Cetrorelix

A synthetic decapeptide GnRH receptor antagonist — EU-authorised in 1999 and FDA-approved in 2000 — used to prevent premature LH surges during controlled ovarian stimulation, suppressing gonadotropins by competitive receptor blockade instead of the flare-then-downregulation route GnRH agonists take.

Also referenced as: Cetrorelix acetate, Cetrotide, Cetrorelix pamoate, AEZS-102, SB-75

What is Cetrorelix?

Cetrorelix is a synthetic decapeptide antagonist of the gonadotropin-releasing hormone (GnRH) receptor, supplied as the acetate salt. Its sequence — Ac-D-Nal(2)-D-Phe(4Cl)-D-Pal(3)-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2, molecular weight 1431.06 as the anhydrous free base — is native GnRH with five of ten positions replaced (1, 2, 3, 6, and 10). Every one of those five substitutions is a D-amino acid, which both resists enzymatic cleavage and converts the molecule from a receptor activator into a competitive blocker.

That reversal of sign is the entire point of the molecule. GnRH agonists such as gonadorelin, triptorelin, and leuprolide first stimulate the pituitary — the “flare” — and only suppress it after days of receptor downregulation. Cetrorelix occupies the same receptors without activating them, so gonadotropin output falls within hours and returns as the drug clears. It is marketed as Cetrotide for one indication: preventing premature luteinizing hormone surges in women undergoing controlled ovarian stimulation.

It turns up in research-compound catalogs mainly as the mechanistic mirror image of the GnRH agonists already circulating there, and because assisted-reproduction protocol drugs are expensive through licensed pharmacy channels.

How it works

• Competitive, non-activating occupancy of the pituitary GnRH receptor. Cetrorelix competes with endogenous GnRH for membrane receptors on gonadotrope cells and lowers LH and FSH release dose-dependently, with no initial stimulatory phase. In an early single-dose study in men, 25 normal subjects received 0.25, 0.5, 1.0, 1.5, or 3.0 mg and serum testosterone fell 25%, 24%, 41%, 53%, and 72% respectively within the first eight hours, with all effects reversible (Klingmüller et al., Acta Endocrinologica, 1993;128(1):15–18).
• D-citrulline at position 6 is what made the class usable. Earlier LHRH antagonists carrying basic D-amino acids at position 6 produced edematogenic reactions that blocked clinical use. Replacing that residue with a D-ureidoalkyl amino acid such as D-citrulline preserved potency — 100% inhibition of ovulation in cycling rats at 3 µg — while producing no edematogenic effect even at 1.5 mg/kg (Bajusz et al., PNAS, 1988;85(5):1637–1641). The lead compounds in that paper carried D-Trp at position 3, so they were close relatives rather than cetrorelix itself; the specific D-Pal(3) analog that became cetrorelix, then coded SB-75, was characterized in male rats two years later, where single doses of 25, 50, and 100 µg dropped testosterone to castration levels by six hours — though only the 100 µg dose held it in the castration range beyond 24 hours (Bokser et al., PNAS, 1990;87(18):7100–7104).
• Fast on; how fast off depends on the dose. Approved labeling puts the onset of LH suppression at roughly one hour for the 3 mg dose and two hours for the 0.25 mg dose, with about 85% subcutaneous bioavailability and peak concentrations at 1.0 hour (0.25 mg) to 1.5 hours (3 mg). Elimination is where the two strengths diverge sharply: terminal half-life is about 5 hours after a single 0.25 mg dose and 20.6 hours on repeated 0.25 mg dosing, but 62.8 hours after a single 3 mg dose, which is why one 3 mg administration establishes a duration of action of at least four days while the 0.25 mg dose must be repeated every 24 hours to maintain the effect. Suppression is occupancy-driven rather than desensitization-driven, so pituitary responsiveness recovers as concentrations fall — but “short-acting” describes the daily protocol, not the single-dose one (Cetrotide prescribing information; Reissmann et al., Human Reproduction Update, 2000;6(4):322–331).
• Leaving the pituitary responsive changes what else is possible. In agonist-suppressed cycles the pituitary cannot answer a GnRH stimulus; in antagonist cycles it can, so a GnRH agonist bolus can substitute for hCG as the ovulation trigger. A Cochrane review of 17 RCTs (n = 1,847) found that in fresh autologous cycles this cut mild, moderate, or severe OHSS sharply (OR 0.15, 95% CI 0.05 to 0.47; 8 RCTs, 989 women) but produced a lower live birth rate (OR 0.47, 95% CI 0.31 to 0.70; 5 RCTs, 532 women). The trade-off is specific to fresh transfer: in donor-recipient cycles there was no evidence of a live birth difference (OR 0.92, 95% CI 0.53 to 1.61; 1 RCT, 212 women) alongside the same drop in OHSS (Youssef et al., Cochrane Database of Systematic Reviews, 2014;2014(10):CD008046).

Research status

Cetrorelix has an approved indication with a solid randomized base behind it, and a well-documented record of failure everywhere else.

Approval. Cetrotide received EU marketing authorisation on April 12, 1999, and FDA approval on August 11, 2000 under NDA 021197 as a Type 1 new molecular entity. The U.S. indication is narrow and unchanged: inhibition of premature LH surges in women undergoing controlled ovarian stimulation. Generic entry began earlier than is usually reported: Teva’s ANDA was approved August 12, 2022 (since discontinued), three more followed in April 2024 (Qilu, Livzon, Gland), and further approvals landed in June 2025 (Xiromed) and April 2026 (Epic Pharma) — six abbreviated applications in all, five of them currently marketed.

Pivotal trials. The European Cetrorelix Study Group randomized 188 patients to cetrorelix and 85 to the agonist buserelin during IVF/ICSI stimulation: 96.3% of the cetrorelix group and 90.6% of the buserelin group reached the day of hCG administration, cetrorelix cycles required significantly fewer hMG ampoules and fewer stimulation days (P < 0.01), and a rise in LH and progesterone occurred in 3 of 188 patients (1.6%). Fertilization, cleavage, and pregnancy rates were similar between arms (Albano et al., Human Reproduction, 2000;15(3):526–531). A parallel French multicenter study tested the single 3 mg late-follicular dose against depot triptorelin in 115 versus 39 patients: no LH surge occurred in any cetrorelix patient, stimulation length, hMG use, and OHSS were lower, but the cetrorelix group produced fewer oocytes and embryos, with pregnancy rates not statistically different (Olivennes et al., Fertility and Sterility, 2000;73(2):314–320).

The class-level evidence. The 2016 Cochrane review pooled 73 RCTs and 12,212 participants comparing GnRH antagonist protocols to the long agonist protocol. Live birth showed no conclusive difference (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs, n = 2,303, moderate-quality evidence), while any-grade OHSS was lower with antagonists (OR 0.61, 95% CI 0.51 to 0.72; 36 RCTs, n = 7,944). Miscarriage was unchanged (OR 1.04, 95% CI 0.82 to 1.30; 33 RCTs, n = 7,022). The result is genuinely two-sided: cancellation for OHSS risk fell (OR 0.47, 95% CI 0.32 to 0.69; 19 RCTs, n = 4,256) but cancellation for poor ovarian response rose (OR 1.32, 95% CI 1.06 to 1.65; 25 RCTs, n = 5,230) (Al-Inany et al., Cochrane Database of Systematic Reviews, 2016;4(4):CD001750). Earlier versions of this same review had reported lower pregnancy rates with antagonists, so citations to “the Cochrane review” can mean materially different conclusions depending on the year.

A failed Phase 3 program in benign prostatic hyperplasia. AEterna Zentaris developed an intramuscular cetrorelix pamoate depot (AEZS-102) for BPH on the rationale that partial androgen suppression could shrink the prostate. Three Phase 3 studies ran from 2007 to 2010. NCT00449150 enrolled 667 patients and is listed as terminated, with the registry recording the reason as failure to meet the primary efficacy endpoint in the double-blind phase. NCT00663858 enrolled 420 patients and posted its results: mean International Prostate Symptom Score change was −6.2 for the cetrorelix 78 + 78 mg arm, −5.1 for 78 mg plus placebo, and −5.7 for placebo alone, with the high-dose versus placebo comparison at p = 0.371 — placebo improved about as much as drug. An open-label safety study (NCT00670306, 528 patients) completed in 2009. No approval followed, and the indication was abandoned.

Exploratory work that never advanced. An open, uncontrolled series gave cetrorelix to 18 premenopausal women with uterine leiomyomas who were candidates for hysterectomy; 16 showed progressive shrinkage, with mean uterine volume falling from 410.4 ± 77.1 mL to 230.8 ± 52.6 mL at three months, while every patient became amenorrheic and had hot flushes (Gonzalez-Barcena et al., Human Reproduction, 1997;12(9):2028–2035). There was no control arm and no follow-on program. Cetrorelix was also reviewed as a candidate in prostate cancer, ovarian cancer, and endometriosis (Reissmann et al., 2000). None of these produced a registered indication.

Where the field is now. ClinicalTrials.gov lists 139 studies naming cetrorelix as an intervention (August 2026), and they are overwhelmingly reproductive — roughly 75 return under infertility, 34 under IVF, 14 under polycystic ovary syndrome, and 11 under ovarian hyperstimulation syndrome (those condition categories overlap heavily), against only 3 in benign prostatic hyperplasia. Current work largely compares antagonist protocols against progestin-primed ovarian stimulation rather than opening new indications, alongside formulation research on non-injectable routes (for example nasal hydrogel and oleogel systems, Wissel et al., European Journal of Pharmaceutical Sciences, 2026;220:107482). There is no approved indication in men.

Common dosage forms

• Prescription single-dose kit (0.25 mg) — sterile lyophilized powder in a glass vial, packaged with a 1 mL prefilled syringe of Sterile Water for Injection plus a 20-gauge and a 27-gauge needle, reconstituted immediately before subcutaneous use. Mannitol is an excipient in the powder.
• 3 mg single-dose vial — the higher single-administration strength studied in the original program. FDA application records list this strength as discontinued, leaving 0.25 mg as the marketed U.S. presentation.
• Generic cetrorelix acetate, 0.25 mg per vial — every approved abbreviated application is for the 0.25 mg strength, so the licensed U.S. supply has not been brand-only since 2022.
• EU presentation — powder and solvent for solution for injection at 0.25 mg, the same strength and route as the U.S. product.
• Investigational intramuscular depot — cetrorelix pamoate, given in the BPH trials as 52 mg at week 0 followed by 26 mg at week 2, a 78 mg treatment course. This formulation has no approved counterpart anywhere.
• Research-market vials — lyophilized powder for reconstitution, with the labeled quantity set by the supplier rather than by the 0.25 mg unit of the licensed product, and without the matched diluent, needles, and release testing that come with the pharmaceutical kit.

This section describes formats only and is not dosing guidance.

Key considerations

• This is a licensed prescription drug, not an unregulated compound. Cetrotide has been FDA-approved since 2000 and has had approved generics since 2022. Its labeling directs that it be prescribed by physicians experienced in fertility treatment, requires that pregnancy be excluded before treatment starts, and contraindicates use in known or suspected pregnancy, in lactation, in severe renal impairment, and in hypersensitivity to cetrorelix acetate, extrinsic peptide hormones, mannitol, or GnRH and other GnRH analogs. It is not intended for people aged 65 and over. Research-market supply sits entirely outside that framework.
• The mechanism runs opposite to most hormone peptides sold alongside it. Gonadorelin is native GnRH and triptorelin and leuprolide are agonist analogs of it — all three activate the receptor cetrorelix blocks; hCG acts one step downstream as an LH-receptor agonist. Cetrorelix suppresses LH and FSH within hours of a single dose — in men, up to a 72% drop in testosterone at 3 mg (Klingmüller et al., 1993). Treating it as interchangeable with an agonist, or combining the two, inverts the intended endocrine effect rather than reinforcing it.
• The evidence base is deep but extremely narrow. Seventy-three randomized trials support the antagonist protocol in controlled ovarian stimulation. Outside that setting the record is a terminated Phase 3 program in BPH where placebo matched drug, plus small exploratory series in fibroids and oncology that never advanced. Depth in one indication is not evidence for any other.
• Naming is unusually crowded in this class. Ganirelix is the other injectable peptide GnRH antagonist approved for the same IVF indication (U.S. approval July 29, 1999, NDA 021057). Degarelix (Firmagon, approved December 24, 2008) is the GnRH antagonist approved for prostate cancer — a different decapeptide, not a cetrorelix presentation. Relugolix (Orgovyx, December 18, 2020; and Myfembree, May 26, 2021, a relugolix/estradiol/norethindrone combination) and elagolix (Orilissa, July 23, 2018) are oral small-molecule antagonists, not peptides at all. Cetrorelix itself also appears as SB-75 in the founding literature and as AEZS-102 for the pamoate depot. The umbrella phrase “GnRH analog” covers agonists and antagonists together and hides exactly the distinction that matters.
• Labeled safety signals, with an attribution caveat. In a 949-patient controlled ovarian stimulation safety population, ovarian hyperstimulation syndrome was reported in 3.5%, nausea in 1.3%, and headache in 1.1%; transient ALT, AST, GGT, and alkaline phosphatase elevations up to three times the upper limit of normal occurred in 1–2%. Hypersensitivity reactions including anaphylactoid reactions have been reported, and labeling advises against use in women with severe allergic conditions. Note that OHSS is a complication of the gonadotropin stimulation cetrorelix accompanies rather than of cetrorelix itself — the class-level data show antagonist protocols lowering OHSS risk, not raising it.