Gonadotrophin-releasing hormone antagonists: will they replace the agonists?

Modern gonadotrophin-releasing hormone (GnRH) antagonists such as cetrorelix and ganirelix reliably prevent premature LH surges in controlled ovarian hyperstimulation for assisted reproductive technologies. Cetrorelix and ganirelix are safe and effective compounds. Because of their distinct pharmacological mode of action, it has been possible to achieve a significant reduction of treatment time. Fertilization and pregnancy rates are comparable to those obtained in agonist protocols for ovarian stimulation. No allergic or hyperergic reactions have been reported, and patient compliance is excellent. The fact that GnRH antagonists allow an immediate suppression of gonadotrophin concentrations while preserving pituitary responsiveness to endogenous GnRH provides enormous flexibility in treatment. GnRH antagonists have helped to overcome some major disadvantages of GnRH agonists, especially of the long protocol, which is currently the standard protocol for ovarian stimulation. The mistaken administration of antagonists during early pregnancy is not possible, since they are only administered during ovarian stimulation when a premature LH surge may be imminent. They are used in the spontaneous cycle or after pretreatment with oral contraceptives. Pregnancy can easily be ruled out by testing for human gonadotrophic hormone before onset of gonadotrophin stimulation on the second or third day of the cycle. Since flare-up effects are absent, there is no risk of cyst formation. Hormonal withdrawal symptoms are eliminated, since no period of pituitary suppression occurs, and therefore exogenous gonadotrophins are not required. Overall, the duration of the stimulation cycle is as short as a normal menstrual cycle. The procedure seems to be safer than the long protocol, since the most serious complication, the occurrence of severe cases of OHSS, is reduced. It is also safe with respect to the course of pregnancies and the health of offspring. Both protocols developed so far, the single dose and multiple dose antagonist protocol, are comparable, utilizing data from the large prospective phase IIIb studies. Although several studies have indicated a slight reduction in pregnancy rate with GnRH antagonists as compared with agonists, this problem may be rectified by developing flexible antagonist regimens designed for individual patients. Introducing flexible GnRH antagonist regimens should be the area of research in the near future.