Cetrorelix

Origin and structure

Cetrorelix is a GnRH antagonist: a synthetic peptide that occupies the pituitary receptor for gonadotrophin-releasing hormone (GnRH, also called LHRH or gonadorelin) without switching it on. It was first described in 1988 by a team around the peptide chemist S. Bajusz at Andrew Schally's Endocrine, Polypeptide and Cancer Institute in New Orleans. Earlier antagonists could cause swelling and histamine release, and in rats fatal breathing problems. The new series, with a neutral D-citrulline at position 6, was free of those toxic effects, and one of its members, coded SB-75, became cetrorelix.

Like natural GnRH it is ten amino acids long, but five of them are D-amino acids and the residues at positions 1, 2, 3, 6 and 10 differ from the natural hormone: Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2, formula C70H92ClN17O14, molar mass about 1431 g/mol. The German company ASTA Medica applied for the EU licence in February 1998, when the product was not licensed anywhere in the world. Today the EU licence for Cetrotide is held by Merck Europe B.V. in Amsterdam and the US one by EMD Serono.

Cetrotide is a freeze-dried powder that is dissolved in the water supplied with it just before an injection under the skin. A higher-strength single-dose version, meant to cover about four days, was part of the original licence; it was removed from the EU licence in 2014 and is discontinued in the US. Ceziboe, from Sun Pharmaceutical, contains the same daily strength as a ready-to-use solution in a pre-filled syringe.

How it works

In a natural cycle the hypothalamus releases GnRH in pulses and the pituitary answers with LH and FSH. Around mid-cycle, rising oestradiol from the growing follicle sets off a large LH surge, which makes the follicle release its egg and turns it into a corpus luteum. During ovarian stimulation for IVF many follicles grow at once and oestradiol climbs fast, so the surge can come too early. The eggs may then be released before the clinic can collect them, and the cycle may have to be cancelled.

Cetrorelix competes with GnRH for its receptor and blocks it. According to the US label, LH starts to fall about one to two hours after an injection, FSH less so, and there is no initial release of hormones as with GnRH agonists. The block lasts only while the drug is present: it is kept up by daily injections and is fully reversible once they stop. After an injection under the skin about 85% reaches the blood, and the EU product information gives a terminal half-life of about 30 hours.

That speed changed how IVF is organised. In the older long protocol a GnRH agonist such as triptorelin or buserelin is started in the second half of the previous cycle and given until the pituitary is desensitised, before stimulation can begin. In an antagonist protocol stimulation with FSH or hMG starts at the beginning of the cycle and the antagonist is added only after several days, when a premature surge becomes possible. Because the pituitary itself is not desensitised, the final maturation of the eggs can then be triggered either with hCG or with a single dose of a GnRH agonist such as triptorelin, which lowers the risk of ovarian hyperstimulation; our triptorelin article covers that evidence.

Cetrorelix belongs to a small group of GnRH antagonists. Ganirelix is used in the same way in IVF, while degarelix, by injection, and relugolix, by mouth, are used to lower testosterone in prostate cancer.

Is cetrorelix approved?

Yes, for a single purpose. In the EU it is authorised to prevent premature ovulation in women having controlled ovarian stimulation followed by egg retrieval and assisted reproduction; the US label speaks of inhibiting premature LH surges in women undergoing controlled ovarian stimulation. Neither label covers men or any other condition.

In the Netherlands cetrorelix is prescription-only, and the product information reserves prescribing for specialists experienced in fertility treatment. Besides Cetrotide, with its central EU licence, the register holds Ceziboe, which the CBG registered on 9 December 2020 after a decentralised procedure led by the Netherlands. Because both products are simple watery solutions at the moment of injection, the regulators accepted Ceziboe without a separate bioequivalence study. Since 1 January 2014 cetrorelix, like the other fertility hormones, has been paid for as part of hospital fertility care instead of through the pharmacy reimbursement system (GVS).

We do not sell cetrorelix, and this article describes the licensed medicines only. Cetrorelix offered as a laboratory chemical has no marketing authorisation, is not made under a medicines licence and may not be used in people.

• EU: the European Commission authorised Cetrotide on 13 April 1999, as a daily injection and a single-dose strength, making it the first GnRH antagonist on the EU market. The single-dose strength was removed from the licence in 2014. In August 2022 a letter to healthcare professionals warned of a temporary shortage; EMA's shortage page, last updated in February 2023, lists it as resolved.
• US: the FDA approved Cetrotide on 11 August 2000 (NDA 021197); ganirelix had been approved a year earlier, on 29 July 1999. The single-dose strength is discontinued. The first generic cetrorelix was approved on 12 August 2022, and five more followed between April 2024 and April 2026.
• Sport: the WADA Prohibited List 2026 does not name cetrorelix or any GnRH antagonist. Its class S2.2.1 bans GnRH and its agonist analogues in men, because they stimulate testosterone production.

What the research shows

Most of the research on cetrorelix is in IVF, where it is compared with other ways of preventing a premature surge rather than with no treatment. Most of the registration trials were open-label, because of the way the treatments are given. The main findings:

• Registration trials (EMA assessment): nine phase 2 and 3 studies gave cetrorelix to 878 women. In the three main studies, which evaluated 770 women, more than 95% of those on cetrorelix had no premature LH surge or reached the day of the hCG trigger, much the same as on buserelin nasal spray or a triptorelin depot. The pregnancy rate was lower, 23% of 649 women on cetrorelix against 32% of 121 on the agonists. The EU committee discussed that gap with the company at a hearing in December 1998; it could not be tested statistically, centres and the women's baseline prognosis differed, and the committee judged the results in line with published data for agonist protocols.
• Head to head in those trials: against buserelin, 96.3% of 188 women on daily cetrorelix and 90.6% of 85 on buserelin reached the day of the hCG trigger, after a mean 5.7 days of cetrorelix. Against a triptorelin depot, 97.4% of 115 women given the single dose and 97.2% of 36 on triptorelin were counted as responders; stimulation was shorter on cetrorelix (9.4 against 10.7 days) and needed fewer ampoules of hMG (24.3 against 35.6).
• Cochrane review (2016), covering cetrorelix and ganirelix: 73 randomised trials with 12,212 women compared antagonist protocols with the long agonist protocol. Live birth showed no clear difference (odds ratio 1.02, 95% CI 0.85 to 1.23; 12 trials, 2,303 women): an assumed 29% on an agonist corresponds to 25 to 33% on an antagonist. Ovarian hyperstimulation syndrome was less frequent (odds ratio 0.61, 95% CI 0.51 to 0.72; 36 trials, 7,944 women), an assumed 11% falling to 6 to 9%. Cycles were cancelled less often for a threat of OHSS (odds ratio 0.47) but more often for a poor response (odds ratio 1.32). The authors rated the evidence moderate quality.
• Guideline: the European Society of Human Reproduction and Embryology (ESHRE) recommends the GnRH antagonist protocol over agonist protocols for the general IVF and ICSI population, given comparable efficacy and higher safety. It is a strong recommendation, first made in 2019 and kept in the 2025 update.
• Cetrorelix against ganirelix (Fertil Steril 2005): 185 women at 16 US clinics were randomised to a single cetrorelix injection or daily ganirelix once the leading follicle reached 14 mm. No woman in either group had a premature LH surge, and pregnancy and other IVF results did not differ significantly; cetrorelix needed fewer injections.
• Starting day (Hum Reprod 2013): a multicentre trial led from UMC Utrecht randomised 617 women to start daily Cetrotide on cycle day 2, together with FSH, or on the usual day 6. Starting early brought no benefit: 21.5% against 24.0% had a live birth after the fresh cycle, and 26.7% against 29.9% when frozen embryos were included, differences that were not significant. The trial stopped early, and the authors concluded that the extra injections were not justified.

Tested beyond IVF

Because it lowers sex hormones quickly, cetrorelix was also tried outside fertility care, at much higher doses and as a slow-release salt. In animal studies cited in the EU assessment it slowed the growth of breast tumours in rat and mouse models, but none of the work in people led to an approval. The largest programme was in men with an enlarged prostate:

• Enlarged prostate (BPH): Aeterna Zentaris ran three phase 3 studies of cetrorelix pamoate injected into the muscle. In the placebo-controlled trial run mainly in the US and Canada (667 men) the symptom score (IPSS) fell by 4.0 and 3.7 points on two cetrorelix schedules after a year and by 3.8 points on placebo; the trial was stopped because it missed its main goal.
• The placebo-controlled European trial (420 men, at 54 centres including nine in the Netherlands, from Amsterdam and Leiden to Maastricht and Winterswijk) found falls of 6.2 and 5.1 points against 5.7 on placebo, and neither cetrorelix schedule differed significantly from placebo. A third, open-label study in 528 men had no control group.
• High doses: the US label notes that single doses far above the IVF dose, given to patients treated for other conditions, caused no signs of overdose, and it records one severe anaphylactic reaction after seven months of daily treatment in a study unrelated to infertility.

Side effects and warnings

In IVF trials cetrorelix was well tolerated, and most side effects are local. Redness, swelling and itching at the injection site were seen in 9.4% of women given the daily injections in clinical trials, usually mild and short-lived. Nausea and headache are uncommon; in the trial data from 949 women summarised in the US label they were reported by 1.3% and 1.1%. Mild to moderate ovarian hyperstimulation syndrome is common, but the product information counts it as a risk of the stimulation itself rather than of cetrorelix; in the same data 3.5% had moderate or severe OHSS. Liver enzymes rose to at most three times the upper limit of normal in 1 to 2% of women, of unclear significance.

The serious risk is allergy. Systemic allergic and pseudo-allergic reactions, including life-threatening anaphylaxis, are uncommon and have occurred with the first dose. That is why the first injection is given under medical supervision, and the product information advises 30 minutes of observation afterwards. When the EMA reviewed the early post-marketing reports, all cases had a history of allergic predisposition, and the product information advises against use in women with severe allergic conditions.

Cetrorelix may not be used in pregnancy, while breastfeeding or with severe kidney impairment, and it has not been studied in liver or kidney disease. Given to pregnant rats and rabbits it caused loss of the embryos, a direct result of the hormone suppression. Follow-up of 316 children born after treatment with cetrorelix did not suggest more birth defects, although these data are limited. Outside IVF it lowers oestrogen in women, with hot flushes and withdrawal bleeding, and testosterone in men, with hot flushes and impotence reported in an early prostate study.

Frequently asked questions

Is Cetrotide available and reimbursed in the Netherlands?

Yes, on prescription, through a fertility clinic. Cetrotide and the ready-to-use Ceziboe are registered in the Netherlands to prevent premature ovulation during IVF or ICSI. Since 1 January 2014 cetrorelix, like the other fertility hormones, has been paid for as part of the hospital's fertility treatment rather than through the pharmacy and the GVS. We do not sell cetrorelix.

What is the difference between cetrorelix and ganirelix (Orgalutran)?

Both are GnRH antagonists given as daily injections during IVF, in the same way. Cetrotide is a powder that is mixed with water just before the injection, whereas Orgalutran and the generic ganirelix products are ready-to-use solutions; Ceziboe now offers cetrorelix ready to use as well. In a randomised trial of 185 women in the US, no premature LH surge occurred with either a single 3 mg dose of cetrorelix or daily ganirelix, and pregnancy rates did not differ significantly. Cetrotide reached the EU market first, in 1999, while in the US ganirelix was approved a year before Cetrotide.

How does the antagonist protocol differ from the long protocol in IVF?

In the long protocol a GnRH agonist is started in the second half of the previous cycle and shuts the pituitary down before stimulation begins. In the antagonist protocol stimulation starts at the beginning of the cycle and an antagonist such as cetrorelix is added after several days, because it works within hours. A Cochrane review of 73 trials found similar live-birth rates and less ovarian hyperstimulation with antagonists, and the ESHRE guideline recommends the antagonist protocol for the general IVF and ICSI population.

Is cetrorelix banned in sport?

It is not named on the WADA Prohibited List 2026. Class S2.2.1 bans, for men only and at all times, GnRH and its agonist analogues, such as buserelin, leuprorelin and triptorelin, as testosterone-stimulating peptides. Cetrorelix is an antagonist that lowers LH and testosterone instead, and GnRH antagonists are not mentioned anywhere on the list. The Dutch translation of the list by the Dopingautoriteit carries the same wording.

Does cetrorelix lower testosterone in men?

Yes. In studies in healthy men it lowered LH, FSH and testosterone in a dose-related way, and at higher doses testosterone fell to castrate levels. It has no approved use in men: it was tested for an enlarged prostate, but two placebo-controlled phase 3 trials found no benefit over placebo, and hot flushes and impotence were reported in an earlier prostate study.

What are the side effects of Cetrotide?

Mostly reactions at the injection site: redness, swelling or itching, seen in 9.4% of women in clinical trials and usually mild. Nausea and headache are uncommon. Mild to moderate ovarian hyperstimulation syndrome is common during IVF stimulation, but it is counted as a risk of the stimulation itself. The uncommon but serious risk is a severe allergic reaction, which has occurred with the first dose; that is why the first injection is given under medical supervision.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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