An Eye to the Future

Ovarian hyperstimulation syndrome represents the most serious iatrogenic complication of ovarian stimulation. The preponderance of scientific evidence has demonstrated that the syndrome arises as a consequence of the elaboration of inflammatory and hyperpermeability intermediates by the multifollicular-hyperstimulated ovary after the ovulatory trigger (with rare exceptions related to polymorphisms of the follicle-stimulating hormone receptor).

Our understanding of the pathophysiology of this fascinating, albeit dangerous, syndrome has allowed us to approach its prevention and treatment rationally. We must recognize that, thus far, our employment of gonadotropin dosage has relied on empirical observations and experience rather than scientific paradigms. Future development and prospective studies should strive to develop patient specific stimulation protocols. This will minimize inadvertent excessive drug intake. Other strategies should aim at reducing the ovulatory trigger and directly blocking the hyperpermeability factors (vascular endothelial growth factor) before they can exert their biological impact. Because hyperpermeability, angiogenesis, and inflammation are all involved in both the ovulatory and implantation process, we must seek to block the elusive postreceptor intermediates that will obviate ovarian hyperstimulation syndrome (OHSS) while not interfering with implantation. At the present time, gonadotropin-releasing hormone (GnRH) antagonist based stimulation protocols along with low-dose gonadotropins and GnRH agonist triggering of final oocyte maturation appear to be the safest alternative for the high-risk patient. Research should continue to refine the methods of luteal phase support that can provide the best outcomes in this setting. The addition of a small dose of human chorionic gonadotropin (hCG) to the GnRH-agonist trigger appears promising, although the amount of hCG that will result in partial rescue of corpus luteum function without risking OHSS still needs to be defined. With a similar rationale, small doses of recombinant luteinizing hormone administered during the luteal phase may mitigate the luteolytic effects of the GnRH-agonist trigger. With improving methods of in vitro maturation of both immature oocytes and even follicles, a day may come when the patient at high risk of OHSS will not need to undergo ovarian stimulation. Until these goals are achieved, we should use those stimulation protocols that have been shown to minimize the risk of developing OHSS.

All in all, one can say that we have already made great progress in preventing if not eliminating OHSS.