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[1] 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.[2] [3] [4] [5] 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[6] in 1969 and Baulieu and Milgrom[7] 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[8] 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.[9] 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.[10] 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[11] 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.[12] Elger et al[13] showed that a synergistic effect existed between PAs and prostaglandins in pregnant guinea pigs. Swahn and Bygdeman[14] 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.[12]

Schrader and O'Malley[15] were the first to show that the progesterone receptor (PR) exists as two separate isoforms. The structural configuration of both isoforms is similar, although the PR-B isoform contains an N-terminal fragment of 164 amino acids, which is absent from the PR-A isoform. In most contexts, PR-B functions as an activator of progesterone-responsive genes, while PR-A is transcriptionally inactive. In addition, PR-A also functions as a strong transdominant repressor of PR-B and human estrogen receptor transcriptional activity in the presence of both PR agonists and antagonists.[16] [17]

Development of knockout mice, in which the activity of one of more specific genes has been inactivated, provides some indication of the gene's normal role in the mouse, and by extrapolation, in humans. Knockout mouse models are widely used to study human diseases and this technology was rapidly adapted to the PR by Lydon et al.[18]

Striking advances in molecular biology techniques have helped elucidate the mechanism of action at the molecular level of both progesterone and PAs. In this regard due to the studies of O'Malley and Parker working independently, it has been appreciated that coactivators and corepressors play a crucial role in determining whether a specific compound will function as an agonist or antagonist.[19] [20] These coregulators may be regarded as power boosters (amplifiers) of transcriptional regulation and act as bridging factors between the receptor and the general transcription machinery.

In the last several years, a new technology, called the DNA microarray method, has attracted tremendous interest among biologists.[21] This technology is able to detect the expression of thousands of genes simultaneously and was rapidly adapted by Bagchis group[22] to evaluate PR-regulated pathways.

One of the interesting observations to emerge during long-term administration of mifepristone and similar compounds is their complex effect on the endometrium where many of them produce antiproliferative effects, a phenomenon first described by Hodgen and subsequently confirmed by other investigators.[23] [24] [25] Hodgen referred to this as a noncompetitive effect because mifepristone does not bind to the estrogen receptor.[24] This endometrial antiproliferative effect is important because it represents the basis for the long-term use of antiprogestins in the treatment of uterine fibroma, endometriosis, and dysfunctional uterine bleeding.

REFERENCES

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