Recombinant gonadotrophins: an introduction.

Abstract

Gonadotrophin preparations of varying composition and purity have been used to promote fertility for over 40 years. During the past 3-4 decades there have also been major advances in the basic scientific understanding of gonadotrophins and their role in health and disease (see Table I). Significant advances in the scientific area have included the recognition that follicle stimulating hormone (FSH) is the major follicular regulator, the 2-cell two-gonadotrophin theory, the identification of the structure of gonadotrophins, and characterization of glycosylation sites. There have also been major advance­ ments in techniques such as bioassays, immunoassays, immunopurification and, most recently, genetic engineering. These developments have led to the production of increasingly pure and well-characterized gonadotrophins for clinical use. The first use of gonadotrophins to induce ovulation in hypogonadotropic women was accomplished in the 1950s using pituitary extracts. This was followed by the development of urinary human menopausal gonadotrophin (HMG) for clinical use during the 1960s and the availability of luteinizing hormone (LH)­ free urinary extracts of FSH in the 1980s. The introduction of immunopurification techniques using specific monoclonal antibodies resulted in the first introduction in the 1990s of highly purified urinary gonadotrophins. The development of pure gonadotrophin products has lagged somewhat behind scientific advances. Although the structure of gonadotrophins was first identified in the 1960s and genetic engineering became possible in the 1980s, it was not until the 1990s before recombinant products were first synthesized. Scientific knowledge in the field continues to advance with the recent understanding of the three-dimensional structure of gonadotrophins and the localization of the sites involved in receptor recognition, signal transduction, and determination of half-life. Urinary-derived gonadotrophins have, to date, been the mainstay in the management of infertility. However, these products are far from ideal and recombinant gonadotrophins represent the future for the treatment of this condition. For urine-derived products, the availability of raw material has limits and is not a constant source. There are also concerns with these products with respect to the co-administration of unwanted biologica:lly-active urinary proteins in relatively large amounts, and of possible effects of concomitant medication taken by donors.