The Development of Gonadotropins for Clinical Use in the Treatment of Infertility

Frontiers in Endocrinology

Veronica Alam¹  Sesh K. Sunkara²  Thomas D'Hooghe³  Bruno Lunenfeld⁴  Salvatore Longobardi⁶  Wilma Bilger⁷ 

[1] A Business of Merck KGaA, Darmstadt, Germany;Assisted Conception Unit, King's College London, Guy's Hospital, London, United Kingdom;Department of Obstetrics and Gynecology, Yale University, New Haven, CT, United States;Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel;Global Clinical Development, EMD Serono, Rockland, MA, United States;Global Medical Affairs Fertility, Merck Healthcare KGaA, Darmstadt, Germany;Medical Affairs Fertility, Endocrinology and General Medicine, Merck Serono GmbH, Darmstadt, Germany;Organ Systems, Group Biomedical Sciences, Department of Development and Regeneration, KU Leuven (University of Leuven), Leuven, Belgium;

关键词: recombinant gonadotropin;    follicle stimulating hormone;    luteinizing hormone;    fertility;    pregnancy;    pre-clinical;   

DOI  :  10.3389/fendo.2019.00429

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown