Key messages
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Live births are probably slightly decreased with recombinant follicle-stimulating hormone (rFSH) compared to purified (HMG) or highly purified (HP-HMG) human menopausal gonadotropin, but probably increased with rFSH compared to biosimilars (manufactured gonadotropins). There is probably little to no difference in live births between rFSH and purified follicle-stimulating hormone (FSH-HP) or follitropin delta. Clinical pregnancy is probably decreased with rFSH compared to HMG/HP-HMG but probably increased with rFSH compared to biosimilars. There is probably little to no difference in clinical pregnancy with rFSH compared with FSH-HP and follitropin delta.
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OHSS is probably higher with rFSH compared to HMG/HP-HMG and follitropin delta, but there is probably little to no difference with rFSH compared to FSH-HP, and there may be little or no difference with rFSH compared to biosimilars.
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Future research should focus on frozen embryos and cumulative outcomes across multiple frozen embryo transfer cycles to give a more complete picture of treatment effectiveness. Strategies for the prevention and management of OHSS should be prioritised.
What is in vitro fertilisation?
In vitro fertilisation (IVF) is a type of fertility treatment. Ovarian stimulation helps women’s ovaries produce more eggs, which are collected, fertilised and transferred back to the woman. Various hormones, including gonadotropins, are used to stimulate the ovaries:
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purified human menopausal gonadotropin (HMG) and highly purified (HP-HMG);
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purified follicle-stimulating hormone (FSH-P) or highly purified follicle-stimulating hormone (FSH-HP);
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recombinant follicle-stimulating hormone (rFSH) was developed in a laboratory to obtain higher purity of the hormone;
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follitropin delta was developed to work in a more personalised way; and
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'biosimilars' are manufactured to offer similar results to rFSH at a potentially lower cost.
Ovarian hyperstimulation syndrome (OHSS) is an unwanted and sometimes serious effect of IVF, in which the ovaries swell and fluid can leak into the abdomen.
What did we want to find out?
We wanted to know which gonadotropin produced more live births, caused less OHSS, and led to more 'clinical' pregnancies, confirmed by ultrasound.
What did we do?
We searched for studies that compared one type of gonadotropin with another for women undergoing IVF. Studies could use fresh or frozen embryos.
What did we find?
We included 59 studies with a total of 18,119 women undergoing fertility treatment in a clinic.
rFSH versus HMG/HP-HMG (17 studies, 5639 women)
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Live births probably decrease with rFSH compared to HMG/HP-HMG. If the chance of live birth with HMG/HP-HMG is 28%, then the chance of live birth with rFSH is between 22% and 27%.
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OHSS is probably higher with rFSH compared to HMG/HP-HMG. If the risk of OHSS with HMG/HP-HMG is 2.6%, then the risk of OHSS with rFSH is between 2.9% and 4.7%.
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Clinical pregnancies probably decrease with rFSH compared to HMG/HP-HMG.
rFSH versus FSH-HP (23 studies, 4612 women)
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There is probably little to no difference in live births between rFSH and FSH-HP. If the chance of a live birth with FSH-HP is 27%, then the chance of a live birth with rFSH is between 24% and 31%.
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There is probably little to no difference in OHSS with rFSH compared to FSH-HP. If the risk of OHSS with FSH-HP is 2.5%, then the risk of OHSS with rFSH is between 1.7% and 3.8%.
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There is probably little to no difference in clinical pregnancy between rFSH and FSH-HP.
rFSH versus follitropin delta (7 studies, 3614 women)
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There is probably little or no difference in live births between rFSH and follitropin delta. If the chance of achieving a live birth with follitropin delta is 29%, the chance of a live birth with rFSH is between 24% and 30%.
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OHSS is probably higher with rFSH. If the risk of OHSS with follitropin delta is 4.4%, then the risk with rFSH is between 5.1% and 9.2%.
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There is probably little or no difference in clinical pregnancy between rFSH and follitropin delta.
rFSH versus biosimilars (8 studies, 2870 women)
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Live birth is probably higher with rFSH compared to biosimilars. If the chance of achieving a live birth with biosimilars is 23%, the chance of a live birth with rFSH is between 25% and 32%.
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There may be little or no difference in OHSS between rFSH and biosimilars. If the chance of OHSS with biosimilars is 9.6%, the chance of OHSS with rFSH is between 5.7% and 10%.
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Clinical pregnancy is probably higher with rFSH compared to biosimilars.
What are the limitations of the evidence?
The results mainly reflect IVF cycles with the transfer of a fresh embryo, so the results may be different for frozen embryos. Many studies were sponsored by pharmaceutical companies that manufacture the hormones in question, which could have affected the results. Furthermore, although we excluded some studies by using an integrity checklist, we have some concerns about the trustworthiness of the data from several of the studies.
How up to date is the evidence?
This updates a review previously published in 2011. The evidence is current to March 2025.
Read the full abstract
Several systematic reviews compared recombinant gonadotrophin with urinary gonadotrophins (HMG, purified FSH, highly purified FSH) for ovarian hyperstimulation in IVF and ICSI cycles and these reported conflicting results. Each of these reviews used different inclusion and exclusion criteria for trials. Our aim in producing this review was to bring together all randomised studies in this field under common inclusion criteria with consistent and valid statistical methods.
Objectives
To compare the effectiveness and safety of recombinant follicle-stimulating hormone (rFSH) with the three main types of urinary gonadotropins, rFSH derived from a human cell line (follitropin delta) and rFSH biosimilars for ovarian stimulation in women undergoing IVF or ICSI treatment cycles.
Search strategy
We carried out an extensive search on 31 March 2025, according to Cochrane guidelines. The databases searched included: the Cochrane Gynaecology and Fertility Specialised Register of controlled trials, CENTRAL, MEDLINE and Embase. We also searched trials registries, reference lists and contacted experts in the field for additional studies.
Selection criteria
All randomised controlled trials reporting data comparing clinical outcomes for women undergoing IVF/ICSI cycles and using recombinant FSH in comparison with HMG or highly purified HMG, purified urinary FSH (FSH-P), and highly purified urinary FSH (FSH-HP) for ovarian hyperstimulation in IVF or ICSI cycles were included.
Data collection and analysis
Data selected by three reviewers (MvW, IK, and AV). Data extraction and risk assessment done by four reviewers (MvW, IK, AB and AV). Primary outcome measure was live birth rate and OHSS per randomised woman. Binary outcomes were analysed using odds ratios and also reported in absolute terms. Grouped analyses were carried out for all outcomes to explore whether relative effects differed due to key features of the trials.
Main results
We included 42 trials with a total of 9606 couples. Comparing rFSH to all other gonadotrophins combined, irrespective of the down-regulation protocol used, did not result in any evidence of a statistically significant difference in live birth rate (28 trials, 7339 couples, odds ratio (OR) 0.97, 95% CI 0.87 to 1.08). This suggests that for a group with a 25% live birth rate using urinary gonadotrophins the rate would be between 22.5% and 26.5% using rFSH. There was also no evidence of a difference in the OHSS rate (32 trials, 7740 couples, OR 1.18, 95% CI 0.86 to 1.61). This means that for a group with 2% risk of OHSS using urinary gonadotrophins, the risk would be between 1.7% and 3.2% using rFSH.
When different urinary gonadotrophins were considered separately, there were significantly fewer live births after rFSH than HMG (11 trials, N=3197, OR 0.84, 95% CI 0.72 to 0.99). This means that for a live birth rate of 25% using HMG, use of rFSH instead would be expected to result in a rate between 19% and 25%. There was no evidence of a difference in live births when rFSH was compared with FSH-P (5 trials, N=1430, OR 1.26, 95% CI 0.96 to 1.64) or when rFSH was compared with FSH-HP (13 trials, N=2712; OR 1.03, 95% CI 0.86 to 1.22).
Authors' conclusions
Live birth and clinical pregnancies are probably lower with rFSH compared to HMG/HP-HMG, while OHSS is probably higher with rFSH when compared to HMG/HP-HMG. There is probably little to no difference in live birth, clinical pregnancy, or OHSS between rFSH and FSH-HP. When compared with follitropin delta, there is probably little or no difference in live birth or clinical pregnancy, while OHSS is probably higher with rFSH. When compared with biosimilars, live birth and clinical pregnancies are probably higher with rFSH, while there may be little or no difference in OHSS.
Funding
This Cochrane review had no dedicated funding.
Registration
Protocol (2005) https://doi.org/10.1002/14651858.CD005354
Review (2011) https://doi.org/10.1002/14651858.CD005354.pub2
