Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor

• Published in: Human reproduction (Oxford) 2006-09, Vol.21 (9), p.2312-2318
• Main Authors: Narvekar, Nitish, Critchley, Hilary O.D., Cheng, Linan, Baird, David T.
• Format: Article
• Language: English
• Subjects: Amenorrhea - chemically induced; Biological and medical sciences; Cell Proliferation; Contraceptive Agents - pharmacology; Contraceptives, Oral, Synthetic - pharmacology; Endometrium - metabolism; Female; Glucocorticoids - metabolism; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Medical sciences; Microcirculation - drug effects; Mifepristone - pharmacology; Platelet Endothelial Cell Adhesion Molecule-1 - biosynthesis; Receptors, Glucocorticoid - biosynthesis; Receptors, Glucocorticoid - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/del182

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. METHODS AND 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 (E2) 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 ≤ 0.01). CONCLUSION: The high incidence of amenorrhoea in women taking mifepristone may be related to changes in the regulation of vascular function.