Low-dose mifepristone inhibits endometrial proliferation and up-regulates
androgen and glucocorticoid receptor
N. Narvekar (1), S. Cameron (1), H.O.D. Critchley (1), S. Lin (2), L.
Cheng (2), D.T. Baird (1)
Contraceptive Development Network, University of Edinburgh, Scotland, UK
(1); Shanghai Institute of Family Planning Technical Instruction, Shanghai (2)
Introduction: Progesterone receptor (PR) antagonists have many
potential uses including treatment of endometriosis, fibroids, breast cancer and
meningiomas. 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 ‘anti-estrogenic’ action is unknown.
Objectives & Methods: 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), 60 and 120 days after
taking 2 or 5 mg mifepristone daily for 120 days. Endometrial proliferation (H3
mitosis marker) and steroid (estrogen, progesterone, androgen and glucocorticoid)
receptor content were studied using standard immunocyotchemistry techniques.
Stromal density was measured using image analysis.
Results: There was a significant decrease in expression of H3 mitosis
marker (p<0.001) and progesterone receptor (PR) (p<0.05) in endometrial glands and stroma by day 60 of treatment. In contrast the expression of androgen receptor (AR) and glucocorticoid receptor (GR) increased (p<0.01) in glands, surface epithelium and stroma as compared to the pre-treatment sample. There was an 18 % increase in stromal density by day 60 of treatment (p=0.002). These changes were maintained at 120 days of treatment. Expression of estrogen (ER) was unchanged in stroma and surface epithelium, however there was a significant decrease in expression after 120 days of treatment (p=0.34).
Conclusions: Since androgens can antagonize estrogen action, enhanced
glandular AR expression induced by mifepristone could play a role in its
anti-proliferative effects.
