Gonadotropins for ovulation induction in women with polycystic ovary syndrome.

Rationale: 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 or letrozole, though induction protocols and types of gonadotropins used vary greatly.

Objectives: 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.

Search methods: 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.

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

Outcomes: We implemented the core outcome set for infertility. Our critical outcomes were live birth rate and multiple pregnancy rate per woman. Important outcomes were clinical pregnancy, pregnancy loss, incidence of ovarian hyperstimulation syndrome (OHSS) per woman, total gonadotropin dose, total duration of stimulation per woman, gestational age at birth, birthweight, neonatal mortality, and major congenital anomaly.

Risk of bias: We used the Cochrane RoB 1 tool to assess bias in the included studies.

Synthesis methods: Where meta-analysis was possible, we combined data using a fixed-effect model to calculate the risk ratio (RR) or mean difference. We summarised the overall certainty of evidence for the main outcomes using GRADE criteria.

Included studies: We included 15 studies with 2348 women. Ten trials compared rFSH with urinary-derived gonadotropins (one compared rFSH with human menopausal gonadotropin (HMG), and nine compared rFSH with urinary FSH). Three trials compared HMG with purified FSH (uFSH). One trial compared HP-FSH with purified FSH (uFSH) and one trial compared gonadotropins with continued clomiphene citrate.

Synthesis of results: Recombinant FSH (rFSH) versus urinary-derived gonadotropins There may be little or no difference in the birth rate between rFSH and urinary-derived gonadotropins (RR 1.21, 95% confidence interval (CI) 0.83 to 1.78; 5 RCTs, 505 participants; low-certainty evidence). This suggests that if the observed average live birth per woman who used urinary-derived gonadotropins is 16%, the chance of live birth with rFSH is between 13% and 28%. There may be little or no difference between groups in multiple pregnancy (RR 0.86, 95% CI 0.46 to 1.61; 8 RCTs, 1368 participants; low-certainty evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88 to 1.27; 8 RCTs, 1330 participants; low-certainty evidence), or miscarriage rate (RR 1.20, 95% CI 0.71 to 2.04; 7 RCTs, 970 participants; low-certainty evidence). We are uncertain whether rFSH reduces ectopic pregnancy (RR 2.81, 95% CI 0.12 to 67.90; 1 RCT, 151 participants; very-low certainty evidence) or the incidence of OHSS (RR 1.48, 95% CI 0.82 to 2.65; 10 RCTs, 1565 participants; very low-certainty evidence) when compared to urinary-derived gonadotropins. Human menopausal gonadotropin (HMG) versus purified urinary FSH (uFSH) When compared to uFSH, we are uncertain whether HMG improves live birth rate (RR 1.44, 95% CI 0.55 to 3.76; 2 RCTs, 79 participants), or reduces multiple pregnancy (RR 6.56, 95% CI 0.28 to 152.45; 3 RCTs, 102 participants). We are also uncertain whether HMG improves clinical pregnancy rate (RR 1.31, 95% CI 0.66 to 2.59; 3 RCTs, 102 participants), reduces miscarriage rate (RR 0.33, 95% CI 0.06 to 1.97; 2 RCTs, 98 participants), or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42 to 117.81; 2 RCTs, 53 participants) when compared to uFSH. No trials reported on ectopic pregnancy. The certainty of the evidence was very low for all outcomes. Gonadotropins versus continued clomiphene citrate Gonadotropins (FSH) probably result in more live births than continued clomiphene citrate (RR 1.24, 95% CI 1.05 to 1.46; 1 RCT, 661 participants; moderate-certainty evidence). This suggests that for a woman with a live birth rate of 41% with continued clomiphene citrate, the live birth rate with gonadotropins was between 43% and 60%. There may be little or no difference in multiple pregnancy between treatments (RR 0.89, 95% CI 0.33 to 2.44; 1 RCT, 661 participants; low-certainty evidence). Gonadotropins probably result in more clinical pregnancies than continued clomiphene citrate (RR 1.31, 95% CI 1.13 to 1.52; 1 RCT, 661 participants; moderate-certainty evidence), and may result in more miscarriages (RR 2.23, 95% CI 1.11 to 4.47; 1 RCT, 661 participants; low-certainty evidence). We are uncertain if there is a difference in ectopic pregnancy between the groups (RR 0.51, 95% CI 0.09 to 2.77; 1 RCT, 661 participants; very low-certainty evidence). None of the women developed OHSS. The main limitations were imprecision, inconsistency, and indirectness.

Authors' conclusions: 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.

Funding: This Cochrane review had no dedicated funding.

Registration: 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.