Development of gonadotrophins for clinical use

Abstract

The 20th century witnessed the steady development of knowledge about reproductive physiology and endocrinology in animals and humans. These advances led to the identification of higher centres governing the ovary and its follicles. Effects of X-rays on the head and other agents, or excision of the pituitary gland, led to anomalies in oestrous and menstrual cycles in animals and women, respectively. Studies on pituitary and placental extracts revealed the presence of hormones regulating the ovarian follicles and the corpus luteum for the implanting embryo. These were identified as follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotrophin (HCG). Increasing understanding of the mechanisms of action of these hormones led to treatments of animals and amenorrhoeic women with FSH- and LH-containing preparations in order to induce the growth of follicles and ovulation.Human FSH-rich preparations were obtained by extracting urinary gonadotrophins from the urine of post-menopausal women, and thousands of amenorrhoeic and/or anovulatory patients were treated with human menopausal gonadotrophin (HMG) and HCG to induce multifolliculation and ovulation. The introduction of IVF greatly increased the numbers of women treated in this fashion, now including cyclic women. By the mid-1980s, following the appearance of Creutzfeld–Jakob disease in women treated with gonadotrophins extracted from human pituitaries, and other safety considerations, attempts were being made to purify urinary gonadotrophin preparations, using antibodies. Increasing interest in recombinant preparations, which were pure, highly specific and highly active preparations, characterized the last years of the 20th century and the new millennium. These preparations included recombinant FSH (rFSH), recombinant LH (rLH) and recombinant HCG (rHCG). Yet, in one sense, the recombinant preparations could change the procedures of ovarian stimulation, because they focused attention on the membranal receptor in the follicle, and how best to stimulate it. Small molecules are currently being investigated, with some proving to be very active and specific, and even capable of bypassing many parts of the receptor conformation. Here lies the immediate future of this field, utilizing small, defined molecules at low cost to stimulate follicle growth, ovulation and luteinization, and perhaps one day to remove the need for gonadotrophins in clinical work.