Preparations of PMSG first appeared in 1937 and successful clinical use to stimulate ovarian follicular growth in patients was achieved as early as 1941. However, a rapidly-developing immune response was soon recognized, that rendered patients insensitive to further treatment after only a few trials. As a result clinical uses of this product were soon abandoned.

Following the clinical failure of PMSG, ovulation stimulation was attempted with an extract of human pituitary tissue. First applied in 1958, the extracts achieved modest success and continued in use until 1988, when the cases of associated Creutzfeldt-Jakob disease became evident. Although clinical use of this preparation would have always been limited by a meager supply of source tissue, these pituitary extracts remain useful today as International Reference Preparations.

The ability to isolate and purify hormones from the urine of post-menopausal women ushered in the true era of gonadotropin use. Using a kaolin-acetone extraction method, Bruno Lunenfeld demonstrated as early as 1945 that it was possible to isolate and purify gonadotropins from menopausal urines. Injections of the extract into immature rats stimulated ovarian follicular growth and testicular spermatogenesis in the testis. Although the potential clinical value of these preparations was easy to predict, it remained impossible to patent this natural human product and thus difficult to convince pharmaceutical companies to engage a project that required massive urine collections, construction of an industrial-sized extraction technology, and development of the necessary safety precautions, based solely on hypotheses derived from animal experiments.

The true history of HMG development finally began in Rome in 1957 when Pietro Donini, a senior research scientist who had extracted HMG at the Instituto Farmacologico Serono, invited Professor Lunenfeld to visit and discuss with the institute’s board the feasibility of mass producing HMG and initiating clinical trials. Initially the proposal was not well received, due to little enthusiasm to convert laboratories into commercial urinals. Fortunately, the Vatican had been holding a major share in the Instituto Farmacologico Serono since 1952, and Don Giulio Pacelli was their representative to the board. He also happened to be a nephew of the Pope and began to take an interest in the project. Professor Lunenfeld was asked to remain in Rome for continued discussions that led to a proposal that the homes of retired nuns could provide ample supplies of urine. The Serono board was convinced to undertake the project.

This offer proved to be very successful: by 1961 Lunenfeld was able to report the first newborn infants from ova stimulated by HMG injections [6], and by this time three collection centers, in Italy, Spain, and the Netherlands, were already operating with more than 600 donors. This same method of HMG production for direct ovarian stimulation continues in use to the present time.

For many years human menopausal gonadotropins remained the only direct ovarian stimulator, and the essentials of stimulation strategy were written through its use. Because the post-menopausal woman is hypogonadal and hypergonadotropic, FSH and LH appear at significant levels in urine. Only a very limited degree of hepatic and renal metabolism occurs, which allows retention of most biological properties.

FSH isoforms in urinary HMG are slightly more acidic, partly because its extremely elevated secretion in hypoestrogenic women contains more of the acidic isoforms, and partly because the acidic isoform population survives hepatic and renal metabolism better. LH content of HMG extracts is proportionately lower than FSH because post-menopausal women secrete more FSH than LH. In order to balance therapeutic concentration of the two hormones closer to equality, it was initially necessary to add pregnancy urine-extracted hCG, the only other hormone preparation available at that time with true LH-like activity. This supplementation was actually unidentified but was suspected for a long time by clinicians. It has only recently been acknowledged by pharmaceutical companies because radioimmunoassay technology has made it possible to distinguish pituitary LH from hCG. hCG supplementation of HMG preparations is no longer permitted and the pharmaceutical manufacturers now claim that a balanced ratio of FSH/LH is achieved by the presence of pituitary hCG that supposedly occurs naturally in post-menopausal urine.

Initially FSH potency varied substantially in the vials supplied by the pioneering manufacturers Serono (Pergonal®, later Neopergonal®) and Organon (Humegon®) that led to variable clinical responses as well. This was likely the result of using a wide variety of urine donors and extraction procedures, and also of using imprecise bioassays to establish international reference units (IU). Vials labeled as containing 75 IU each of FSH and LH could in fact range from 55 to 80 IU of either hormone. Clinicians often blamed these potency variations as the cause of irregular results from IVF procedures, although early embryology technology also brought a number of uncertainties.

Up through the 1980s, the preparations of hMG permitted a satisfactory cure for most dysovulatory or anovulatory patients, save those afflicted with polycystic ovarian disease (PCOD). Initially known as the Stein-Leventhal syndrome, PCOD is typified by excess body weight, anovulation, hyperandrogenism, and an excessive LH secretion that produces a lower serum FSH/LH ratio, along with a possible metabolic syndrome with an enhanced risk of Type II diabetes mellitus. Pathophysiology of this syndrome was believed to result from a relative shortfall of FSH secretion accompanied by LH excess, and it was initially proposed that treatment with pure FSH would restore successful ovulations.

Although this assumption was later shown to be incorrect, it did lend energy to resolving the purity problems of HMG, and a more purified FSH product (uFSH) appeared in 1988. Nevertheless, this preparation offered no therapeutic improvement. It took a return to the original principles of defining an FSH threshold, and the design of a slower “step-up” protocol, to restore normal ovulations in PCOD patients. It turned out that rates of both success and complications were quite the same, whether hMG or uFSH were used [7].

Development of a refined uFSH preparation became the last example of a progressive step initially sought by clinicians, and to which the manufacturers responded. In a considerable shift of roles, most all of the subsequent developments in gonadotropin preparations have been initiated by the pharmaceutical companies themselves. In the meantime, the market for gonadotropin preparations has been greatly expanded due to increased use for in vitro fertilization procedures. From a “craft” developed and practiced by a relatively small number of gynecologic specialists, the therapeutic approaches to infertility have blossomed into a substantial industry, and include a new set of philosophies and practices. This has resulted in significant conflicts between product design and marketing on the one hand, and uses of therapeutic agents and therapeutic goals on the other.