Gonadotrophins to induce ovulation in women with polycystic ovary syndrome (PCOS)

Review question

To compare the effectiveness and safety of gonadotrophins, hormones that regulate the reproductive system, as a second-line treatment to stimulate ovulation in women with PCOS who do not ovulate or conceive on clomiphene citrate.

Background

Infertility due to ovulation disorders is the most common reason for women to seek counselling or treatment. These women are treated by stimulating ovulation with medication, so-called 'ovulation induction'. This is usually done with tablets containing clomiphene citrate, as the first line of treatment. If women do not react to this medication, the most common second-line treatment in these women is ovulation induction with gonadotrophins, which are injectable drugs. Various types of gonadotrophin have been developed: urinary-derived products, available in purified (FSH-P), and highly purified (FSH-HP) form, and human menopausal gonadotrophin, also available in highly purified form (HP-HMG). Finally, recombinant FSH (rFSH) was developed artificially to obtain even higher purity.

Women who do react, but do not conceive within six ovulatory clomiphene citrate cycles, may continue with clomiphene citrate or switch to gonadotrophins.

Study characteristics

The review includes 15 trials, covering 2387 women. Ten trials compared urinary-derived gonadotrophins with rFSH. Of these, three trials compared rFSH with human menopausal gonadotrophin, and seven trials compared rFSH with FSH-HP. Four trials compared FSH-P with human menopausal gonadotrophin. One trial compared gonadotrophins with continued clomiphene citrate. We found no trials that compared rFSH with FSH-P, or FSH-HP with FSH-P. The evidence is current to January 2018.

Key results

There may be little or no difference in live birth, multiple pregnancy, clinical pregnancy, or miscarriage rate between urinary-derived gonadotrophins and recombinant FSH. We are uncertain whether human menopausal gonadotrophin or urinary follicle stimulating hormone improves pregnancy outcomes in women with PCOS. We are uncertain whether the interventions decrease the incidence of ovarian hyperstimulation syndrome.

When compared to continued treatment with clomiphene citrate, gonadotrophins resulted in more live births without increasing the rate of multiple pregnancies. Gonadotrophins resulted in more clinical pregnancies, but also in more miscarriages than clomiphene citrate, while there were no cases of ovarian hyperstimulation syndrome.

Quality of the evidence

The quality of the evidence was low to very low for outcomes from rFSH versus urinary gonadotrophins, and human menopausal gonadotrophin versus FSH-P. The quality of the evidence was moderate for outcomes from gonadotrophins versus continued clomiphene citrate.

Ten of the fifteen studies included in this review reported a commercial sponsor.

Authors' conclusions: 

There may be little or no difference in live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate between urinary-derived gonadotrophins and recombinant follicle stimulating hormone in women with polycystic ovary syndrome. For human menopausal gonadotropin or highly purified human menopausal gonadotrophin versus urinary follicle stimulating hormone we are uncertain whether one or the other improves or lowers live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate. We are uncertain whether any of the interventions reduce the incidence of ovarian hyperstimulation syndrome. We suggest weighing costs and convenience in the decision to use one or the other gonadotrophin. In women with clomiphene citrate failure, gonadotrophins resulted in more live births than continued clomiphene citrate without increasing multiple pregnancies.

Read the full abstract...
Background: 

Ovulation induction with follicle stimulating hormone (FSH) is a second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate.

Objectives: 

To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS), and women who do not ovulate or conceive after clomiphene citrate.

Search strategy: 

In January 2018, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, the World Health Organisation clinical trials register, Clinicaltrials.gov, LILACs, and PubMed databases, and Google Scholar. We checked references of in all obtained studies. We had no language restrictions.

Selection criteria: 

All randomised controlled trials reporting data on clinical outcomes in women with PCOS who did not ovulate or conceive on clomiphene citrate, and undergoing ovulation induction with urinary-derived gonadotrophins, including urofollitropin (uFSH) in purified FSH (FSH-P) or highly purified FSH (FSH-HP) form, human menopausal gonadotropin (HMG) and highly purified human menopausal gonadotrophin (HP-HMG), or recombinant FSH (rFSH), or continuing clomiphene citrate. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that described co-treatment with clomiphene citrate, metformin, luteinizing hormone, or letrozole.

Data collection and analysis: 

Three review authors (NW, EK, and MvW) independently selected studies for inclusion, assessed risk of bias, and extracted study data. Primary outcomes were live birth rate per woman and multiple pregnancy per woman. Secondary outcomes were clinical pregnancy, miscarriage, incidence of ovarian hyperstimulation syndrome (OHSS) per woman, total gonadotrophin dose, and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the risk ratio (RR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria.

Main results: 

The review included 15 trials with 2387 women. Ten trials compared rFSH with urinary-derived gonadotrophins (three compared rFSH with human menopausal gonadotrophin, and seven compared rFSH with FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P. One trial compared FSH with continued clomiphene citrate.

Recombinant FSH (rFSH) versus urinary-derived gonadotrophins

There may be little or no difference in the birth rate between rFSH and urinary-derived gonadotrophins (RR 1.21, 95% confidence interval (CI) 0.83 to 1.78; five trials, N = 505; I² = 9%; low-quality evidence). This suggests that for the observed average live birth per woman who used urinary-derived FSH of 16%, the chance of live birth with rFSH is between 13% and 28%. There may also be little or no difference between groups in incidence of multiple pregnancy (RR 0.86, 95% CI 0.46 to 1.61; eight trials, N = 1368; I² = 0%; low-quality evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88 to 1.27; eight trials, N = 1330; I² = 0; low-quality evidence), or miscarriage rate (RR 1.20, 95% CI 0.71 to 2.04; seven trials, N = 970; I² = 0; low-quality evidence). We are uncertain whether rFSH reduces the incidence of OHSS (RR 1.48, 95% CI 0.82 to 2.65, ten trials, n=1565, I² = 0%, very low-quality evidence).

Human menopausal gonadotrophin (HMG) or HP-HMG versus uFSH

When compared to uFSH, we are uncertain whether HMG or HP-HMG improves live birth rate (RR 1.28, 95% CI 0.65 to 2.52; three trials, N = 138; I² = 0%; very low quality evidence), or reduces multiple pregnancy rate (RR 2.13, 95% CI 0.51 to 8.91; four trials, N = 161; I² = 0%; very low quality evidence). We are also uncertain whether HMG or HP-HMG improves clinical pregnancy rate (RR 1.31, 95% CI 0.66 to 2.59; three trials, N = 102; I² = 0; very low quality evidence), reduces miscarriage rate (RR 0.33, 95% CI 0.06 to 1.97; two trials, N = 98; I² = 0%; very low quality evidence), or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42 to 117.81; two trials, N = 53; very low quality evidence) when compared to uFSH.

Gonadotrophins versus continued clomiphene citrate

Gonadotrophins resulted in more live births than continued clomiphene citrate (RR 1.24, 95% CI 1.05 to 1.46; one trial, N = 661; I² = 0%; moderate-quality evidence). This suggests that for a woman with a live birth rate of 41% with continued clomiphene citrate, the live birth rate with FSH was between 43% and 60%. There is probably little or no difference in the incidence of multiple pregnancy between treatments (RR 0.89, 95% CI 0.33 to 2.44; one trial, N = 661; I² = 0%; moderate-quality evidence). Gonadotrophins resulted in more clinical pregnancies than continued clomiphene citrate (RR 1.31, 95% CI 1.13 to 1.52; one trial, N = 661; I² = 0%; moderate-quality evidence), and more miscarriages (RR 2.23, 95% CI 1.11 to 4.47; one trial, N = 661; I² = 0%; moderate-quality evidence). None of the women developed OHSS.

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