The role of gonadotropins in follicular development and their use in ovulation induction protocols for assisted reproduction.

During the 1960s, hypogonadotropic patients with polycystic ovary syndrome and those with clomiphene citrate resistance were the first to achieve pregnancy after urinary human menopausal gonadotropin (hMG) administration plus preovulatory human chorionic gonadotropin injection, with cumulative pregnancy rates ranging from 40% to 80% after six to 12 treatment cycles. Ever since, dramatically more progress has been achieved regarding methods and medication in assisted conception techniques, involving both a rapidly increased number of subfertile couples, as well as many practitioners in obstetrics and gynecology. The purpose of this review was to highlight the most crucial historical steps of this remarkable process, by emphasizing the role of gonadotropins in ovulation induction protocols according to the various clinical categories of subfertile patients. In the late 1970s, urinary hMG was the most widely used gonadotropin for ovarian stimulation during in vitro fertilization-embryo transfer for assisted reproduction. The often concurrent problems of premature luteinizing hormone (LH) surges and premature luteinizations, and thus cancellations of the cycles, were efficiently overcome by 'reversible medical hypophysectomy', performed by gonadotropin releasing hormone (GnRH) analogs, introduced in 1982. According to its initiation and duration, GnRH analog use was divided into three protocols: the long, most widely used, protocol, which was the best for suppression of endogenous, high tonic LH levels, especially in polycystic ovary syndrome and normogonadotropic patients; and the short and ultra-short protocols, which were mainly used in poor responders to ovarian stimulation treatment, older or hypergonadotropic patients with ovarian failure, because of the well-known 'flare-up phenomenon'. Recently, GnRH antagonists, which directly do not permit GnRH action by binding to the GnRH gonadotropic cell receptors, have been used, but no final results from large, multicenter clinical trials that are still being undertaken have yet been achieved. Various sub-products of urinary hMG have been produced since the 1980s, with the intention of eliminating most or all of the LH, such as a form with a 3:1 proportion ratio between follicle stimulating hormone (FSH) and LH, as well as a form resulting in the removal of almost all of the LH, the 'pure' urinary FSH. Finally, in the mid-1990s, recombinant pure FSH was produced in vitro from hamster ovarian cell cultures. The theoretical basis for the broad use of pure urinary FSH and recombinant FSH is that the very low endogenous LH levels after pituitary desensitization are sufficient for proper theca steroidogenesis; still, data in the literature and clinical experience may be controversial upon that issue. From the clinical point of view, clinicians nowadays tend to stimulate polycystic ovary syndrome patients with recombinant FSH plus the application of GnRH analogs in a long protocol. However, in poor responders, patients in whom ovulation is resistant to clomiphene citrate, those older than 40 years or hypergonadotropic patients with ovarian failure, urinary hMG, because endogenous LH levels are obviously not sufficient for proper steroidogenesis in the theca cells of the follicles of these patients, is necessary in add to the administration of GnRH analogs in a short or ultra-short protocol. Regarding normogonadotropic women (the majority of patients), most authors agree with the long-protocol application of GnRH analogs. In these patients, it is not certain whether recombinant FSH alone is sufficient for the best possible induction or whether exogenous LH administration in the form of urinary hMG still remains necessary.