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Mol. Hum. Reprod. Advance Access published online on March 23, 2006
Molecular Human Reproduction, doi:10.1093/molehr/gal014
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received December 1, 2005
Accepted January 9, 2006

Article

Trimegestone differentially modulates the expression of matrix metalloproteinases in the endometrial stromal cell

M. Wahab 1, A.H. Taylor 2, J.H. Pringle 3, J. Thompson 4, and F. Al-Azzawi 5 *

1 George Eliot Hospital, Nuneaton, Warwickshire
2 Reproductive Sciences Section
3 Cell Signalling Section, Department of Cancer Studies and Molecular Medicine
4 Department of Health Sciences, Faculty of Medicine and Biological Sciences, University of Leicester
5 Gynaecology Research Unit, University Hospitals of Leicester, Leicester, UK

* To whom correspondence should be addressed.
F. Al-Azzawi, E-mail: farookalazzawi{at}yahoo.co.uk


  Abstract

Matrix metalloproteinases (MMP) are considered to be of critical importance in the initiation of menstruation where MMP protein levels are reciprocally modulated by the actions of the gonadal steroid hormones, estradiol (E2) and progesterone (P4), with P4 being considered the principal suppressor of endometrial MMP expression. Trimegestone (T) is a novel progestagen that tightly controls menstruation timing and duration through mechanisms that might involve MMP suppression. Endometrial stromal cells treated with 10-6 M E2, P4 or T in the presence and absence of 10-6M RU486 showed that both T and P4 suppressed the expression of MMP-1 and MMP-3 transcripts and secreted protein, whereas MMP-9 was not produced in culture. The suppressive effect of T or P4 on MMP-1 and MMP-3 transcript levels was enhanced in the presence of E2 and attenuated in the presence of RU486, although MMP-1 proteins were unaffected by the presence of RU486, which alone acted as a partial progesterone agonist in these cultures. Immunohistochemistry with MMP-1, MMP-3 and MMP-9-specific antibodies performed on endometrial biopsies obtained from non-treated, LH-dated, normally cycling women and endometrial biopsies obtained from postmenopausal women treated with T-based HRT showed that immunoreactive MMP-1 and MMP-3 was higher in the menstrual phase, whilst MMP-9 expression was higher in the late luteal phase (P = 0.03) and T significantly inhibited the presence of MMP-9+ cells. These data suggest that T acts in a similar manner to P4, but causes subtle differences in expression patterns of MMPs that may explain the different clinical effect that this progestagen has on endometrial behaviour compared to P4.

Keywords: endometrium/HRT/metalloproteinases/progesterone/trimegestone.
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