Direct ovarian effects and safety aspects of GnRH agonists and antagonists

In in-vitro fertilization programmes, gonadotrophin releasing hormone (GnRH) agonists are now routinely used in order to prevent the undesired pre-ovulatory spontaneous luteinizing hormone surge. The first publications are now appearing in which GnRH antagonists are used with the same purpose. More attention should be addressed to the safety aspects of these drugs. This review aims to summarize studies on direct ovarian effects of GnRH agonists and GnRH antagonists in non-primates and primates with respect to the functional and morphological aspects in-vitro as well as in-vivo. We conclude that there is a wide variety of functional and morphological effects of GnRH analogues on the ovary. The sometimes paradoxical effects indicate that a variety of factors may be involved in the various processes. Those factors are: (i) the type and dose of the analogue, (ii) the different regimens of administration, (iii) ovarian status at the time of exposure, (iv) ovarian cell types in in-vitro systems, (v) hormonal pre-treatment of these cultures, (vi) the type of hormonal stimulation added to the in-vitro culture, (vii) further methodological differences in the experiments and finally (viii) physiological variations in GnRH receptor abundance which depends on species and/or timing in the cycle. With the increasing number of patients using GnRH analogues in assisted reproduction treatments, there will be an increasing number of pregnancies exposed to these drugs. So far, there does not appear to be an increased risk of birth defects or pregnancy wastage in human pregnancies exposed to daily low-dose GnRH agonist therapy in the first weeks of gestation.