Hum. Reprod. Advance Access published online on September 23, 2008
Human Reproduction, doi:10.1093/humrep/den339
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Differential elevation of matrix metalloproteinase expression in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time
1 Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R), Laboratory of Tumor and Development Biology, Centre de Recherche en cancérologie Expérimentale (CRCE), University of Liège, Tour de Pathologie (B23), Sart-Tilman, B-4000 Liège, Belgium 2 Department of Pathology and Cell Biology Unit, Université catholique de Louvain, Bruxelles, Belgium 3 Department of Gynecology, University of Liège, B-4000 Liège, Belgium
4 Correspondence address. Tel: +32-4-366-25-68; Fax: +32-4-366-29-36; E-mail: jmfoidart{at}ulg.ac.be
BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is an effective contraceptive and has many non-contraceptive health benefits. However, it is commonly associated with irregular endometrial bleeding. Metalloproteinases contribute to extracellular matrix (ECM) remodelling and regulate bleeding during the menstrual cycle. Enhanced metalloproteinase expression participates in the pathogenesis of breakthrough bleeding. Thus the objective of this study was to compare matrix metalloproteinase (MMP) expression in endometrium during luteal phase and in short-term (1 month) and long-term (
6 months) LNG-IUS users.
METHODS: MMP expression was analysed by semi-quantitative RT-PCR and immunohistochemistry. Gelatinase activity was determined by gelatin zymography.
RESULTS: MMP-1, -2, -3, -7, -9 and -12 mRNAs levels were increased, whereas that of MMP-26 was decreased in the endometrium of LNG-IUS users. MMP-1, -2, -3, -7 and -9 were localized by immunohistochemistry in all biopsies in the short-term group but in only 0–27% in the control group. The incidence of positive immunostaining for MMP-2 and -3 decreased significantly in the long-term compared with short-term LNG-IUS users. MMP-26 was localized in all biopsies from the control group but in only 14 and 25% from the short- and long-term LNG-IUS groups, respectively. In both LNG groups, the numbers of macrophages (the major source of MMP-12) was increased.
CONCLUSIONS: MMP-1, active MMP-2, MMP-3, MMP-7, MMP-9 and MMP-12 are more prevalent in the short-term LNG-IUS group, suggesting their important contribution to ECM breakdown and transient bleeding. The decrease in the percentage of women expressing MMP-2 and -3 might contribute to the decreased occurrence of unwanted spotting and bleeding in long-term LNG-IUS users.
Key words: levonorgestrel-IUS/matrix metalloproteinases/endometrial bleeding/contraceptive
Submitted on April 28, 2008; resubmitted on July 17, 2008; accepted on August 11, 2008.