Abstract

Gonadotropins were first extracted from urine in the 1940s. Further improvements in purification methods led to the production of the first FSH-only product in the 1980s. Advances in DNA technology enabled the development of recombinant hFSH, which became commercially available in 1995. In 2000, recombinant hLH became available and, with the launch of recombinant hCG in 2001, the complete recombinant gonadotrophin portfolio was available. Recombinant technology meets the need for a more reliable source of FSH. The production of r-hFSH is accomplished by a carefully selected transfected Chinese hamster ovary (CHO) cell line. The protein secreted by these cells is collected by extracting the supernatant. After concentrating the supernatant, the protein is purified by chromatography, followed by ultrafiltration. The final product is purer when recombinant technology is used. To administer the same amount of FSH, more protein must be injected when using urinary products compared with r-hFSH. The conventional method used to quantify the activity of FSH in gonadotropin products is the Steelman–Pohley assay, which is an in vivo rat bioassay. As well as being costly and subject to ethical concerns related to the use of animals, this technique has an inherent variability of up to 20%. In 2003, the specific activity, isoform pattern and sialylation profile or-hFSH (follitropin alfa) have been depicted. Following this, a novel physiochemical method was developed for measuring FSH content (by protein mass). These advances led to the development of a filled-by-mass rec-FSH preparation, which is formulated based on r-hFSH protein content and provides precise and accurate dosing, and enables FSH dosing in relatively small increments. 

The ability to prevent premature endogenous luteinizing hormone (LH) surge was also a major breakthrough in ovulation induction for in vitro fertilization. By using gonadotropin releasing hormone agonists (GnRH-a) or antagonists the cycle cancellation rates decreased from 20% to approximately 2%. GnRH-agonists can be used in a long protocol format and have been considered the “gold standard” in ovarian stimulation for assisted reproductive techniques (ART) for more than 20 years. GnRH-antagonists, on the other hand, can be used in a short protocol format and have been recently introduced. Protocol choice is often based on baseline patient characteristics, previous stimulation records (when available), physician’s preference, patients’ convenience or a combination of factors. By tailoring the use of agonists or antagonists the goal is to individualize treatment in order to optimize ovarian stimulation, oocyte quality, endometrial receptivity, patient satisfaction and live birth rates. With the GnRH-a used in the long protocol (started either in the midluteal phase or in the early follicular phase of the preceding cycle), 2 or 3 weeks of treatment is needed to achieve pituitary desensitization. GnRH-a causes an initial “flare-up” stimulatory effect ovarian cyst formation is occasionally seen. On the other hand, GnRH antagonists cause an immediate suppression of gonadotropin secretion, without the initial stimulatory effect; therefore, they can be given after starting gonadotropin administration. Several studies have directly compared protocols involving GnRH-agonists and antagonists. In general, total doses of gonadotropins, incidence of ovarian hyperstimulation syndrome (OHSS), duration of treatment and side effects are significantly lower in the antagonist protocol compared to the agonist one, suggesting that the former is less aggressive; hence, more patient-friendly. A recent recent meta-analysis compared GnRH-agonists and antagonists in IVF with respect to the probability of live birth per patient randomized, and concluded that live birth rates between both drugs were not significantly different (Kolibianakis et al., 2006). 

Recent protocols combining GnRH antagonists and recombinant filled-by-mass gonadotropins show comparable clinical results than conventional ones, but they are associated with increased patient compliance and lower complication rates. 

Recent advances in stimulation protocols