Uterus and endometrium: Effects of daily low dose mifepristone on endometrial maturation and proliferation

Abstract

Following an ovulatory control cycle, six women took 2 mg of mifepristone daily for 30 days. Endometrial biopsies were collected in the control cycle between 7 and 11 days after the plasma luteinizing hormone (LH) surge and on the corresponding day of the treatment cycle (days 19-28). In order to investigate the effects of unopposed oestrogen on the endometrium, persistent proliferative endometrium was obtained from six women with anovulatory infertility due to polycystic ovarian syndrome (PCOS) on a similar cycle day (days 21-23) following a progestogen-induced withdrawal bleed. Endometrium was evaluated for histology and immunolocalization of oestrogen receptors (ER), progesterone receptors (PR) and the cell proliferation markers [proliferating cell nuclear antigen (PCNA) and Ki67]. Treatment with mifepristone inhibited ovulation in four of the six subjects. In the two subjects in whom ovulation did occur, secretory transformation was delayed, suggesting that successful implantation of a blastocyst would be unlikely. In subjects who remained anovulatory during treatment, the histology and pattern of steroid receptor expression was similar to proliferative phase endometrium. In women with PCOS, mitoses and intense immunostaining for ER, PR and cell proliferation markers were observed in both glands and stroma. Although PCNA and Ki67 immunostaining were also present in mifepristone-treated endometrium from subjects who did not ovulate, there were no mitoses and significantly less ER immunostaining in spite of exposure to unopposed oestrogen for a similar duration. Since PCNA and Ki67 detect cells throughout all stages of the cell cycle this would suggest that mifepristone might affect the entry of cells into the mitotic phase of the cell cycle and, therefore, might prevent endometrial hyperplasia. These findings add further evidence to support the contraceptive potential and antiproliferative activity of daily low dose mifepristone.

Collaborative work on evaluation of ovarian toxicity 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats

“…It has been reported that postcoital administration of mifepristone modulates egg transport through the oviduct (Roblero, et al, 1987;Fuentealba, et al, 1987;Yang and Wu, 1990), retards early embryonic development (Psychoyos and Prapas, 1987;Roblero and Croxatto, 1991), delays endometrial maturation (Roblero and Croxatto, 1991;Batista, et al, 1992;Cameron, et al, 1996) and thereby inhibits or delays implantation (Psychoyos and Prapas, 1987;Roblero and Croxatto, 1991;Dao, et al, 1996). In the present study, treatment with 4 mg/kg mifepristone during the post-coital phase produced small numbers of live embryos and a high postimplantation embryonic mortality but did not reduce the number of implantations.…”

The spectrum of endometrial pathology induced by progesterone receptor modulators

“…Some PRMs exert anti-estrogenic effects, either through partial progesterone receptor agonist activity, 6,7 or, exert these effects independently of the progesterone receptor itself, that is by upregulation of the androgen receptor response. 8,9 These PRM effects are evident as dose-dependent suppression of estrogen-induced mitotic activity, [10][11][12] and appearance of glandular secretory changes. 7 Assessment of PRM induced changes in the endometrium by pathologists is not only a prerequisite step to determine suitability for widespread clinical use, but also indicates how community pathologists are likely to respond to endometrial biopsies from women on these agents.…”

“…Access to material is generally confined to individuals involved in ongoing clinical trials, members of the parent pharmaceutical companies, a few researchers, and regulatory agencies. Now that the histological features referable to PRM administration are starting to emerge, 7,[12][13][14][15] there are unanswered questions of how they relate, if at all, to known diagnostic entities such as endometrial hyperplasia.…”

Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor

“…Low doses of RU486 administered chronically to women also inhibited glandular mitosis and induced stromal compaction in the endometrium (Cameron et al, 1996). Anti-proliferative and apoptotic effects of anti-progestins have also been observed in vitro in various breast cancer cell lines, and these effects have been referred to as receptor-mediated 'cytostatic and cytotoxic' effects.…”

“…Such chronic, low dose treatment suppresses endometrial maturation and makes successful implantation unlikely (Batista et al, 1992;Cameron et al, 1996). The third group consisted of women who were treated with 200 mg oral mifepristone (or vehicle) 2 days after the ovulatory surge of LH and sampled 4-6 days later.…”