Future use of clomiphene in ovarian stimulation

Although the first in-vitro fertilization (IVF) pregnancy was established in a natural cycle by laparoscopic retrieval of the oocyte after accurate timing of the ovulation (Steptoe and Edwards, 1978), this natural-cycle IVF was soon replaced by IVF in stimulated cycles in order to bring multiple follicles to maturity and hence to increase the chances of conception. Clomiphene citrate was the first agent used for ovarian stimulation in 1981 (Trounson et al., 1981), but it was later replaced by gonadotrophins in order to increase further the number of fertilizable eggs (Laufer et al., 1984). Furthermore, the implementation of gonadotrophin-releasing hormone (GnRH) agonists in various ovarian stimulation protocols was thought to be a significant improvement since it allowed an even more intense ovarian response and a better control over the stimulation process by avoiding interference from endogenous gonadotrophin secretion (Smitz et al., 1992; Tarlatzis and Grimbizis, 1997a). However, the question is how many eggs are necessary to offer the best chances for conception in an IVF cycle, without increasing the risks for the patient. It is well known that the development of a high number of oocytes during the ovarian stimulation process and, subsequently, of many more embryos than required for a fresh embryo transfer does not really increase the success rate of the embryo transfer itself, but only makes embryos available for cryopreservation. However, only the good quality embryos can be stored; some of them are destroyed during the freezing–thawing process and the rest do not have the same implantation capacity as the fresh ones. It seems, therefore, that after a certain point, a significant part of the biological material obtained by ovarian stimulation is lost. Moreover, apart from the financial cost of cryopreservation, the medical and ethical problems raised are also important: how many years can these embryos be stored safely and what is the future of embryos abandoned by their owners? Is it ethically right to destroy them, as it was recently done in the UK? On the other hand, controlled ovarian hyperstimulation is not a risk-free process. It may lead to ovarian hyperstimulation syndrome (OHSS) which is a potentially lifethreatening condition and its occurrence depends on the number of follicles developed; the higher the number of follicles the greater the possibility of OHSS.