Will GnRH antagonists provide new hope for patients considered `difficult responders' to GnRH agonist protocols?

Abstract

We have assessed the use of cetrorelix, a gonadotrophin releasing hormone (GnRH) antagonist, in conjunction with clomiphene citrate and gonadotrophin in 31 in-vitro fertilization (IVF)/gamete intra-Fallopian transfer (GIFT) cycles for 25 difficult responders. Group I included 18 poor responders (24 cycles) with no live birth in 23 previous IVF cycles with GnRH agonists. Group II included seven patients (seven cycles) with polycystic ovaries. Thirteen previous IVF/GIFT cycles with GnRH agonists had resulted in one live birth and three of these patients had developed ovarian hyperstimulation syndrome (OHSS). The treatment protocol involved a daily dose of clomiphene citrate 100 mg for 5 days and gonadotrophin injections from cycle day 2. Cetrorelix 0.25 mg/day was started when the leading follicle reached 14 mm. The outcome in both groups was favourable compared to previous treatment with GnRH agonists. In group I the abandoned cycle rate was 29 versus 57% (P = 0.06). More oocytes were produced (6.4 versus 4.7 oocytes/cycle) at a lower dose of follicle-stimulating hormone (FSH) (709 versus 1163 IU/oocyte; P = 0.08) and two live births resulted (11.8%). In group II fewer oocytes were produced (10.2 versus 14.5 oocytes/cycle), using a lower dose of gonadotrophin (170 versus 189 IU/oocyte) and resulted in one ongoing pregnancy. No patients experienced OHSS. This report is preliminary and a further controlled randomized study is required.

GnRH Antagonist Improved Blastocyst Quality and Pregnancy Outcome After Multiple Failures of IVF/ICSI–ET with a GnRH Agonist Protocol

“…Using the scoring system, transfer of at least one expanded blastocyst has been demonstrated to result in a significant increase in the implantation and ongoing pregnancy rates (22). All of the ongoing pregnancies achieved in the present study were in women who had received at least one expanded blastocyst, and these results supported the findings by Minaretzis et al (15) and Craft et al (16).…”

“…Moreover, the use of GnRH antagonists has been shown to be capable of improving pregnancy outcome in "difficult responders" to GnRHa protocols, and a better outcome of IVF with the cetrorelix protocol, which included clomiphene citrate and HMG, was obtained not only in poor responders to previous GnRHa protocols but also in patients with PCO (16). These results led us to suspect that prolonged use of GnRHa might adversely affect oocyte quality in some patients who had multiple failures of conception after IVF or ICSI-ET.…”

“…Nevertheless, the results of all of the studies showed higher fertilization rates, mean numbers of good-quality embryos, and pregnancy rates, as well as a low incidence of OHSS, indicating the usefulness of GnRH antagonists in ovarian stimulation protocol. Minaretzis et al (15) observed better embryo quality in patients treated with GnRH antagonist than in those treated with the GnRHa protocol, and Craft et al (16) reported a favorable clinical outcome of IVF when a GnRH antagonist was used in patients who had a poor response to GnRHa.…”

“Mild” vs. “long” protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial

“…A previous report [14] studied 145 IVF patients with a prior poor response and showed that the CC/Gn/GnRHant regimen was able to obtain better results than the "long" protocol; however, in this study a high Gn dose was associated to CC, rendering the results just suggestive of the possibility of using the CC/Gn/GnRH-ant protocol with a low Gn amount in poor responders. A small pilot study on 18 poor responders to whom the CC/Gn/GnRH-ant regimen was administered showed light improvements in the cycle cancellation rate and oocyte yield in comparison to a previous standard GnRHagonist cycle, with a relevantly lower Gn consumption [12].…”

“…Some studies have been planned to check whether the "mild" strategy may be applied also to expected poor responders: a combination of Clomiphene citrate (CC), Gn and GnRH antagonists (CC/Gn/GnRH-antag) was tested on expected poor responders in a few studies [12][13][14]. Unfortunately, the number of recruited patients was so low that these studies did not allow drawing well definite conclusions.…”