(Circulation. 2001;104:e146.)
© 2001 American Heart Association, Inc.
Correspondence |
Does Tamoxifen Enhance Endothelial Function by Lowering the Plasma Levels of Homocysteine?
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine, IRCCS Ospedale Maggiore, University of Milano, Via Pace 9, 122 Milano, Italy, marco.cattaneo@unimi.it
To the Editor:
In their interesting study, Clarke et al1 showed that treatment with tamoxifen (40 mg/d) for 56 days caused an increase in endothelium-dependent flow-mediated dilatation (ED-FMD) of the brachial artery in men with angiographically proven coronary artery disease (CAD) and in men with angina-like symptoms but normal coronary arteries (as shown by angiography). In contrast, tamoxifen did not affect endothelium-independent FMD in the same subjects. The ED-FMD response to tamoxifen was unlikely to have been caused by the associated increase in plasma estradiol or a reduction in plasma cholesterol levels.1
A possible mechanism for the observed enhanced endothelial function in men treated with tamoxifen could be the reduction in plasma total homocysteine (tHcy) levels. High tHcy levels are associated with increased risk for CAD and other atherothrombotic diseases.2 Compelling evidence indicates that both long- and short-term (induced by oral methionine loading) increases in the plasma levels of tHcy impair the ED-FMD of the brachial artery without affecting endothelium-independent FMD. Two studies showed that the oral administration of folic acid, alone3 or in combination with vitamin B12,4 improved the ED-FMD in patients with CAD. The improvement in ED-FMD correlated with the reduction in total3 or free Hcy levels4 caused by vitamin treatment. Tamoxifen, at oral doses ranging between 20 and 30 mg/d, reduces tHcy levels not only in patients with advanced breast cancer,2 but also in healthy women,5 indicating that its lowering effect is not only due to its antitumoral activity, but also to its direct effect on estrogen-regulated targets. The reduction of tHcy levels by tamoxifen (20 mg/d) was seen in women with moderate hyperhomocystinemia and in women with normal tHcy levels.5 On the basis of these considerations, it seems reasonable to hypothesize that the improvement of vascular endothelial function after treatment with tamoxifen, as described by Clarke et al,1 can be attributed, at least in part, to the lowering effect of the drug on plasma tHcy levels.
References
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Clarke CC, Schofield PM, Grace AA, et al. Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation. 2001; 103: 1497–1502.
[Abstract/Free Full Text]
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Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost. 1999; 81: 165–176.[Medline]
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Title LM, Cummings PM, Giddens K, et al. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol. 2000; 36: 758–765.
[Abstract/Free Full Text]
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Chambers JC, Ueland PM, Obeid OA, et al. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation. 2000; 102: 2479–2483.
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Cattaneo M, Baglietto L, Zighetti ML, et al. Tamoxifen reduces plasma homocysteine levels in healthy women. Br J Cancer. 1998; 77: 2264–2266.[Medline]
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Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis
Assistant Professor, Laboratory of Physiology, Medical School, University of Ioannina, Ioannina, Greece, margyrop@cc.uoi.gr
Professor, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
To the Editor:
We read with great interest the article by Clarke et al1 assessing the effects of tamoxifen on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. The authors found that endothelium-dependent flow-mediated dilatation of the brachial artery was substantially increased after tamoxifen therapy in men with coronary artery disease (CAD). Thus, they suggest that tamoxifen and other selective estrogen receptor modulators should be clinically evaluated for the treatment of men with CAD.1 However, they did not take into account important safety issues regarding the long-term use of tamoxifen. Many studies performed in rats have shown an association between the administration of tamoxifen and the development of hepatocellular carcinoma (HCC).2,3 No studies thus far have demonstrated an increased incidence of HCC in women treated with tamoxifen. However, the above studies followed patients for <5 years. It is probable that an increased risk of HCC may not become apparent until after a longer period of tamoxifen treatment. Furthermore, in these patients, HCC might be under-reported because liver biopsies were rarely performed, because tumor lesions in the liver are considered metastatic from the breast. Moreover, several cases of liver cancer were recently reported after long-term treatment with tamoxifen.4,5 It is of interest to note that the histological pattern of these lesions is similar to that seen in tamoxifen-induced HCC occurring in rat models.
According to the results of the study by Clarke et al,1 to have a substantial clinical benefit, men with CAD should be treated with tamoxifen for a very long time, possibly for the rest of their lives. Consequently, we think that although tamoxifen might have some beneficial effects on the coronary arteries, it may not be an appropriate treatment for men with CAD.
References
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Clarke SC, Schofield PM, Grace A, et al. Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation. 2001; 103: 1497–502.
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Hirsimaki P, Hirsimaki Y, Nieminen L, et al. Tamoxifen induces hepatocellular carcinoma in rat liver: a 1-year study with two antiestrogens. Arch Toxicol. 1993; 67: 49–4.[Medline]
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Karki A, Mantyla E, Hirsimaki Y, et al. Comparison of the effects of tamoxifen and toremifene on rat hepatocarcinogenesis. Arch Toxicol. 2000; 74: 240–56.
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Law CH, Tandan VR. The association between tamoxifen and the development of hepatocellular carcinoma: case report and literature review. Can J Surg. 1999; 42: 211–14.[Medline]
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Moffat DF, Oien KA, Dickson J, et al. Hepatocellular carcinoma after long-term tamoxifen therapy. Ann Oncol. 2000; 11: 1195–196.
[Abstract/Free Full Text]
Effects of Tamoxifen on Endothelial Function and Cardiovascular Risk Factors in Men With Advanced Atherosclerosis
Department of Cardiology, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK S10 2JF, kevin.channer@csuh.nhs.uk
To the Editor:
We read with interest the article by Clarke et al1 regarding the effects of tamoxifen in men with or without coronary artery disease. The rationale behind studying the effects of selective estrogen receptor modulators in men was that high-dose estrogen therapy may modulate their cardiovascular risk factors; however, unacceptable side effects preclude its use. In fact, estrogen therapy seems to be detrimental to the male cardiovascular system. The Coronary Drug Project, a large study of secondary prevention of myocardial infarction, was stopped early in 1970 after a 2-fold excess of nonfatal myocardial infarction and a 3.5% excess of coronary death in men treated with conjugated estrogens.2
The authors report that tamoxifen treatment increased endothelium-dependent vasodilatation and improved several cardiovascular risk factors. They postulate that these changes may be associated with the witnessed increase in estradiol levels of 40%. Unfortunately, despite a much greater increase (82%) in testosterone levels, the authors have not fully considered this effect. This increase in testosterone levels may help explain the findings of this study because it has been repeatedly demonstrated that testosterone acts as a potent vasodilator.3 These experimental findings are well-supported by clinical studies demonstrating the beneficial effects of testosterone on myocardial ischemic threshold.4 Changes in testosterone levels have also been shown to be associated with improvements in lipid profile and changes in levels of coagulation factors.5 Although the witnessed effects of tamoxifen are interesting, a failure to discuss the effects of the increased levels of androgens is misleading to those not familiar with the literature. Promotion of further research into the effects of selective estrogen receptor modulators in men without due consideration of the beneficial effects of androgens and the potentially detrimental effects of estrogens may be unwise.
References
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Clarke SC, Schofield PM, Grace AA, et al. Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation. 2001; 103: 1497–1502.
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The Coronary Drug Project. Initial findings leading to modifications of its research protocol. JAMA. 1970; 214: 1303–1313.[Medline]
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Ong PJL, Patrizi G, Chong WCF, et al. Testosterone enhances flow mediated brachial artery reactivity in men with coronary artery disease. Am J Cardiol. 2000; 85: 269–272.[Medline]
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English KM, Steeds RP, Diver MJ, et al. Low dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina. Circulation. 2000; 102: 1906–1912.
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English KM, Steeds RP, Jones TH, et al. Testosterone and coronary heart disease: is there a link? Q J Med. 1997; 90: 787–791.[Medline]
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Response
Department of Cardiology, Papworth Hospital NHS Trust, Papworth Everard, UK
Department of Biochemistry, University of Cambridge, Cambridge, UK
Kiortsis and Elisaf question the safety of women being treated very-long-term with tamoxifen in relation to hepatocellular carcinoma (HCC). They cite 2 case reports of patients who developed HCC, one after tamoxifen treatment for 6 years and the other after treatment for 12 years.1,2 We agree that no studies have demonstrated an increased incidence of HCC in women treated with tamoxifen since it was licensed by the Food and Drug Administration (FDA) in 1977 and with others who concluded that "small and/or later increases in the risk of HCC are possible and warrant continued monitoring of women treated with tamoxifen."3 The same conclusion applies to men if phase 3 trials support the medium-term safety and efficacy of tamoxifen or other selective estrogen receptor modulators (SERMs) for cardiovascular indications.
The studies quoted by Kiortis and Elisaf show an association between the administration of tamoxifen and the development of HCC in rats. However, other investigators have concluded that the clinical risks have been inappropriately linked to these studies because much higher doses were administered to rats than those used for women.4 SERMs other than tamoxifen may be more appropriate for treating women with coronary artery disease (CAD) because of the small risk of endometrial cancer associated with tamoxifen therapy. A phase 3 trial of raloxifene (Raloxifene Use for The Heart [RUTH]) for CAD in women is in progress.
Kiortis and Elisaf comment that our study, in which patients were treated with tamoxifen for 56 days,5 shows that "to have a substantial clinical benefit, men with CAD should be treated with tamoxifen for a very long time, possibly for the rest of their lives." If phase 3 clinical trials demonstrate that SERMs have therapeutic benefit for CAD, the duration of treatment required will also require clinical evaluation. It is not known whether treatment with tamoxifen or other SERMs will cause regression and/or stabilization of atherosclerotic plaques or whether such effects will be maintained after therapy is terminated.
The interesting question of the mechanism of tamoxifen effects on endothelial function and the role of the hormone responses is raised by English, Pugh, and Channer. We noted that there were no correlations at baseline between endothelial function and levels of estradiol or any of the other parameters assayed, including testosterone. Therefore, we suggested that "the estradiol response to tamoxifen is unlikely to be a major determinant of enhanced endothelial function." We have subsequently examined the effect of testosterone on endothelial function in a placebo-controlled and blinded study of men with CAD, which was completed in July 2001.
We agree with the point raised by Cattaneo that the improvement in vascular endothelial function after treatment with tamoxifen may be caused, in part, by a reduction in total plasma homocysteine levels. Studies of the effects of tamoxifen on a number of cardiovascular risk factors and markers of endothelial dysfunction, including homocysteine levels, are in progress.
References
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Law CH, Tandan VR. The association between tamoxifen and the development of hepatocellular carcinoma: case report and literature review. Can J Surg. 1999; 42: 211–14.
-
Moffat DF, Oien KA, Dickson J, et al. Hepatocellular carcinoma after long-term tamoxifen therapy. Ann Oncol. 2000; 11: 1195–196.
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Muhlemann K, Cook LS, Weiss NS. The incidence of hepatocellular carcinoma in US white women with breast cancer after the introduction of tamoxifen in 1977. Breast Cancer Res Treat. 1994; 30: 201–204.[Medline]
[Order article via Infotrieve]
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Yao K, Jordan C. Questions about tamoxifen and the future use of antiestrogens. Oncologist. 1998; 3: 104–110.
[Abstract/Free Full Text]
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Clarke SC, Schofield PM, Grace AA, et al. Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis. Circulation. 2001; 103: 1497–1502.
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