Abstract
The first commercially available gonadotropin product was a human chorionic gonadotropin (hCG) extract, followed by animal pituitary gonadotropin extracts. These extracts were effective, leading to the introduction of the two-step protocol, which involved ovarian stimulation using animal gonadotropins followed by ovulation triggering using hCG. However, ovarian response to animal gonadotropins was maintained for only a short period of time due to immune recognition. This prompted the development of human pituitary gonadotropins; however, supply problems, the risk for Creutzfeld–Jakob disease, and the advent of recombinant technology eventually led to the withdrawal of human pituitary gonadotropin from the market. Urinary human menopausal gonadotropin (hMG) preparations were also produced, with subsequent improvements in purification techniques enabling development of products with standardized proportions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity. In 1962 the first reported pregnancy following ovulation stimulation with hMG and ovulation induction with hCG was described, and this product was later established as part of the standard protocol for ART. Improvements in immunopurification techniques enabled the removal of LH from hMG preparations; however, unidentified urinary protein contaminants remained a problem. Subsequently, monoclonal FSH antibodies were used to produce a highly purified FSH preparation containing <0.1 IU of LH activity and <5% unidentified urinary proteins, enabling the formulation of smaller injection volumes that could be administered subcutaneously rather than intramuscularly. Ongoing issues with gonadotropins derived from urine donations, including batch-to-batch variability and a finite donor supply, were overcome by the development of recombinant gonadotropin products. The first recombinant human FSH molecules received marketing approvals in 1995 (follitropin alfa) and 1996 (follitropin beta). These had superior purity and a more homogenous glycosylation pattern compared with urinary or pituitary FSH. Subsequently recombinant versions of LH and hCG have been developed, and biosimilar versions of follitropin alfa have received marketing authorization. More recent developments include a recombinant FSH produced using a human cell line, and a long-acting FSH preparation. These state of the art products are administered subcutaneously via pen injection devices.
Highlights
It was observed in 1927, by Ascheim and Zondek, that the blood and urine of pregnant women contained a gonad-stimulating substance, human chorionic gonadotropin [1, 2]
This review provides an overview of the major milestones in the development of gonadotropin products (Figure 1), as well as issues that may have affected decision making during the development processes, and summarizes the available evidence supporting the use of recombinant gonadotropin products for the treatment of infertility
Reproducibility was greatly improved in 1939 when the League of Nations developed the international standard for human chorionic gonadotropin (hCG); one International Unit (IU) of hCG was defined as the activity contained in 0.1 mg of the reference hCG preparation which was pooled from six sources [8]
Summary
It was observed in 1927, by Ascheim and Zondek, that the blood and urine of pregnant women contained a gonad-stimulating substance, human chorionic gonadotropin (hCG) [1, 2]. In 1929, Zondek proposed, based on his experiments and those of Smith, that two hormones were produced by the pituitary gland, both of which stimulated the gonads [4,5,6]. These hormones were described as gonadotropins and subsequently named follicle-stimulating hormone (FSH) and luteinizing hormone (LH), according to their specific actions. The biological activity of gonadotropins suggested that they might be useful for the treatment of patients who were infertile These observations eventually led to the development of pure gonadotropin products that have enabled the birth of millions of children to people affected by infertility. This review provides an overview of the major milestones in the development of gonadotropin products (Figure 1), as well as issues that may have affected decision making during the development processes, and summarizes the available evidence supporting the use of recombinant gonadotropin products for the treatment of infertility
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