and antagonist of the GnRH were developed to control the synthesis and release of FSH and LH by the gonadotrophs (Karten and Rivier, 1986; Arimura, 1991
; Reissmann et al., 1995). As everyone is aware, the results did not turn out to be quite as the research team planned. A GnRH agonist, after a burst of stimulation of FSH/LH (flare-up), behaves as an antagonist, and the GnRH antagonist develops an unpleasant `gusto' for histamine release (Morgan et al., 1986
; Rivier et al., 1996
). Nevertheless, the suppression of FSH and LH secretion by the GnRH agonist generated a lot of success in clinical practice, and was soon used as the standard treatment to control the growth of hormonally-dependent tumours (Filicori et al., 1983
; Broekmans, 1996
). Later, GnRH agonists were introduced in the protocols for ovulation induction as a means of avoiding premature luteinization (Meldrum, 1994
; Fauser et al., 1999
). They have been indispensable ever since.
More that 10 years of research by a group of selected scientists were needed to untie the labyrinth of chemistry to develop a GnRH antagonist free of histamine release (Bajusz et al., 1988; Schally et al., 1989
; Rivier et al., 1996
). Finally, they have arrived, i.e. Cetrorelix® (ASTA Medica AG; Frankfurt, Germany) and Ganirelix® (Organon, Oss, The Netherlands). Recent studies have shown that these GnRH antagonists are effective in preventing the LH rise during ovarian stimulation for IVF (Frydman et al., 1991
; Diedrich et al., 1994
; Leroy et al., 1994
; Olivennes et al., 1994
; Felberbaum et al., 1995
; Diedrich and Felberbaum, 1998
; Felberbaum and Diedrich, 1999
) and their clinical efficacy has been confirmed by large multicentre phase III clinical trials (Ganirelix® Dose-Finding Study Group, 1998
). So far, in all the clinical studies with the GnRH antagonists (independent of the dose used; 0.25 mg/day or 3.0 mg as depot), LH has been successfully suppressed, a lower amount of FSH was required, patient satisfaction was highly rated (no histamine release) and ovarian hyperstimulation syndrome (OHSS) was cut by half, when compared with patients treated with the GnRH agonist. Furthermore, no significant differences in the number of oocytes retrieved, fertilization rates and embryo quality between patients treated with GnRH agonist or GnRH antagonist, were found. However, a decrease in oestradiol concentrations, pregnancy rates and ongoing pregnancies seem to suggest that implantation rates per transferred embryo are reduced in GnRH antagonist-stimulated cycles (Ganirelix® Dose-Finding Study Group, 1998
; Felberbaum and Diedrich, 1999
; Fauser et al., 1999
). Although not statistically significant (with 0.25 mg or 3 mg of GnRH antagonist), it is worth mentioning that these parameters were aggravated in a dose-dependent manner. For example, implantation rates varied from 1 to 20% when 2 or 0.25 mg/day of the GnRH antagonist was administered respectively (Ganirelix® Dose Finding Study Group, 1998
; Felberbaum and Diedrich, 1999
). In my opinion, these data bring to light a little known area to clinicians: the role of GnRH antagonists at the cellular level in extrapituitary tissues. The notion that the mechanism of action by which the GnRH antagonist controls the growth and differentiation of tissues and organs by suppressing gonadotrophin and steroid production is incomplete; the GnRH antagonist is more powerful than that. There are sufficient data in the literature to support the notion that GnRH antagonists are a potent inhibitor of the cell cycle by decreasing the synthesis of locally-produced growth factors, in a dose dependent manner (Emons et al., 1992
; Hershkovitz et al., 1993
; Kleinman et al., 1993
; Emons and Schally, 1994; Moretti et al., 1996
). Given that folliculogenesis, blastomere formation and endometrium development, mitosis is everything; and that GnRH receptors are present in all these cells and tissues (Dekel et al., 1988
; Emons et al., 1992
; Emons et al., 1993
; Minaretzis et al., 1995a
; Murdoch, 1995
; Emons et al., 1997
; Ortmann and Diedrich, 1999
; Casañ et al., 1999
), the possibility of an interaction between the GnRH antagonist and the GnRH receptor is possible and manifested as lower implantation rates. This is the Rubicon for the GnRH antagonist: to demonstrate irrevocably that, at the minimal doses necessary to suppress LH release, it does not impact implantation, embryo development and folliculogenesis. Given that the clinical data seem to suggest that this may not be the case, it is time to assemble what is known from basic and clinical research to understand why the implantation rates per transferred embryo are reduced in GnRH antagonist-stimulated cycles. In order to do so, it is important to review how GnRH works at the cellular level, the presence of extrapituitary GnRH receptors and binding and mode of intracellular signalling of the complex GnRH receptor/GnRH antagonist.
GnRH is a hypothalamic decapeptide which controls the release of LH and FSH in the pituitary gland (Knobil, 1980). When GnRH binds to its receptor (characteristic of the G protein couple receptor family) it activates phospholipase C, the second messengers (diacylglycerol and inositol 1,4,5 trisphosphatase), protein kinase C and Ca2+ release (Catt, 1999
). The conclusion of this cascade is the synthesis and secretion of FSH and LH by the gonadotrophs. In addition to this differentiation process, GnRH induces the activation of the c-fos proto-oncogene, showing that the GnRH receptor is coupled to a putative mitogenic signal-transduction pathway (Beckers et al., 1995
). In the gonadotrophs, GnRH binds to two classes of receptors, one with high affinity/low capacity and a second one with a low affinity/high capacity (Catt, 1999
). Chronic administration of the GnRH induces desensitization and receptor down-regulation of the GnRH receptor, a rationale for the use of GnRH agonists in the clinic. The GnRH antagonist acts by competitive binding to the pituitary GnRH receptor, a situation that can be reversed by the GnRH at any moment. Nevertheless, it is important to mention that continuous exposure to the GnRH antagonist will induce a down-regulation of the GnRH receptors and a decrease in GnRH receptor gene expression (Schally et al., 1995
; Pinski et al., 1996
; Halmos et al., 1996
). A crucial point to understand the modus operandi of the GnRH antagonist outside the gonadotrophs is the presence of GnRH receptors in a variety of extrapituitary tissues and cell types. Binding sites for GnRH have been demonstrated in ovary, testis, uterus, in human endometrium of fertile patients, mammary gland and a number of different malignant cells (Hsueh and Jones, 1981
; Dekel et al., 1988
; Fekete et al., 1989a
,b
; Srkalovic et al., 1990
; Emons et al., 1992
, 1993
; Minaretzis et al., 1995a
; Murdoch, 1995
; Ortmann and Diedrich, 1999
).
Although the concentration of hypothalamic GnRH in the systemic circulation is considered to be too low to interact with the extrapituitary GnRH receptors, it is important to keep in mind that the amount of GnRH antagonist used in reproductive medicine may lead to values that can activate the extrapituitary GnRH receptor (Rivier et al., 1996; Ortmann and Diedrich, 1999
).
To determine the mechanism of action of GnRH antagonist at the cellular level, human ovarian cancer, breast cancer, prostate carcinoma, and JAR human choriocarcinoma cell lines have been used (Fekete et al., 1989a; Sharoni et al., 1989
; Emons et al., 1992
; Reismann et al., 1992
; Emons et al., 1993
; Horvath et al., 1995
). In these in-vitro studies, GnRH antagonists restrain cell growth by decreasing the synthesis and the growth stimulatory effect of insulin-like growth factors (IGF); probably through effects on a post-receptor mechanism (Hershkovitz et al., 1993
; Kleinman et al., 1993
). Furthermore, inositol 1,4,5-trisphosphate (a second messenger of GnRH) was inhibited by GnRH antagonists (Beckers et al., 1995
). Moreover, receptors for epidermal growth factor (EGF) were significantly down-regulated, and a decrease in EGF receptor mRNA and EGF peptide to non-detectable values was seen in culture in the presence of the GnRH antagonist (Pinski et al., 1994
; Shirahige et al., 1994
; Moretti et al., 1996
). Taken together, these studies demonstrate that GnRH antagonist is able to control the growth of the cell by governing the production of growth factors. Interestingly, IGF and EGF are peptides of a family of growth factors that exert their action through receptors with intrinsic tyrosine kinase activity (LeRoith et al., 1995
). These receptors that phosphorylated tyrosine residues form the basis for the generation of an important mitogenic cascade that involved p21-ras, MAP kinases (MAPK) and activation of c-fos and c-jun. MAPK are some of the central enzymes in the growth factor-induced signalling pathway, because they control the concentrations of cyclin D/CdK4 and cyclin E/CdK2. In the G1 phase of the cell cycle, these cyclins are important because they control the overall proliferation process, since entry into the S-phase requires both cyclins activated (Van Zoelen, 1999
). In fact, embryonic fibroblast from the mutants lacking IGF-I receptors showed that the cell cycle is 2.5-fold longer than normal, indicating that this signalling system influences the most important determinant: the rate of cellular division that increases total cell number (Sell et al., 1994
).
Theoretically, if IGF and EGF (which control the cell cycle by activation of MAPK and cyclins) are inhibited by the GnRH antagonist (Schally and Vargas, 1999), a direct effect of the GnRH antagonist in the cascade that regulates the transition through the checkpoints of the cell cycle in folliculogenesis, implantation and embryo development cannot be excluded. In my opinion, these are the reproductive targets where the GnRH antagonist may impact when used in assisted reproductive techniques.
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At the level of the ovarian cells |
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At the oocyte level |
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At the embryo development level |
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At the endometrial cell level |
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In conclusion, given that GnRH receptors are ubiquitously localized in the reproductive tract, oocyte and embryo, activation of the GnRH receptor by the GnRH antagonist may be possible. As a result, this binding will decrease the synthesis of growth factors involved in the control of the cell cycle, compromising the mitotic programme of granulosa and endometrial cells (in IVF cycles) and fertilization mechanism and zygote development (in IUI cycles) as well.
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Future perspectives |
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Notes |
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References |
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