Control of endogenous secretion of LH by gonadotropin-releasing hormone agonists during ovarian hyperstimulation for in vitro fertilization and embryo transfer

Human infertility is regarded as a major health problem. About ten years ago, the first successful clinical application of extracorporal human oocyte fertilization, followed by the remplacement of the conceptus in the mother’s uterus, launched a new and rapidly expanding field of medically assisted reproduction (Stepoe and Ewards, 1978). Each year, in Western Europe, between 200 and 300 new couples per millions inhabitants could seek in vitro fertilization (IVF) or related procedures to obtain the child they desire (Hull et al., 1986). In the United States, there are currently at least 2.8 million infertile couples who want to have children. Due to the accumulation of unsolved cases over the years, the pool of patients who might benefit from IVF is now believed to exceed one million (Seibel, 1988). In addition to its therapeutic interest, IVF has provided a large amount of new data for the understanding of the physiology and pathology of human reproduction. This will contribute to the development of new methods of fertility control and to the prevention or improved treatment of certain diseases which lead to infertility. Medically assisted reproduction has also opened a large public debate on fundamental, social and economic choices that mankind must make for its future. In our catholic university, a permanent, specific ethical reflexion guides the clinical developments in this field (Loumaye and Malherbe, 1988). The IVF procedure requires the retrieval of healthy fetilisable oocyes from the female ovary. At first, the oocyte was collected from the preovulatory follicle by needle aspiration during a spontaneous cycle. However it became clear that the recovery of several oocyte during one procedure of oocyte recovery would increase the probability of pregnancy by (1) increasing the chance to have at least one embryo to transfer, and (2) allowing the replacement in the uterus of more than one embryo (Ewards and Stepoe, 1983; Wood et al., 1985). Drugs such as clomiphene citrate and human menopausal gonadotropin, which has been used for more than three decades to induce ovulation in anovulatory patients, were used successfully to provoke controlled ovarian hyperstimulation (COH) and simultaneous maturation of several oocytes (Trouson et al., 1981; Jones et al., 1982). The main female indications for IVF are inoperable or unsuccessfully operated tubal diseases, failure of medical and surgical treatment of endometriosis, cervical pathology, and unexplained infertility. In addition, more and more healthy women undergo IVF in order to solve the problem of their mal partner’s infertility. This means that the vast majority of these patients have a normal ovulatory cycle and that the COH is superimposed upon this cycle. IVF teams then realized that the persistence of endogenous secretion of LH during COH has negative consequences in the IVF success rate, on the treatment convenience for the patient and on the cost of the procedure. The availability of GnRH agonists for clinical use renders attractive the possibility of exploiting the paradoxical inhibition of these peptides upon pituitary gonadotrope cells to control the deleterious endogenous secretion of LH. The last few years have seen an extensive evaluation of the clinical suitability of the use of such agonists during COH for IVF. In this review, we will (1) summarize the mechanisms by which GnRH induces the secretion of LH, (2) study the endogenous secretion of LH during COH for IVF and its consequences upon IVF treatment, (3) characterized the control of LH secretion using GnRH analogs, (4) report on the information regarding the safety of the use of such compounds during the maturation of oocyte which have to be subsequently fertilized, and (5) report on and discuss the current clinical experience of the use of GnRH-a during COH for IVFThèse d'agrégation de l'enseignement supérieur (Faculté de médecine) -- UCL, 198