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Impact of gonadotropin‑releasing hormone antagonist addition on pregnancy rates in gonadotropin‑stimulated intrauterine insemination cycles

ABSTRACT
OBJECTIVES: The objective of the study is to evaluate the efficacy of gonadotropin releasing hormone (GnRH) antagonist in improving clinical pregnancy rate in gonadotropin stimulated intrauterine insemination (IUI) cycles in patients of unexplained infertility. STUDY DESIGN: This was a prospective, randomized case–controlled study. SETTINGS: The study was conducted in the infertility clinic of a tertiary care center. MATERIALS AND METHODS: Four hundred twenty seven women undergoing IUI following controlled ovarian stimulation with gonadotropins (recombinant follicle stimulating hormone [r FSH] 75 IU/day) were randomly divided into two groups. Women in Group I received GnRH antagonist (Cetrorelix 0.25 mg/day) in a multiple dose flexible protocol. Women in Group II received r FSH alone. Ovulatory trigger was given with human chorionic gonadotropin 5000 IU when dominant follicle was ≥18 mm. IUI was performed within 44–48 h. Both groups received similar luteal phase support. Primary outcome measure was clinical pregnancy rate. The trial was powered to detect an absolute increase in clinical pregnancy rate by 13% from an assumed 20% clinical pregnancy rate in the control group, with an alpha error level of 0.05 and a beta error level of 0.20. RESULTS: Clinical pregnancy rate in Groups I and II was 27.6% (n = 56) and 26.5% (n = 54), respectively (P=0.800). Ongoing pregnancy and multiple pregnancy rates were likewise similar between the groups. CONCLUSIONS: Addition of GnRH antagonist to gonadotropin stimulated IUI cycles results in no significant difference in clinical pregnancy rate.

INTRODUCTION

Unexplained infertility contributes to about 10–30% of subfertility, depending on diagnostic criteria. Intrauterine insemination (IUI) combined with controlled ovarian stimulation (COS) has been established as a first-line treatment for couples with unexplained infertility. The rationale of COS and IUI is to increase the number of available female and male gametes at the site of fertilization by achieving two to three dominant follicles, followed by a perfectly timed insemination. The use of IUI with COS in a well selected group of patients with unexplained infertility results in comparable cumulative pregnancy rate when compared to in vitro fertilization (IVF) and hence appears more cost effective.

To increase the chances of success in terms of pregnancy rate in COS IUI cycles, various therapeutic approaches have been tried by various researchers, such as different ovarian stimulation protocols, double insemination, and prevention of premature luteinizing hormone (LH) surge. According to the Cochrane review on ovarian stimulation protocols for IUI in the women with subfertility, use of gonadotropins for COS in IUI results in higher pregnancy rate than clomiphene citrate-stimulated cycles (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.2–2.7). A recent meta-analysis clearly indicated that double insemination does not result in higher clinical pregnancy rate compared with single IUI in couples with unexplained infertility. Double insemination has been suggested by researchers because of the hypothesis that capacitated sperms in the inseminate are active for only 2–3 h, so they may not be able to back up ovulation which takes place in between the next 20 and 24 h. However, it appears that precise timing of insemination in relation to ovulation so as to enable active sperms to reach and fertilize the oocyte should obviate the need for double insemination.

Premature LH surge is defined as the surge that precedes the triggering of ovulation iatrogenically. Prospective data have shown that premature LH surge occurs in almost 23% of COS cycles (95% CI 22–43%), which appears quite significant and can interfere with the optimal timing of the insemination. LH surge can be effectively prevented by administering a gonadotropin releasing hormone (GnRH) agonist or GnRH antagonist. Use of GnRH agonist is not recommended in IUI cycles because of prolonged administration of injections prior to and during stimulation to achieve complete downregulation of GnRH receptors, risk of excessive follicular stimulation, and higher cost and inconvenience to the patient.

On the other hand, GnRH antagonist competitively blocks the GnRH receptors and immediately causes pituitary suppression, thereby reduces LH and follicle-stimulating hormone (FSH) secretion within 2–4 h. The efficacy of GnRH antagonist in prevention of premature LH surge is well-established.[17,18] The inhibitory effect of GnRH antagonist is reversible, dose-dependent and is associated with the equilibrium between endogenous GnRH and GnRH antagonist concentration. Cetrorelix (Cetrotide, EMD Serono) and Ganirelix (Antagon, Organon) are the two GnRH antagonists available for clinical use.
The protocols of GnRH antagonist administration in COS IUI cycles are well defined; however; the flexible regimen is the one which is used commonly in mild stimulation cycles.



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