Infertility: treatment and what GnRH peptide research shows

What is infertility and how many people does it affect?

The World Health Organization defines infertility as failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse, and estimates that approximately one in six people of reproductive age experience it in their lifetime¹. The WHO adds that assisted reproductive technologies remain largely unavailable, inaccessible and unaffordable in many parts of the world, particularly in low- and middle-income countries¹.

The American Society for Reproductive Medicine (ASRM) published an updated definition in 2023, replacing the 2020 version². The 2023 document is limited to defining infertility².

Causes and how infertility is diagnosed

Infertility is not a single diagnosis: it can stem from ovulatory, tubal, uterine or male factors, or be unexplained. Among ovulatory causes is polycystic ovary syndrome (PCOS), and the 2023 international guideline on its assessment and management specifically addresses ovulation induction⁵.

The ESHRE ovarian stimulation guideline includes pre-stimulation evaluation and pre-treatment therapies among its sections, which reflects that the starting point is individualised³.

Standard treatment today: what the guidelines recommend

Treatment depends on cause, age and duration of infertility. In women with PCOS and anovulation, the NICHD trial of 750 women compared letrozole with clomiphene: cumulative live births were higher with letrozole (27.5% versus 19.1%; rate ratio 1.44; 95% CI 1.10 to 1.87) as was the ovulation rate (61.7% versus 48.3% of cycles)⁶. The 2023 international PCOS guideline sets out the current recommendations for this indication⁵.

When simpler treatment is not enough, in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) is used, which require controlled ovarian stimulation. The guideline of the European Society of Human Reproduction and Embryology (ESHRE), updated in 2025, offers 121 recommendations: 4 on pre-stimulation evaluation, 7 on pre-treatment therapies, 50 on pituitary suppression and ovarian stimulation, 17 on monitoring, 18 on triggering of final oocyte maturation and luteal support, and 8 on prevention of ovarian hyperstimulation syndrome (OHSS)³. Its critical outcomes were cumulative live birth or live birth per started cycle and moderate or severe OHSS³.

The guideline is candid about its own foundation: of the evidence-based recommendations, none was supported by high-quality evidence, and for most newer interventions it formulated a recommendation against, or research-only, because of insufficient evidence³. The 2019 version already gathered the core recommendations on protocols and triggers⁴.

What peptide research has shown in ovarian stimulation

The reproductive axis is governed by GnRH, a hypothalamic decapeptide. Most peptides relevant to fertility act on this axis. The history of the class is in A century of therapeutic peptides and its use in another hormone-dependent disease in Endometriosis: treatment and the GnRH evidence.

GnRH antagonists (cetrorelix, ganirelix). These are approved synthetic peptides. The FDA labels for ganirelix and cetrorelix (Cetrotide) indicate them for inhibiting premature luteinizing hormone (LH) surges in women undergoing controlled ovarian stimulation⁹¹⁰. The best evidence is the 2016 Cochrane review: 73 trials and 12,212 participants comparing antagonists with the long agonist protocol. There was no conclusive difference in live birth (OR 1.02; 95% CI 0.85 to 1.23; moderate certainty), but a lower incidence of OHSS of any grade (OR 0.61; 95% CI 0.51 to 0.72; moderate certainty): if the risk with agonists is 11%, with antagonists it would be between 6% and 9%⁷. In exchange, cycle cancellation for poor ovarian response was higher with antagonists (OR 1.32; 95% CI 1.06 to 1.65)⁷.

GnRH agonists as the trigger. In antagonist cycles, GnRH agonists can also trigger final oocyte maturation instead of human chorionic gonadotropin (hCG). The 2014 Cochrane review (17 trials, 1847 women) found, in fresh autologous cycles, less OHSS with the agonist (OR 0.15; 95% CI 0.05 to 0.47) but also fewer live births (OR 0.47; 95% CI 0.31 to 0.70; moderate certainty) and more early miscarriage (OR 1.74)⁸. In oocyte donation cycles there was no difference in live birth (OR 0.92) and OHSS was less frequent⁸. The authors considered it could be useful for women who choose to avoid fresh transfer, oocyte donors, or fertility preservation⁸.

Kisspeptin-54. This is the endogenous peptide that stimulates hypothalamic GnRH release; it is covered in Kisspeptin: real science, wrong molecule?. In 2014, a study gave a single subcutaneous injection of kisspeptin-54 to 53 women undergoing IVF after stimulation with recombinant FSH and an antagonist: egg maturation was observed at every dose tested, fertilisation and embryo transfer occurred in 92% (49/53), and biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53)¹¹. There was no comparison group¹¹.

In 2017, a randomized, placebo-controlled phase 2 trial in 62 women at high risk of OHSS showed that a second dose of kisspeptin-54 at 10 hours raised the proportion with an oocyte yield of at least 60% from 45% (14/31) to 71% (21/31) (absolute difference +26%; 95% CI 2 to 50%; P = 0.042), with one case of moderate OHSS (3.2%) in the single-dose group and none in the double-dose group¹². The authors note that studies comparing kisspeptin-54 directly with established triggers are needed, and it was a single-centre study¹². A 2022 review describes this line of work as a potential novel trigger, not an established practice¹⁴, and a 2018 review frames it among novel concepts for inducing final oocyte maturation¹⁷.

MVT-602 (kisspeptin receptor agonist). In two randomized placebo-controlled trials in healthy women aged 18 to 35 (24 without stimulation, 75 with minimal stimulation), MVT-602 was safe and well tolerated, with an elimination half-life of 1.3 to 2.2 hours; ovulation occurred within 5 days in 75% to 100% depending on dose, versus 60% with placebo and 100% with triptorelin¹³. These are pharmacology data in healthy women, not live-birth data in infertile patients¹³.

Oxytocin antagonist (atosiban). Atosiban is a peptide that blocks the oxytocin receptor; it has been tested to reduce uterine contractions at embryo transfer. In a randomized, double-blind, placebo-controlled trial of 1,100 women with one previous implantation failure undergoing single frozen blastocyst transfer, live birth occurred in 49.5% with atosiban and 44.7% with placebo (difference 4.8%; 95% CI −1.1 to 10.7; RR 1.11; P = 0.10); the authors do not support routine use¹⁵. For oxytocin itself, see Intranasal oxytocin: anatomy of a replication crisis, a different topic.

Growth hormone as an adjuvant. It is a protein rather than a small peptide, but it is mentioned for its use in poor responders. The 2021 Cochrane review (16 trials, 1,352 women) rated the evidence low to very low certainty: in poor responders the live birth OR was 1.77 (95% CI 1.17 to 2.70; very low certainty) and the pregnancy OR 1.85 (95% CI 1.35 to 2.53; low certainty); in routine use the evidence was very uncertain (OR 1.32; 95% CI 0.40 to 4.43)¹⁶.

Safety: adverse effects and precautions

The ganirelix and cetrorelix labels contraindicate use in hypersensitivity to the drug or to any GnRH analogue, and in known or suspected pregnancy⁹¹⁰. They describe hypersensitivity reactions reported after marketing, including anaphylaxis on the ganirelix label and anaphylactoid reactions on the cetrorelix label⁹¹⁰. The ganirelix label says it should not be used by lactating women⁹, and the cetrorelix label contraindicates lactation¹⁰. In ganirelix trials, OHSS is among the reported adverse reactions (2.4%, 19 women), alongside vaginal bleeding, injection site reaction and nausea⁹.

The main risk of ovarian stimulation is OHSS, which depends on the response to gonadotropins more than on the suppressing peptide. The antagonist protocol reduces OHSS compared with the long agonist protocol⁷, and an agonist trigger reduces it further at the cost of fewer live births in fresh transfers⁸. With kisspeptin, trials in high-risk women reported very few OHSS cases, but sample sizes do not allow estimating rare risks¹².

Summary by agent

Frequently asked questions

How many people have infertility? The WHO estimates that approximately one in six people of reproductive age experience it in their lifetime¹.

Are there approved peptides in infertility treatment? Yes, in the context of ovarian stimulation: cetrorelix and ganirelix, peptide GnRH antagonists, carry the FDA label indication of inhibiting premature LH surges⁹¹⁰. Kisspeptin is not approved for this or any indication in the sources consulted.

Do GnRH antagonists improve live birth rates? There is no conclusive evidence of a difference compared with the long agonist protocol (OR 1.02; 95% CI 0.85 to 1.23); the demonstrated advantage is a lower incidence of OHSS (OR 0.61)⁷.

Can kisspeptin replace hCG to trigger ovulation? It has not been shown yet. The published trials are phase 2, single-centre and without a direct comparison against established triggers¹¹¹².

What is gained and lost with an agonist trigger? OHSS falls (OR 0.15) but, in fresh autologous cycles, there were fewer live births (OR 0.47)⁸; the authors consider it useful when fresh transfer is avoided⁸.

How much evidence supports current ovarian stimulation practice? The 2025 ESHRE guideline states that, of its evidence-based recommendations, none was supported by high-quality evidence³.