GnRH ant have been designed to obtain
GnRH-ant have been designed to obtain pharmacological compounds to block the pituitary–gonadal axis without the undesirable flare effect exerted by GnRH itself or by the GnRH-a (see Section 2.2). GnRH-ant competitively block the binding of GnRH to GnRHRs (Schally, 1999; Tan & Bukulmez, 2011); they present a very low amino GW5074 synthesis similarity with the decapeptide and contain a Ac-d-Nal-d-Cpa-d-Pal motif in the N-terminal, d-Ala in position 10 and different amino acid substitutions in positions 5, 6, and 8 (Cook & Sheridan, 2000; Schally, 1999) (Fig. 1). Among different synthesized compounds, cetrorelix, ganirelix, and degarelix show the highest binding affinity and inhibitory activity. Abarelix was found to be highly active, but it was shown to induce systemic allergic reaction that restricted its marketing to European countries (Huhtaniemi, White, McArdle, & Persson, 2009).
GnRH-a are used both to stimulate and to suppress reproductive functions according to their regimen of administration. Actually, a pulsatile treatment is used to mimic GnRH activity and maintain pituitary functions (i.e., induction of puberty, fertility restoration in patients with GnRH deficiency) (Abel et al., 2013; Zimmer, Ehrmann, & Rosenfield, 2010), while continuous (normally for 1–3 weeks) administration of GnRH-a induces a downregulation of GnRHRs and, after an initial flare effect, suppresses the release of pituitary gonadotropins (McArdle, 2012); its therapeutic regimen is indicated for central precocious puberty, endometriosis, hirsutism, and polycystic ovarian disease (Magon, 2011; Maheshwari, Gibreel, Siristatidis, & Bhattacharya, 2011).
GnRH-ant have several clinical applications in reproductive medicine and in gynecology and are particularly effective in the control of ovarian hyperstimulation protocols in assisted reproduction technology (Mancini et al., 2011; Tan & Bukulmez, 2011).
Conclusions and Future Directions
Introduction Over the last two decades, two gonadotrophin-releasing hormone (GnRH) antagonists, ganirelix and cetrorelix, have been introduced to assisted reproductive technologies for the prevention of a premature LH surge during ovarian stimulation (Hayden, 2008). For this purpose, a 0.25 mg daily dose of ganirelix appears to be sufficient, while achieving optimal clinical outcomes following IVF treatment (Ganirelix Dose-Finding Study Group, 1998). However, several studies have shown that during ovarian stimulation, multiple premature LH peaks may occur in GnRH antagonist cycles (Borm and Mannaerts, 2000, Engel et al., 2002, Messinis et al., 2005). This can probably be explained by the inability of ganirelix to block the positive feedback effect of exogenous oestrogen in normal women (). Additionally, although basal concentrations of LH, FSH and oestradiol were significantly suppressed within a few hours from the injection of 0.25 mg ganirelix, hormone values returned to pre-injection concentrations at 24 h (Duijkers et al., 1998, Oberyé et al., 1999). It is likely, therefore, that the daily dose of 0.25 mg is not a suitable approach to prevent early activation of the pituitary in IVF cycles. Nevertheless, despite these observations, no significant difference in the clinical outcome has been shown between agonists and antagonists in IVF protocols (Al-Inany et al., 2016, Lambalk et al., 2017), which indicates that the importance of the premature LH peaks needs further investigation. Although many studies have investigated the actions of GnRH antagonists on gonadotrophin secretion, there are no data in the literature on the effect of ganirelix on normal follicle maturation, while data on the use of cetrorelix are scanty. In particular, when a single high dose of 3 or 5 mg cetrorelix was injected in women on the day on which follicles reached a diameter of 16 mm, no further growth of the follicle over the next 48 h was observed (). Also, cetrorelix, at the daily high dose of 3 mg from day 8 of the cycle and for 7 days, delayed ovulation (). Additionally, when cetrorelix was injected at the daily dose of 0.25 mg from cycle days 3 to 16, ovulation was delayed by 5 days (). However, in none of these studies was ultrasonic data on the pattern of follicular growth presented, while untreated control cycles for comparison were not included. Although the study of the impact of an antagonist on follicle maturation may be difficult in stimulated cycles, due to the exogenous administration of FSH, this may be feasible during the normal menstrual cycle. Such information may provide new insights into the action of the GnRH antagonists on the pituitary–ovarian axis and help better understand normal follicle maturation.