Progesterone receptor antagonists and the endometrial antiproliferative effect.

Progesterone receptors (PR) mediate multiple aspects of female reproduction and are important targets for reagents that can modulate progesterone-dependent events. Many such reagents have been developed, and they range from full PR antagonists (PAs) to compounds with mixed agonist/antagonist actions, currently known as selective progesterone receptor modulators (SPRMs). In women and nonhuman primates, many PR antagonists suppress estrogen-dependent mitotic activity in the endometrial glands as well as block progestational development of the endometrium. These latter effects are tissue- and species-specific, are most dramatic in women and nonhuman primates, and are referred to as endometrial antiproliferative effects. Recent evidence suggests that the endometrial androgen receptor plays an important role in these effects. For example, endometrial androgen receptors are increased by treatment with PAs, and combination treatment with estrogen, a PA, and an antiandrogen (flutamide) prevents the endometrial antiproliferative effect. Various PR modulators have great promise as gynecological therapeutics, but additional research is needed to improve our understanding of their endometrial effects.