Gonadotrophin-releasing hormone antagonists for assisted conception

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Abstract
Over the last two decades, a long protocol of Gonadotrophin‐releasing hormone agonist (GnRHa) to prevent premature LH surges has been the standard treatment for ovarian stimulation in assisted reproduction. In the long protocols (with GnRHa started either in the mid luteal phase or in the early follicular phase of the preceding cycle) gonadotrophin administration is delayed until pituitary desensitization has been achieved, which usually takes two to three weeks. Gonadotrophin‐releasing hormone antagonists produce immediate suppression of gonadotrophin secretion, hence, they can be given after starting gonadotrophin administration. This will result in dramatic reduction in the duration of treatment cycle and will avoid estrogen deprivation symptoms associated with GnRH agonist induced down‐regulation. Assuming comparable clinical outcome, these benefits would justify a change from the standard long protocol of GnRH agonists to the new GnRH antagonist regimens. To compare the efficacy of gonadotrophin‐releasing hormone (GnRH) antagonists with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception. Search strategies included on‐line searching of the MEDLINE and EMBASE databases and the Cochrane Menstrual Disorders and Subfertility Group's Specialised Register from 1982 to 2001, and hand searching of bibliographies of relevant publications and reviews, and abstracts of scientific meetings. Only randomised controlled studies comparing different protocols of GnRH antagonists with GnRH agonists in assisted conception cycles were included in this review. Data were extracted into two by two tables. For the primary outcomes, clinical pregnancy per woman randomised and prevention of premature LH surge, the overall common odds ratio (OR) and the risk difference with 95% confidence interval (CI) were calculated after verifying the presence of homogeneity of treatment effect across all trials. Secondary outcomes considered were the number of oocytes retrieved, clinical pregnancy per oocyte retrieval and per embryo transfer, spontaneous abortion, incidence of severe ovarian hyperstimulation syndrome and the amount of gonadotrophins used. Where relevant data were missing or unclear the authors were consulted. Five trials comparing the new fixed protocol of GnRH antagonist to the long protocol of GnRH agonist fulfilled the inclusion criteria and were included. In four studies, the multiple low‐dose (0.25 mg) antagonist regimen was applied and in one study, the single high‐dose (3 mg) antagonist regimen was investigated. In all trials, reference treatment included a long protocol of GnRHa (buserelin, leuprorelin or triptorelin) starting in the mid‐luteal phase of the preceding cycle. In comparison to the long protocol of GnRHa, the overall OR for the prevention of premature LH surges was 1.76 (95% CI 0.75, 4.16), which is not statistically significant. There was a significantly fewer clinical pregnancies in those treated with GnRH antagonists (OR 0.79, 95% CI 0.63, 0.99). The absolute treatment effect (ATE) was calculated to be 5%. The number needed to treat (NNT) was 20. There was no statistically significant reduction in incidence of severe ovarian hyperstimulation syndrome, (RR 0.51, 95% CI 0.22, 1.18) using antagonist regimens as compared to the long GnRHa protocol. The new fixed GnRH antagonist protocol (i.e. with antagonist start fixed on day six of gonadotrophin stimulation) is a short and simple protocol but with a lower pregnancy rate compared to the GnRH agonist long protocol. There is no significant difference between both protocols regarding prevention of premature LH surge and prevention of severe ovarian hyperstimulation syndrome. The clinical outcome may be further improved by developing more flexible antagonist regimens taking into account individual patient characteristics. The GnRH antagonist flexible regimen should be the area of research in the near future.

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