Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding?
BACKGROUND
Abnormal uterine bleeding is commonly associated with progestin-only contraceptives, including depot medroxyprogesterone acetate (DMPA), and remains the main reason why these agents are discontinued. Matrix metalloproteinases (MMP), enzymes which degrade specific extracellular matrix components, and leukocytes are implicated in menstruation. Alteration in endometrial MMP-9 and leukocytes has been described in users of other progestin-only contraceptives, suggesting a potential role in the pathogenesis of abnormal uterine bleeding.


METHODS
This study describes the immunohistochemical localization of MMP-9, the tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2 and TIMP-3, and leukocytes [CD3+ T lymphocytes, CD68+ macrophages and CD56+ uterine natural killer cells (uNK cells)] in the endometrium of women using DMPA. Comparison is made with perimenstrual endometria from normal cycling women.


RESULTS
Similar to the perimenstrual period, an influx of MMP-9 positive cells (identified as neutrophils and CD3+ T cells on the basis of dual immunofluorescence), macrophages and uNK cells was observed in the endometrium of DMPA users. However, significantly more endometrial T lymphocytes were observed in DMPA users. Immunoreactive TIMP, present in all endometrial compartments, demonstrated a significantly decreased immunostaining intensity score in endometrial epithelium (TIMP-1 and TIMP-2), stroma (TIMP-1, TIMP-2 and TIMP-3), endothelium (TIMP-1 and TIMP-2) and vascular smooth muscle (TIMP-1) of DMPA users compared with controls. No correlation was observed between the parameters studied and bleeding patterns reported by subjects.


CONCLUSIONS
These findings provide additional evidence for the importance of the MMP/TIMP balance in the loss/maintenance of endometrial integrity and in the complex pathological mechanisms involved in the troubling side-effect of menstrual bleeding disturbance.
Vincent
A J
AJ
Prince Henry's Institute of Medical Research, P.O.Box 5152, Clayton, Victoria, 3168, Australia.
Zhang
J
J
Ostör
A
A
Rogers
P A W
PA
Affandi
B
B
Kovacs
G
G
Salamonsen
L A
LA
D003271:Contraceptive Agents, Female / Q000008:administration & dosage* / Q000009:adverse effects*; D003692:Delayed-Action Preparations; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage* / Q000009:adverse effects*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014592:Uterine Hemorrhage / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
D003271:Contraceptive Agents, Female; D003692:Delayed-Action Preparations; D020033:Protein Isoforms; D019714:Tissue Inhibitor of Metalloproteinases; D017258:Medroxyprogesterone Acetate; D020780:Matrix Metalloproteinase 9