Safety of GnRH agonists and antagonists

The widespread application of protocols using gonadotropin-releasing hormone (GnRH) agonists or antagonists in assisted reproduction treatment has led to an increasing number of pregnancies exposed to these drugs. This issue has raised scepticism as to the safety of these medications, concerning both pregnant women and their offspring. The main parameters that can be studied to ensure the safety of GnRH analogues include: a) systemic and local reactions to the medication; b) incidence of ovarian hyperstimulation syndrome (OHSS); c) direct effect on oocytes and embryos; and d) the health of those children exposed. So far, no systemic side effects and no major local reactions have been reported following the use of GnRH agonists or third-generation antagonists. On the other hand, the incidence of OHSS seems to be higher with GnRH agonist protocols compared to conventional or GnRH antagonist protocols. The recent cloning of the GnRH receptor has led to the demonstration of GnRH receptor gene expression in the human ovary, although the existence of GnRH receptors per se remains controversial. Similarly, the potential direct effect of GnRH analogues on the follicles and oocytes remains a matter of debate. The incidence of miscarriage and the health of children born as a result of in vitro fertilisation (IVF) treatment do not appear to be influenced by the GnRH agonist treatment. This also seems to be the case for the GnRH antagonists, although the available information on this issue is still limited. Therefore, most of the accumulated data concerning the safety of the GnRH analogues are encouraging, and no serious side effects have been reported. On the other hand, as no definite conclusions about the safety of these drugs can be drawn until now, continued assessment of the aforementioned parameters in long-term follow-up studies is recommended.