doi: 10.1161/01.ATV.0000090569.11739.B9
© 2003 American Heart Association, Inc.
Letter to the Editor |
Different Effects of Oral and Transdermal Estrogen Replacement Therapy on Matrix Metalloproteinase and Their Inhibitor in Postmenopausal Women
Department of Obstetrics and Gynecology Kochi Medical School, Kochi, Japan
To the Editor:
The Heart and Estrogen/Progestin Replacement Study1 and the Women’s Health Initiative2 showed no benefit of oral hormone replacement therapy (HRT) on the risk of coronary heart disease (CHD). Oral estrogen replacement therapy (ERT) has been reported to elevate plasma concentrations of C-reactive protein (CRP), an independent risk factor for cardiovascular disease in healthy postmenopausal women.3 Macrophages in human atherosclerotic plaques produce matrix metalloproteinase (MMP) that degrades collagen and elastin, the major components of the extracellular matrix in the fibrin cap, and predispose it to rupture with thrombus formation. Although little is known about the effect of HRT on MMP, one clinical study has demonstrated that oral ERT increases plasma concentrations of MMP in women with CHD.4 It is likely, therefore, that raised levels of CRP and MMP induced by oral ERT may account in part for the increased number of early cardiovascular events observed in the recent trials. In contrast to oral ERT, plasma CRP concentration is reduced5 or not influenced6 by transdermal ERT. Accordingly, neutral effect of transdermal ERT on CRP might possibly be associated with a safer profile on early CHD risk. However, the effect of transdermal ERT on MMP has not been evaluated. In the present study, to investigate whether transdermal ERT can eliminate oral estrogen’s adverse effects, we measured plasma concentrations of MMP and their inhibitors such as tissue inhibitor of MMP (TIMP) in postmenopausal women treated with estrogen orally or transdermally.
Subjects in the oral estrogen group (n=20) received 0.625 mg oral conjugated equine estrogen (CEE) daily, and those in the transdermal estrogen group (n=19) received 17-beta estradiol (E2) patch (absorption rate, 50 µg/d) for 3 months. Subjects in the control group (n=15) did not receive any treatment for 3 months. CEE significantly increased the concentration of MMP-3, but significantly reduced TIMP-1 concentrations. In contrast, transdermal E2 tended to increase the concentration of TIMP-1, but MMP-3 concentrations did not change significantly. Concentrations of MMP-1 and MMP-9 did not change significantly in any group. No significant changes were observed in these parameters in the control group (Table).
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MMP and TIMP-1 are secreted by monocyte-derived macrophages and smooth muscle cells. MMP-1 cleaves collagen types I, II, and III; MMP-3 is active on collagen types IV, IX, and X, whereas MMP-9 degrades denatured collagen and elastin. In the present study, oral ERT increased MMP-3 and decreased TIMP-1 concentrations. One clinical study has demonstrated that postmenopausal ERT increases serum levels of MMP-9.4 In addition, 17-beta E2 has been reported to be a specific stimulator of MMP-2 derived from vascular cells.7 Because MMP degrades collagen obtained from fibrin caps of human atherosclerotic plaques and their inhibitors such as TIMP-1 block this process, our results indicate that oral ERT may increase the plaque vulnerability. In contrast, transdermal ERT did not change MMP concentrations, but tended to increase TIMP-1 concentrations, suggesting that transdermal ERT may be less likely to promote plaque destabilization and rupture.
In the present study, CEE was administered orally and 17-beta E2 was administered transdermally. Previous findings demonstrated that oral CEE increased,3 while transdermal E2 decreased plasma CRP concentration.5 In addition, our results demonstrated that oral CEE but not transdermal E2 increased MMP-3 and decreased TIMP-1. Based on these findings, estrone (E1) but not E2 appears to have a pro-inflammatory effect. However, two randomized trials demonstrated that either opposed or nonopposed oral CEE and 17-beta E2 raised CRP concentrations.8,9 Furthermore, Wingrove et al7 have demonstrated that 17-beta E2 enhances release of MMP-2 from vascular smooth muscle cells. These studies indicate that E2 as well as E1 may have a pro-inflammatory effect. Therefore, a different route of estrogen administration may affect plasma concentrations of vascular inflammatory markers.
The present study demonstrates that while oral ERT produces an imbalance between MMP and TIMP, transdermal ERT reverses this adverse effect. In addition, our previous findings have also demonstrated that transdermal ERT can ameliorate the adverse effects of oral ERT on size and oxidative susceptibility of LDL.10 Further studies are needed to investigate whether transdermal ERT can prevent increases in the risk of CHD in women with or without coronary disease.
Acknowledgments
This study was supported by Research Grant 12671607 from the Ministry of Education of Japan
References
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2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288: 321–333.
3. Ridker PM, Hennekens CH, Rifai N, Buring JE, Manson JE. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation. 1999; 100: 713–716.
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7. Wingrove CS, Garr E, Godsland IF, Stevenson JC. 17beta-oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells. Biochim Biophys Acta. 1998; 1406: 169–174.[Medline] [Order article via Infotrieve]
8. van Baal WM, Kenemans P, van der Mooren MJ, Kessel H, Emeis JJ, Stehouwer CD. Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost. 1999; 81: 925–928.[Medline] [Order article via Infotrieve]
9. Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP. Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation. 1999; 100: 717–722.
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