Key messages
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In women with polycystic ovary syndrome (PCOS), there may be little or no difference in live birth, multiple pregnancy (twins or triplets), pregnancy, or miscarriage rates between urinary-derived gonadotropins (derived from urine from menopausal women) and recombinant follicle-stimulating hormone (developed with recombinant DNA technology).
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For human menopausal gonadotropin (also derived from the urine of menopausal women) versus purified urinary follicle stimulating hormone, we are uncertain whether one or the other improves or reduces the chance of a live birth, multiple pregnancy, pregnancy, or miscarriage.
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In women who do not conceive after taking clomiphene citrate, gonadotropins probably result in more live births and pregnancies compared to continuing treatment with clomiphene citrate, without increasing the risk of having twins or triplets. Gonadotropins may increase the risk of a miscarriage.
What is the problem?
One in seven couples worldwide may experience infertility, defined as having trouble getting pregnant after one year of trying. Infertility due to problems with the release of an egg (ovulation) during the menstrual cycle is the most common reason for women to seek counselling or treatment. These women are treated by stimulating the release of an egg from the ovaries with medication, so-called 'ovulation induction'. This is usually done with pills containing clomiphene citrate, as the first choice of treatment. If women do not respond to clomiphene, the most common second choice of treatment is stimulation of egg release with gonadotropins, which are injectable drugs.
What are the available treatments?
Various types of gonadotropins have been developed by processing urine from menopausal women. These gonadotropins include human menopausal gonadotropin, available in purified and highly purified form, and purified and highly purified follicle-stimulating hormone. Finally, recombinant follicle-stimulating hormone was developed artificially to obtain even higher purity. Women who do ovulate, but do not get pregnant within six cycles of treatment with clomiphene citrate, may continue with clomiphene citrate or switch to gonadotropins. Gonadotropins can result in the development of multiple follicles. To prevent multiple pregnancy and ovarian hyperstimulation syndrome (OHSS), which is a serious condition, the cycle needs to be cancelled.
It is important to know which medication works best to enable doctors and women to make informed decisions about the course of treatment.
What did we want to find out?
We wanted to find out which gonadotropin is the best choice to trigger egg release in women with PCOS who do not ovulate or get pregnant after taking clomiphene citrate pills.
What did we do?
We searched for studies comparing different gonadotropins to stimulate ovulation in women with PCOS. We summarised the results of the included studies and rated our confidence in the evidence by evaluating factors such as study methods and study size.
What did we find?
The review includes 15 studies with 2348 women with PCOS. Ten trials compared recombinant FSH with urinary-derived gonadotropins. Three trials compared human menopausal gonadotropin with purified urinary follicle-stimulating hormone and one trial compared gonadotropins with continued clomiphene citrate.
Main results
There may be little or no difference in live birth, multiple pregnancy, clinical pregnancy, or miscarriage rate between purified urinary-derived gonadotropins and recombinant follicle-stimulating hormone. We are uncertain whether human menopausal gonadotropin improves pregnancy outcomes in women with PCOS compared to urinary follicle-stimulating hormone. We are uncertain whether any of the treatments reduce the risk of OHSS or ectopic pregnancy.
When compared to continued treatment with clomiphene citrate, gonadotropins probably result in more live births and pregnancies without increasing the rate of multiple pregnancies. Gonadotropins may result in more miscarriages than clomiphene citrate, while there were no cases of OHSS.
What are the limitations of the evidence?
Our confidence in the evidence ranged from very low to moderate. Many studies had small sample sizes and were conducted a long time ago, meaning important information about study methods was missing. Ten of the 15 studies included in this review reported a commercial sponsor. We did not take costs and convenience into account; we do encourage patients to discuss costs, convenience and unwanted effects with their healthcare provider.
How up to date is the evidence?
This is a review update. The evidence is current to March 2024.
There may be little or no difference in live birth, multiple pregnancy, clinical pregnancy, or miscarriage rates between rFSH and uFSH in women with PCOS. For HMG versus uFSH, we are uncertain whether one or the other improves or lowers rates of live birth, multiple pregnancy, clinical pregnancy, or miscarriage. We are uncertain whether any of the interventions reduce ectopic pregnancy or the incidence of OHSS. In women with clomiphene citrate failure, gonadotropins (FSH) probably result in more live births and clinical pregnancies than continued clomiphene citrate without increasing multiple pregnancies. Gonadotropins may increase the miscarriage rate per woman. We are uncertain if gonadotropins reduce ectopic pregnancy. None of the women developed OHSS.
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.
To compare the effectiveness and safety of gonadotropins as a second-line treatment for ovulation induction in women with PCOS who do not ovulate or conceive after clomiphene citrate or letrozole.
In March 2024, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO. We checked references of all relevant studies. We had no language or date restrictions.
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.
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.
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.
This Cochrane review had no dedicated funding.
Protocol (2012) https://doi.org/10.1002/14651858.CD010290
Review (2015) https://doi.org/10.1002/14651858.CD010290.pub2/full
Update (2019) https://doi.org/10.1002/14651858.CD010290.pub3