Differential elevation of matrix metalloproteinase expression in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time

Hum Reprod. 2009 Jan;24(1):113-21. doi: 10.1093/humrep/den339. Epub 2008 Sep 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Contraceptive Agents, Female / administration & dosage*
  • Contraceptive Agents, Female / pharmacology
  • Endometrium / cytology
  • Endometrium / drug effects*
  • Endometrium / metabolism
  • Female
  • Gelatinases / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Immunohistochemistry
  • Intrauterine Devices, Medicated*
  • Levonorgestrel / administration & dosage*
  • Levonorgestrel / pharmacology
  • Luteal Phase / drug effects*
  • Luteal Phase / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinases / genetics
  • Matrix Metalloproteinases / metabolism*
  • Middle Aged
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors


  • Contraceptive Agents, Female
  • RNA, Messenger
  • Levonorgestrel
  • Gelatinases
  • Matrix Metalloproteinases
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9