Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction

Background Gonadotrophin-releasing hormone agonists (GnRHa) are used in assisted reproduction technology (ART) cycles to prevent a luteinizing hormone surge. Various protocols have been described in the literature, such as long protocols (continuous and stop or reduce dose, long luteal, or long follicular protocol); short protocols and ultrashort protocols. Objectives To determine the most effective GnRHa protocol as an adjuvant to gonadotrophins in ART cycles. Search strategy We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINHAHL and PsycINFO. Reference lists of relevant articles were also searched. All the searches were updated to August 2010. Selection criteria Only randomised controlled trials comparing any two protocols of GnRHa in in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) cycles were included. Data collection and analysis The primary outcome measure was live births per women. Secondary outcome measures were pregnancy rate, ongoing pregnancy rate, number of oocytes retrieved and amount of gonadotrophins used. Data were independently extracted in 2 x 2 tables by two authors. Odds ratios (OR) with 95% confidence intervals (CI) were calculated after verifying the presence of homogeneity of treatment effect across all trials. For continuous variables mean differences (MD) were calculated. Main results Of 29 included studies, 17 compared long with short protocols; two compared long with ultrashort protocols; four compared a follicular versus luteal start of GnRHa; three compared continuation versus stopping the GnRHa at the start of stimulation; three compared continuation of the same dose versus reduced dose of GnRHa and one compared a short versus short stop protocol. There was no evidence of a difference in the live birth rate but this outcome was only reported by three studies. There was evidence of a significant increase in clinical pregnancy rate (OR 1.50, 95% CI 1.16 to 1.93) in a long protocol when compared to a short protocol. That is there is a 50% increase in chance of achieving pregnancy if a long protocol is used as compared to a short protocol, although this difference could range from 16% to 93% increased chance of pregnancy. This difference did not persist when the meta-analysis was done only on the studies with adequate randomisation (OR 1.38, 95% CI 0.93 to 2.05). There was evidence of an increased number of oocytes (MD 1.61, 95% CI 0.18 to 3.04) obtained when a long protocol was used as compared to a short protocol. That is there is a 60% increase in the number of oocytes retrieved when a long protocol is used as compared to a short protocol, although this difference could range from 18% to 304% more oocyte. There was evidence of an increase (MD 12.90, 95% CI 3.29 to 22.51) in the requirement for gonadotrophins in long as compared to short protocols. That is approximately 12.9 more ampoules of gonadotrophins were consumed when a long protocol was used as compared to a short protocol. This difference could range from 3.29 to 22.51 more gonadotrophin ampoules. There was no evidence of a difference in any of the outcome measures for luteal versus follicular start of GnRHa and stopping versus continuation of GnRHa at the start of stimulation. Authors' conclusions The pregnancy rate was found to be higher when GnRHa was used in a long protocol as compared to a short or ultrashort protocol. There was no evidence of a difference in live birth rate, but this outcome was only reported by three studies. There was no evidence of a difference in the outcomes amongst various long protocols; nor that stopping or reducing GnRHa at the start of stimulation was associated with a reduced pregnancy rate. For all comparison, except a long versus short protocol, there was a lack of power.