Progesterone Receptor Antagonists and Selective Progesterone Receptor Modulators (SPRMs)

HISTORICAL OVERVIEW Progesterone, the hormone secreted by the corpus luteum and placenta, plays an indispensable role in the maintenance of pregnancy in most, if not all mammals, including the human. Consequently, it is essential for both the propagation and survival of these species. In 1901, Fraenkel and Cohn showed that the corpus luteum was needed for implantation of rabbit embryos. The isolation of the pure progestational hormone was reported in 1934 by four groups who were working independently of one another. The hormone was named progesterone in 1935. Recognition of the important role of progesterone for pregnancy establishment and maintenance led to the search for progestins, synthetic compounds with progestational activity. This step proved crucial in the development of oral contraceptives, which has been acknowledged as one of the most important medical breakthroughs of the last century. The next step in the saga came with the discovery of the progesterone receptor by O’Malley et al in 1969 and Baulieu and Milgrom in 1970. Since then, scientists have been looking for progesterone receptor antagonists (PAs), substances that would prevent the biological effects of progesterone on its target organs. Eventually, in 1981, Philibert, Deraedt, and Teutsch from the French pharmaceutical company, Roussel Uclaf, reported on a newly synthesized glucocorticoid receptor antagonist known as RU 38486. It soon became evident that this antiglucocorticoid was also a potent PA. RU 38486 was subsequently abbreviated to RU 486, and is now currently known by the generic name mifepristone. In addition to the initiation and maintenance of pregnancy, progesterone has other physiological actions in the human. By inhibiting myometrial contractility, it maintains the uterus in a quiescent state. It also facilitates the luteinizing hormone (LH) surge, transforms the endometrium from a proliferative to a secretory state and, together with estradiol, maintains endometrial integrity. Progesterone also contributes to mammary gland morphogenesis and function. A progesterone antagonist could conceivably inhibit any or all of these actions. Thus, it is not surprising that 1 year after the discovery of mifepristone, Hermann et al showed that mifepristone was effective in terminating pregnancy. It was soon appreciated that mifepristone alone was only effective in 64 to 85% of women with duration of amenorrhea of 7 weeks or less. This was clearly inadequate for routine clinical use. Elger et al showed that a synergistic effect existed between PAs and prostaglandins in pregnant guinea pigs. Swahn and Bygdeman then noted that in pregnant women, the success rate for pregnancy termination could be considerably improved by the addition of a prostaglandin to the mifepristone-primed uterus. This firmly established the feasibility of effective medical abortion and gave women in the developed world another option for terminating pregnancy. However, for the many millions of women in the developing world, where surgical procedures may be neither sterile nor safe, this medical method may be the only one readily available, and thus has the potential of saving the lives of thousands of women.