Differential elevation of matrix metalloproteinase expression in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time.
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 (> or =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.
Labied
Soraya
S
Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R), Laboratory of Tumor and Development Biology, Centre de Recherche en cancérologie Expérimentale, University of Liège, Tour de Pathologie (B23), Sart-Tilman, B-4000 Liège, Belgium.
Galant
Christine
C
Nisolle
Michelle
M
Ravet
Stéphanie
S
Munaut
Carine
C
Marbaix
Etienne
E
Foidart
Jean-Michel
JM
Frankenne
Francis
F
D000328:Adult; D003271:Contraceptive Agents, Female / Q000008:administration & dosage* / Q000494:pharmacology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007436:Intrauterine Devices, Medicated; D016912:Levonorgestrel / Q000008:administration & dosage* / Q000494:pharmacology; D008183:Luteal Phase / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D003271:Contraceptive Agents, Female; D012333:RNA, Messenger; D016912:Levonorgestrel; D018093:Gelatinases; D020782:Matrix Metalloproteinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9