Gonadotropin stimulation: past, present and future

Abstract

Gonadotropin therapy is so central to infertility treatment that it is easy to overlook the considerable discovery and research that preceded production of the effective and safe products available today. The history underpinning this development spans over 300 years and provides a splendid example of how basic animal experimentation and technological advances have progressed to clinical application. Following the discovery of germ cells in 1677 and realizing, in 1870, that fertilization involved the merging of two cell nuclei, one from the egg and one from sperm, it took another 40 years to discover the interplay between hypothalamus, pituitary and gonads. The potential roles of gonadotropin regulation were discovered in 1927. Gonadotropin, such as pregnant mare serum gonadotropin (PMSG), was first introduced for ovarian stimulation in 1930. However, use of PMSG leads to antibody formation, and had to be withdrawn. Following withdrawal of PMSG, human pituitary gonadotropin (HPG) and urinary menopausal gonadotropin (hMG) appeared on the market, and 50 years ago the first child was delivered by our group in 1961 and opened the path to controlled ovarian stimulation. HPG produced good results, but its use came to an end in the late 1980s when it was linked to the development of Creutzfeldt-Jakob disease (CJD). HMG preparations containing a high percentage of unknown urinary proteins, making quality control almost impossible, were then the only gonadotropins remaining on the market. With the availability of hMG, clomiphene citrate, ergot derivatives, GnRH agonists and antagonists, as well as metformin, algorithms were developed for their optimal utilization and were used for the next four decades. Following the first human IVF baby in 1978 and ICSI in 1991, such procedures became standard practice. The main agents for controlled ovarian stimulation for IVF were gonadotropins and GnRH analogues, with batch to batch consistent gonadotropic preparations; methods could be developed to predict and select the correct dose and the optimal protocol for each patient. We are now seeing the appearance of gonadotropin with sustained action and orally active GnRH analogues as well as orally active molecules capable to stimulate follicle growth and inducing ovulation. These new developments may one day remove the need for the classical gonadotropin in clinical work.

Keywords: FSH; Gonadotropins; Human reproduction; Infertility; LH.

Figure 1

The fathers of human reproduction

Figure 2

Schematic view of endocrine regulation of the ovarian cycle as seen by Bernard Zondek in 1929

Figure 3

hMG administration to female hypophisectomized infantile rats results in linear increase on ovarian (a, b) and uterine weights (c) and in male hypophisectomized infantile rats this same extract results in a linear increase of ventral prostate weight (a)

Figure 4

Hormonal pattern during follicular phase, ovulation, luteal phase and pregnancy following stimulation with hMG (step‐up, continuous and step‐down) of a primary amenoreic patient with hypopituitary hypogonadism

Figure 5

Classification of infertile patients

Figure 6

The fathers of in vitro fertilization

Figure 7

Growing demands for gonadotropins requires expanding urine collections by increased recruitment of donors

Figure 8

Steps involved in bulk production of rhFSH

Figure 9

Comparison of pregnancy rate/cycle in patients stimulated with either hMG or rFSH. Calculated for patients below and above the age of 35 years from data published in the German IVF directories, 1998–2007

Figure 10

Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor—% of patients ovulating with different doses of Org 43553