Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor.
BACKGROUND
We have previously shown that the progesterone antagonist mifepristone is a contraceptive when given in a dose of 2 or 5 mg per day. The majority of women experience amenorrhoea rather than the irregular break through bleeding usually occurring with other estrogen-free contraceptive pills, such as progestogen-only pill (POP). We investigated the effects of low-dose mifepristone on endometrial parameters which may be associated with changes in endometrial function, such as microvasculature, vascular endothelial growth factor (VEGF) and glucocorticoid receptor (GR) content.


RESULTS
Endometrial biopsies were collected from 16 women before (late proliferative phase) and 60 and 120 days after taking 2 or 5 mg mifepristone daily for 120 days. Seven of the eight women who received 2 mg mifepristone and all eight women who received 5 mg were amenorrhoeic during the study. Mean estradiol (E(2)) concentrations remained in the mid-proliferative range, and the majority (9/16) of women showed proliferative endometrial histology at 60 and 120 days following treatment. There was a significant increase in the density of the endometrial stroma (P < 0.05) and microvessels (P < 0.01) following 120 days of treatment. Immunocytochemistry showed that GR, hitherto localized specifically in endometrial stroma, was up-regulated in the nuclei of glands (P < 0.05) and surface (luminal) epithelium (P < 0.01) by 60 days and maintained at 120 days. There was a significant reduction in stromal VEGF protein expression by day 120 of treatment (P < or = 0.01).


CONCLUSIONS
The high incidence of amenorrhoea in women taking mifepristone may be related to changes in the regulation of vascular function.
Narvekar
Nitish
N
Contraceptive Development Network, Centre for Reproductive Biology, Edinburgh, UK.
Critchley
Hilary O D
HO
Cheng
Linan
L
Baird
David T
DT
D000568:Amenorrhea / Q000139:chemically induced*; D049109:Cell Proliferation; D003270:Contraceptive Agents / Q000494:pharmacology; D003280:Contraceptives, Oral, Synthetic / Q000494:pharmacology*; D004717:Endometrium / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008833:Microcirculation / Q000187:drug effects*; D015735:Mifepristone / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D003270:Contraceptive Agents; D003280:Contraceptives, Oral, Synthetic; D005938:Glucocorticoids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011965:Receptors, Glucocorticoid; D042461:Vascular Endothelial Growth Factor A; D015735:Mifepristone