Recombinant follicle stimulating hormone: Development of the first biotechnology product for the treatment of infertility

Abstract

Genes encoding the common gonadotrophin α subunit and follicle stimulating hormone (FSH)-specific β subunit were isolated from a DNA library derived from human fetal liver cells, and inserted into separate expression vectors containing a selectable/amplifiable gene. These vectors were inserted into the genome of the Chinese hamster ovary cell line, resulting in expression of large amounts of biologically active human (h)FSH. This cell line was cultured on microcarrier beads in a large-scale bioreactor. hFSH in the cell culture supernatant was purified to homogeneity by a multistep process. The mature β subunit had seven fewer amino acid residues than reported in the literature and three other differences were found in the sequence. Similar oligosaccharide structures were present on recombinant (r)-hFSH and a purified urinary (u)-hFSH preparation. In-vitro and in-vivo, the biological activities of u- and r-hFSH were indistinguishable. r-hFSH was formulated in ampoules containing 75 IU FSH activity (~ 7.5 μg FSH), which accounts for > 99% of the protein content of the preparation. Studies in nonhuman primates and human volunteers showed the pharmacokinetics of u- and r-hFSH to be similar. In healthy volunteers, r-hFSH stimulated follicular development and induced significant increases in serum oestradiol and inhibin. Clinical experience with r-hFSH has shown it is more effective at stimulating ovarian follicle growth than urinary gonadotrophins. It is also effective at initiating spermatogenesis when given together with human chorionic gonadotrophin.