Gonadotrophin-releasing hormone agonist for improving fertility

Women undergoing in vitro fertilisation (IVF) need to take a series of hormones. The use of the drug GnRHa (gonadotrophin-releasing hormone agonist) during one stage of this process increases the chance of pregnancy. There are several options for GnRHa use. Long courses of GnRHa can be given either as daily low-dose injections, or using a single higher-dose longer-acting injection (depot version). The review of 16 randomised controlled trials found no evidence that depot versus daily GnRHa injections produce different rates of live birth/ongoing pregnancy, clinical pregnancy or ovarian hyperstimulation syndrome (OHSS). However, substantial differences could not be ruled out. For example, for a woman with a 25% chance of achieving a live birth or ongoing pregnancy using GnRHa depot, the corresponding chance using daily injection would be between 16% and 30%. For a woman with a 25% risk of severe OHSS using GnRHa depot, the corresponding risk using daily injection would be between 4% and 89%. For a woman with a 25% chance of achieving a live birth or ongoing pregnancy using daily GnRHa injections, the corresponding chance using a depot injection would be between 19% and 30% . For a woman with a 25 % chance of severe OHSS using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 9 % and 45 % . Depot GnRHa may increase the cost of an IVF cycle, because it lengthens the period to ovulation and requires the use of higher doses of other hormone drugs. The quality of the studies was unclear due to poor reporting, and only four studies reported live births.

Authors' conclusions: 

We found no evidence of a significant difference between depot and daily GnRHa use for pituitary down regulation in IVF cycles using the long protocol, but substantial differences could not be ruled out. Since depot GnRHa requires more gonadotrophins and a longer duration of use, it may increase the overall costs of IVF treatment.

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Background: 

Gonadotrophin-releasing hormone agonist (GnRHa) is commonly used to switch off (down regulate) the pituitary gland and thus suppress ovarian activity in women undergoing in vitro fertilisation (IVF). Other fertility drugs (gonadotrophins) are then used to stimulate ovulation in a controlled manner. Among the various types of pituitary down regulation protocols in use, the long protocol achieves the best clinical pregnancy rate. The long protocol requires GnRHa administration until suppression of ovarian activity occurs, within approximately 14 days. GnRHa can be used either as daily low-dose injections or through a single injection containing higher doses of the drug (depot). It is unclear which of these two forms of administration is best, and whether single depot administration may require higher doses of gonadotrophins.

Objectives: 

To compare the effectiveness and safety of a single depot dose of GHRHa versus daily GnRHa doses in women undergoing IVF.

Search strategy: 

We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7), MEDLINE (1966 to July 2012), EMBASE (1980 to July 2012) and LILACS (1982 to July 2012). We also screened the reference lists of articles.

Selection criteria: 

We included RCTs comparing depot and daily administration of GnRHa for long protocols in IVF treatment cycles in couples with any cause of infertility, using various methods of ovarian stimulation. The primary review outcomes were live birth or ongoing pregnancy, clinical pregnancy and ovarian hyperstimulation syndrome (OHSS). Other outcomes included number of oocytes retrieved, miscarriage, multiple pregnancy, number of gonadotrophin (FSH) units used for ovarian stimulation, duration of gonadotrophin treatment, cost and patient convenience.

Data collection and analysis: 

Two review authors independently selected studies, extracted data and assessed study quality. For dichotomous outcomes, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) per woman randomised. Where appropriate, we pooled studies.

Main results: 

Sixteen studies were eligible for inclusion (n = 1811 participants), 12 (n = 1366 participants) of which were suitable for meta-analysis. No significant heterogeneity was detected.

There were no significant differences between depot GnRHa and daily GnRHa in live birth/ongoing pregnancy rates (OR 0.95, 95% CI 0.70 to 1.31, seven studies, 873 women), but substantial differences could not be ruled out. Thus for a woman with a 24% chance of achieving a live birth or ongoing pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 18% and 29%.

There was no significant difference between the groups in clinical pregnancy rate (OR 0.96, 95% CI 0.75 to 1.23, 11 studies, 1259 women). For a woman with a 30% chance of achieving clinical pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 25% and 35%.

There was no significant difference between the groups in the rate of severe OHSS (OR 0.84, 95% CI 0.29 to 2.42, five studies, 570 women), but substantial differences could not be ruled out. For a woman with a 3% chance of severe OHSS using daily GnRHa injections, the corresponding risk using GnRHa depot would be between 1% and 6%.

Compared to women using daily GnRHa, those on depot administration required significantly more gonadotrophin units for ovarian stimulation (standardised mean difference (SMD) 0.26, 95% CI 0.08 to 0.43, 11 studies, 1143 women) and a significantly longer duration of gonadotrophin use (mean difference (MD) 0.65, 95% CI 0.46 to 0.84, 10 studies, 1033 women).

Study quality was unclear due to poor reporting. Only four studies reported live births as an outcome and only five described adequate methods for concealment of allocation.

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