Portal de Periódicos da CAPES

Different Effects of Oral and Transdermal Estrogen Replacement Therapy on Matrix Metalloproteinase and Their Inhibitor in Postmenopausal Women

2003; Lippincott Williams & Wilkins; Volume: 23; Issue: 10 Linguagem: Inglês

10.1161/01.atv.0000090569.11739.b9

1524-4636

Akihiko Wakatsuki, Nobuo Ikenoue, Koichi Shinohara, Kazushi Watanabe, Takao Fukaya,

Protease and Inhibitor Mechanisms

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 23, No. 10Different Effects of Oral and Transdermal Estrogen Replacement Therapy on Matrix Metalloproteinase and Their Inhibitor in Postmenopausal Women Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBDifferent Effects of Oral and Transdermal Estrogen Replacement Therapy on Matrix Metalloproteinase and Their Inhibitor in Postmenopausal Women Akihiko Wakatsuki, Nobuo Ikenoue, Koichi Shinohara, Kazushi Watanabe and Takao Fukaya Akihiko WakatsukiAkihiko Wakatsuki Department of Obstetrics and Gynecology Kochi Medical School, Kochi, Japan Search for more papers by this author , Nobuo IkenoueNobuo Ikenoue Department of Obstetrics and Gynecology Kochi Medical School, Kochi, Japan Search for more papers by this author , Koichi ShinoharaKoichi Shinohara Department of Obstetrics and Gynecology Kochi Medical School, Kochi, Japan Search for more papers by this author , Kazushi WatanabeKazushi Watanabe Department of Obstetrics and Gynecology Kochi Medical School, Kochi, Japan Search for more papers by this author and Takao FukayaTakao Fukaya Department of Obstetrics and Gynecology Kochi Medical School, Kochi, Japan Search for more papers by this author Originally published1 Oct 2003https://doi.org/10.1161/01.ATV.0000090569.11739.B9Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1948–1949To 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). Changes in Matrix Metalloproteinases and Their Inhibitor (ng/mL)ControlOralTransdermalBeforeAfterBeforeAfterBeforeAfter*P<0.1;†P<0.05.MMP-11.55±1.821.25±1.111.19±2.021.31±1.321.13±1.041.14±0.73MMP-311.2±6.011.3±6.213.8±6.416.8±8.9†13.8±5.313.3±7.5MMP-925.6±5.228.1±16.125.6±8.925.2±8.031.1±13.033.7±10.8TIMP-168.1±11.969.9±18.471.2±17.263.2±13.1†76.4±14.783.4±19.9*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.This study was supported by Research Grant 12671607 from the Ministry of Education of Japan1 Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998; 280: 605–613.CrossrefMedlineGoogle Scholar2 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.CrossrefMedlineGoogle Scholar3 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.CrossrefMedlineGoogle Scholar4 Zanger D, Yang BK, Ardans J, Waclawiw MA, Csako G, Wahl LM, Cannon RO 3rd. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management. J Am Coll Cardiol. 2000; 36: 1797–1802.CrossrefMedlineGoogle Scholar5 Sattar N, Perera M, Small M, Lumsden MA. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet. 1999; 354: 487–488.CrossrefMedlineGoogle Scholar6 Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, Virkamaki A, Hovatta O, Hamsten A, Taskinen MR, Yki-Jarvinen H. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost. 2001; 85: 619–625.CrossrefMedlineGoogle Scholar7 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.CrossrefMedlineGoogle Scholar8 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.CrossrefMedlineGoogle Scholar9 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.CrossrefMedlineGoogle Scholar10 Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women. Circulation. 2002; 106: 1771–1776.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Comhaire F and Depypere H (2015) Hormones, herbal preparations and nutriceuticals for a better life after the menopause: part I, Climacteric, 10.3109/13697137.2014.985645, 18:3, (358-363), Online publication date: 4-May-2015. Matsuyama Y and Satake M (2013) Three cases of brain infarction with hormone replacement therapy, Nosotchu, 10.3995/jstroke.35.301, 35:4, (301-305), . Pompei L, Steiner M, Theodoro T, Souza P, Romanini A, Coulson-Thomas V, Pinhal M and Fernandes C (2012) Effect of estrogen therapy on vascular perlecan and metalloproteinases 2 and 9 in castrated rats, Climacteric, 10.3109/13697137.2012.667173, 16:1, (147-153), Online publication date: 1-Jan-2012. Miksztowicz V, Siseles N, Machulsky N, Schreier L and Berg G (2012) Increase in MMP-2 activity in overweight and obese women is associated with menopausal status, Climacteric, 10.3109/13697137.2012.667174, 15:6, (602-606), Online publication date: 1-Dec-2012. Mizunuma H (2011) Clinical usefulness of a low-dose maintenance therapy with transdermal estradiol gel in Japanese women with estrogen deficiency symptoms, Climacteric, 10.3109/13697137.2011.570388, 14:5, (581-589), Online publication date: 1-Oct-2011. MICHELS K and MANSON J (2007) Postmenopausal Hormone Therapy in the 21st Century: Reconciling Findings from Observational Studies and Randomized Clinical Trials Treatment of the Postmenopausal Woman, 10.1016/B978-012369443-0/50056-9, (619-626), . Mueck A, Genazzani A, Samsioe G, Vukovic-Wysocki I and Seeger H (2007) Low-dose continuous combinations of hormone therapy and biochemical surrogate markers for vascular tone and inflammation, Menopause, 10.1097/gme.0b013e318054e2e7, 14:6, (978-984), Online publication date: 1-Nov-2007. Manson J, Bassuk S, Harman S, Brinton E, Cedars M, Lobo R, Merriam G, Miller V, Naftolin F and Santoro N (2006) Postmenopausal hormone therapy: new questions and the case for new clinical trials, Menopause, 10.1097/01.gme.0000177906.94515.ff, 13:1, (139-147), Online publication date: 1-Jan-2006. Lewandowski K, Komorowski J, Mikhalidis D, Bienkiewicz M, Tan B, O’Callaghan C, Lewinski A, Prelevic G and Randeva H (2006) Effects of Hormone Replacement Therapy Type and Route of Administration on Plasma Matrix Metalloproteinases and Their Tissue Inhibitors in Postmenopausal Women, The Journal of Clinical Endocrinology & Metabolism, 10.1210/jc.2005-2789, 91:8, (3123-3130), Online publication date: 1-Aug-2006. Mueck A and Seeger H (2009) Biochemical markers surrogating on vascular effects of sex steroid hormones, Gynecological Endocrinology, 10.1080/09513590600629258, 22:3, (163-173), Online publication date: 1-Jan-2006. Cox D and Helvering L (2006) Extracellular matrix integrity: A possible mechanism for differential clinical effects among selective estrogen receptor modulators and estrogens?, Molecular and Cellular Endocrinology, 10.1016/j.mce.2005.12.020, 247:1-2, (53-59), Online publication date: 1-Mar-2006. Sumino H, Ichikawa S, Kasama S, Takahashi T, Kumakura H, Takayama Y, Kanda T and Kurabayashi M (2006) Different effects of oral conjugated estrogen and transdermal estradiol on arterial stiffness and vascular inflammatory markers in postmenopausal women, Atherosclerosis, 10.1016/j.atherosclerosis.2005.12.030, 189:2, (436-442), Online publication date: 1-Dec-2006. Kuhl H and Stevenson J (2009) The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits – an attempt to interpret the Women's Health Initiative results, Gynecological Endocrinology, 10.1080/09513590600717368, 22:6, (303-317), Online publication date: 1-Jan-2006. Allison M and Manson J (2006) Observational studies and clinical trials of menopausal hormone therapy: can they both be right?, Menopause, 10.1097/01.gme.0000194571.05427.87, 13:1, (1-3), Online publication date: 1-Jan-2006. Kuhl H (2009) Pharmacology of estrogens and progestogens: influence of different routes of administration, Climacteric, 10.1080/13697130500148875, 8:sup1, (3-63), Online publication date: 1-Aug-2005. SUMINO H, ICHIKAWA S, KASAMA S, KUMAKURA H, TAKAYAMA Y, SAKAMAKI T and KURABAYASHI M (2005) Effect of Transdermal Hormone Replacement Therapy on Carotid Artery Wall Thickness and Levels of Vascular Inflammatory Markers in Postmenopausal Women, Hypertension Research, 10.1291/hypres.28.579, 28:7, (579-584), . Seed M and Knopp R (2004) Estrogens, lipoproteins, and cardiovascular risk factors: an update following the randomized placebo-controlled trials of hormone-replacement therapy, Current Opinion in Lipidology, 10.1097/01.mol.0000137231.84772.80, 15:4, (459-467), Online publication date: 1-Aug-2004. (2004) Current World Literature, Current Opinion in Lipidology, 10.1097/01.mol.0000137218.37245.2e, 15:4, (469-474), Online publication date: 1-Aug-2004. October 2003Vol 23, Issue 10 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000090569.11739.B9PMID: 14555643 Originally publishedOctober 1, 2003 PDF download Advertisement