Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study

This European multicenter Phase III study, led by Ricardo Felberbaum and colleagues at the University of Lübeck, was the pivotal trial that established the multiple-dose protocol (0.25 mg/day) of the GnRH antagonist cetrorelix as the standard for preventing premature LH surge in controlled ovarian stimulation. 346 women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) were enrolled.

The protocol started with human menopausal gonadotropin (HMG) on day 2 or 3 of the cycle, and subcutaneous cetrorelix (0.25 mg/day) was introduced on stimulation day 6 — when follicles reach a size at which the risk of endogenous LH surge becomes clinically relevant. Injections continued until final ovulation induction with hCG.

Results confirmed protocol efficacy: 93.6% of patients reached follicular puncture, fertilization rate was approximately 60%, and ongoing clinical pregnancy rate was 24% per embryo transfer. The incidence of premature luteinization was only 0.9% — a dramatic reduction compared to protocols without hypophyseal suppression. Severe ovarian hyperstimulation syndrome (OHSS) occurred in only 0.6% of patients, demonstrating a favorable safety profile.

This work was fundamental for the regulatory approval of cetrorelix (Cetrotide®) in Europe and the United States. The multiple-dose protocol established by Felberbaum became the worldwide clinical standard for IVF/ICSI with GnRH antagonists, progressively replacing long agonist (downregulation) protocols — with advantages of shorter treatment duration, lower gonadotropin consumption, and reduced OHSS risk.