Progesterone antagonists and the non-human primate endometrium

The importance of progesterone (P) in reproductive physiology cannot be overestimated. Progesterone prepares the uterus for implantation and is key to the maintenance of pregnancy.1-3 Like other steroid hormones, the genomic effects of P are mediated through interactions with specific intracellular progesterone receptors (PRs). Because PRs play key roles in so many aspects of human reproduction, numerous PR ligands with either agonist or antagonist actions have been synthesized by pharmaceutical companies to modulate the actions of this key hormone. Compounds with mixed agonist and antagonist effects, known as selective progesterone receptor modulators (SPRMs),4,5 are the most recently developed ligands, and these are reviewed in Chapter 38. A recent, very thorough review of the human endometrium has been published in Endocrine Reviews, with extensive coverage of normal physiology, angiogenesis, steroid receptors, cytokines, and menstruation.6 In this chapter, we focus on strongly antagonistic ligands (antiprogestins, PR antagonists; abbreviated here as PAs) and their effects on the non-human primate endometrium. For preclinical studies of endometrial effects of PAs, non-human primates are the animal model of choice. First, their reproductive tracts closely resemble those of women. Secondly, in these species, unlike most other laboratory animals, PAs can block the effects of estrogens on endometrial proliferation in addition to blocking the action of P on progestational differentiation.7 Thirdly, ovariectomized macaques can be treated sequentially with implants of estradiol (E2) and P to induce artificial menstrual cycles that provide a controlled hormonal environment in which to test various doses and modalities of PA treatments. Hodgen8 was the first to report that development of a fully functional endometrium that could sustain pregnancy could be established in ovariectomized monkeys treated sequentially with Silastic implants of E2 and P. In such an artificial cycle, the withdrawal of P at the end of the cycle results in menstruation identical to natural menses. Because they allow such precise control of hormonal states, we used induced cycles to assess the effects of several PAs, including mifepristone (RU 486; Roussel UCLAF) ZK 137 316, and ZK 230 211 (Schering AG).9-11 Our review begins with a survey of the normal parameters of the primate endometrial cycle as background for comparison with the effects of PAs. Figure 9.1 shows a rhesus macaque uterus cut along the longitudinal axis from fundus to cervix. The dotted line indicates the plane of all the histological sections presented in this review. Figure 9.2 illustrates the histology of the rhesus macaque endometrium at the end of the induced Fundus Endo-myo border Myo Myo Endo Uterine lumen 1 cm Corpus Isthmus proliferative phase (14 days of E2 alone) and at the end of the induced secretory phase (14 additional days of E2 + P). After 14 days of E2 treatment the upper endometrial layers contain relatively straight tubular glands. Most of the proliferating cells are in the mid and upper functionalis zones, not the basalis12 (Figure 9.2c; Figure 9.3a-c). Stromal cell proliferation occurs in all zones. The upper zones also contain abundant apoptotic cells (Figure 9.2c), suggesting that during the proliferative phase there is a balance of cell birth and cell death. New growth of small blood vessels in the upper functionalis zone peaks on day 8 of the proliferative phase.13 In the proliferative phase, spiral arteries begin to grow but are confined to the basalis zone.