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Mechanisms of Irregular Bleeding with Hormone Therapy: The Role of Matrix Metalloproteinases and Their Tissue Inhibitors

School of Women’s and Infants’ Health (M.H., J.C., L.A.M., D.A.D.), University of Western Australia, Perth, Australia 6008; Sydney Centre for Reproductive Health Research (I.S.F.), Family Planning Association Health and Department of Obstetrics and Gynaecology, University of Sydney, Sydney, Australia 2006; and Prince Henry’s Institute of Medical Research (L.A.S.), Melbourne, Victoria, Australia 5152

Address all correspondence and requests for reprints to: Associate Professor Martha Hickey, School of Women’s and Infants’ Health, King Edward Memorial Hospital, Subiaco, Perth, Western Australia 6008. E-mail: mhickey{at}obsgyn.uwa.edu.au.

Context: Irregular bleeding is common in users of combined hormone therapy (HT) and often leads to invasive and expensive investigations to exclude underlying pathology. The mechanisms of HT-related bleeding are poorly understood. Endometrial matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are believed to regulate bleeding during the normal menstrual cycle and are known to be altered in breakthrough bleeding with progestogen-only contraception.

Objective: The aim of this study was to determine how HT exposure alters endometrial production of MMP-1, -3, -9, and -14 and their tissue inhibitors TIMP-1, -2, -3, and -4 and to determine the relationship between MMP and TIMP production and bleeding patterns in HT users. Endometrial leukocytes regulating MMP production and activation were also assessed.

Design: A prospective observational study was conducted between 2003 and 2005.

Setting and Patients: The study occurred at a tertiary referral menopause clinic at King Edward Memorial Hospital, Western Australia, and included 25 postmenopausal women not taking HT and 73 women taking combined HT.

Interventions: Endometrium was obtained during and outside bleeding episodes.

Main Outcome Measures: We assessed production of MMP-1, -3, -9, and -14 and their tissue inhibitors TIMP-1, -2, -3, and -4 and their relationship to bleeding patterns in HT users.

Results: All MMPs studied, with the exception of MMP-9, were expressed at low levels in postmenopausal endometrium. Increases in both MMP-3 and -9 localization were seen in association with irregular bleeding, but these did not reach statistical significance. Endometrial production of TIMP-1 was significantly increased in association with bleeding. Endometrial leukocytes were not related to bleeding, with the exception of uterine natural killer cells, which were significantly increased during bleeding, as previously published.

Conclusions: Irregular bleeding in HT users is associated with a distinct pattern of MMP and TIMP production that differs from that seen in normal menstrual bleeding and from that seen in contraceptive-related breakthrough bleeding. This suggests that the endometrial balance between MMP and TIMP contributes to vascular breakdown with HT but by a different mechanism than that seen in normal menstruation or in breakthrough bleeding.

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