Low-Dose Mifepristone Inhibits Endometrial Proliferation and Up-Regulates Androgen Receptor

Abstract

Mifepristone in daily low doses has contraceptive potential by inhibiting ovulation. Follicular development is maintained, and although the endometrium is exposed to unopposed estrogen, there are no signs of hyperplasia or atypia. The mechanism of this antiestrogenic action is unknown. We have investigated the effect of daily low-dose mifepristone on proliferation markers and steroid receptors in surface epithelium, glands, and stroma of the endometrium. Endometrial biopsies were collected from 16 women before (late proliferative) and 60 and 120 d after taking 2 or 5 mg mifepristone daily for 120 d. Endometrial proliferation (H3 mitosis marker) and steroid (estrogen, progesterone, and androgen) receptor content were studied using standard immunocyotchemistry techniques. There was a significant decrease in the expression of H3 mitosis marker (P <or= 0.001) and progesterone receptor (P < 0.05) in endometrial glands and stroma by d 60 of treatment. In contrast, the expression of androgen receptor increased (P < 0.01) in glands, surface epithelium, and stroma compared with the pretreatment sample. These changes were maintained at 120 d of treatment. The expression of estrogen receptor was unchanged in stroma and surface epithelium; however, there was a significant decrease in expression after 120 d of treatment (P = 0.034). As androgens can antagonize estrogen action, enhanced glandular androgen receptor expression induced by mifepristone could play a role in its antiproliferative effects.

The spectrum of endometrial pathology induced by progesterone receptor modulators

“…A similar effect has been described with mifepristone, in which higher doses induce androgen receptors, a change with known antiestrogen effects. 8,9 Changes in agent dose potentially modify the endometrial appearance by varying affinities for multiple steroid hormone receptors, and for each receptor class, a dose dependentbalance of antagonist with agonist activity.…”

“…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.…”

Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator

“…[16][17][18][19] Most mitotically active CDB-4124-treated endometria also had an increase in epithelial apoptotic bodies. The proliferative effect is thus, in part, counterbalanced by an increase in cell death.…”

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…The mechanism of attenuation of estradiol effects on the endometrium is not well understood, and although steroidal PRAs appear to block cell proliferation in various in vitro cell-based systems, the concentrations needed for this effect are considerably greater than those which elicit the effect in vivo (Freeburg et al, 2009a;Goyeneche et al, 2007;Murphy et al, 2000;Ohara et al, 2007;. One clue to a potential mechanism has emerged from observations of elevated endometrial androgen receptor (AR) expression (Narvekar et al, 2004;Slayden & Brenner, 2003) following PRA administration and the known effects of AR modulators (e.g. danazol) on endometrium (Rose et al, 1988).…”

“…If AR is inducing a genomic effect, what are the transcripts that are altered and confer the inhibitory effect on PRA? Other important and, as yet, unaddressed questions also include whether these effects are only manifested only by the steroidal class of PRAs, but the observation that RU-486 can elevate endometrial AR expression in women goes some way to understanding the translational significance of the macaque findings (Narvekar et al, 2004).…”