Correspondence
Estrogen Therapy and Coronary-Artery Calcification
N Engl J Med 2007; 357:1252-1254September 20, 2007
- Article
To the Editor:
In their article on the Women's Health Initiative Coronary-Artery Calcium Study (WHI-CACS), Manson et al. (June 21 issue)1 provide insight into another mechanism by which estrogen therapy reduces coronary heart disease (CHD) in women who have undergone hysterectomy and who initiate such therapy close to menopause.2 The authors' findings further support the hypothesis that early initiation of such therapy has a beneficial effect.3
For women under the age of 60 years, scientific evidence indicates that estrogen therapy is as efficacious in reducing CHD as are other primary prevention therapies, such as lipid-lowering drugs and aspirin, and is more effective in reducing total mortality.4 For women in this age group, estrogen therapy has a risk profile that is no greater than that of other medications used for primary prevention of CHD in women.4 Studies by the WHI, other randomized trials, and observational studies (including the WHI observational study) show significant trends toward a greater benefit with respect to total mortality and CHD with a longer duration of estrogen therapy.2,4
WHI-CACS was similar to the Estrogen in the Prevention of Atherosclerosis Trial5 in providing mechanistic evidence for a role of estrogen therapy in the prevention of CHD in postmenopausal women. WHI not only has confirmed the known benefits from observational studies but also has clearly shown the relative safety of estrogen therapy under randomized, controlled conditions in women under the age of 60 years (Table 1Table 1
Effect of Therapy with Conjugated Equine Estrogen on Major Outcomes in Women under the Age of 60 Years.).2,4 Howard N. Hodis, M.D.
Wendy J. Mack, Ph.D.
University of Southern California, Los Angeles, CA 90033
athero@usc.edu Dr. Hodis reports receiving consulting fees from Wyeth. No other potential conflict of interest relevant to this letter was reported.
5 References1
Manson JE ,Allison MA ,Rossouw JE , et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-2602
Full Text | Web of Science | Medline2
Hodis HN ,Mack WJ . Postmenopausal hormone therapy and cardiovascular disease: making sense of the evidence. Curr Cardiovasc Risk Rep 2007;1:138-147
CrossRef3
Hodis HN ,Mack WJ ,Azen SP , et al. Hormone therapy and progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med 2003;349:535-545
Full Text | Web of Science | Medline4
Hodis HN, Mack WJ. Postmenopausal hormone therapy in clinical perspective. Menopause (in press).
5
Hodis HN ,Mack WJ ,Lobo RA , et al. Estrogen in the Prevention of Atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939-953
Web of Science | Medline
To the Editor:
With regard to the report by Manson et al. on the effect of estrogen therapy on calcium scores in a subgroup of middle-aged women from the WHI trial,1 we feel it is somewhat unfortunate to state that the data provide some reassurance that estrogen therapy may not be harmful. Conclusions with regard to clinical outcome should be drawn only from trials that are designed and powered to address clinical events. If a surrogate end point is presented, it should have an established association with a clinical outcome and be obtained in a trial with optimal methodology.
The WHI trial was not designed to address the effect of estrogen on calcium scores, which accounts for the lack of a baseline calcium score and explains why modifiable risk factors (e.g., smoking) and the use of concomitant medication were not routinely scored during follow-up. Moreover, in low-risk subjects, the prognostic effect of calcium scores is far from established.2,3 In our opinion, the reported effects of estrogen therapy on calcium scores should be considered as hypothesis-generating. We look forward to the clinical follow-up after computed tomography has been performed to provide insight into the possible prognostic value of these findings.
3 ReferencesMarc A. Brouwer, M.D., Ph.D.
Hendrik-Jan Dieker, M.D.
Freek W.A. Verheugt, M.D., Ph.D.
Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, the Netherlands
m.brouwer@cardio. umcn. nl 1
Anderson GL ,Limbacher M ,Assaf AR , et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701-1712
CrossRef | Web of Science | Medline2
ACC/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain. J Am Coll Cardiol 2007;49:378-402
CrossRef | Web of Science | Medline3
Greenland P ,LaBree L ,Azen SP , et al. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291:210-215
CrossRef | Web of Science | Medline
To the Editor:
Manson et al. convincingly show that estrogen-only replacement therapy, when started between the ages of 50 and 59 years in postmenopausal women who have undergone hysterectomy, reduced coronary-artery calcification. This article and the accompanying editorial by Mendelsohn and Karas1 provide us with valuable arguments when translating evidence into clinical practice. Since bone represents the body's largest storage compartment for calcium, and estrogen-only replacement therapy increased bone mass,2 the antiresorptive effects of estrogen may have contributed to reduced vascular calcification by reducing the efflux of calcium from bone. Were bone markers or measurements of bone mineral density available for these women, and were such measures correlated with calcification scores?
As the authors mention, the vascular effects of estrogens are complex and occur at multiple levels, including gene expression of bone-related factors.1 Osteoprotegerin represents an estrogen-responsive cytokine with skeletal and vascular effects,3 and deletion of this protein in mice leads to osteoporosis and vascular calcification.4 Were serum osteoprotegerin levels assessed in this study? In our opinion, this cohort represents a pivotal opportunity to shed further light on the mechanisms underlying the osteoporosis–vascular calcification syndrome.
4 ReferencesLorenz C. Hofbauer, M.D.
Technical University Medical Center, D-01307 Dresden, Germany
lorenz.hofbauer@uniklinikum-dresden. de Sundeep Khosla, M.D.
Mayo Clinic College of Medicine, Rochester, MN 55905Michael Schoppet, M.D.
Philipps University, D-35033 Marburg, Germany1
Mendelsohn ME ,Karas RH . HRT and the young at heart. N Engl J Med 2007;356:2639-2641
Full Text | Web of Science | Medline2
Jackson RD ,Wactawski-Wende J ,LaCroix AZ , et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized trial. J Bone Miner Res 2006;21:817-828
CrossRef | Web of Science | Medline3
Hofbauer LC ,Schoppet M . Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004;292:490-495
CrossRef | Web of Science | Medline4
Bucay N ,Sarosi I ,Dunstan CR , et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998;12:1260-1268
CrossRef | Web of Science | Medline
Author/Editor Response
Hodis and Mack state that for women under the age of 60 years who have undergone hysterectomy, estrogen reduces CHD and is more effective in reducing total mortality than are other primary prevention therapies. Moreover, they assert that the WHI has “clearly shown” the relative safety of estrogen therapy in women under 60. We disagree that the WHI conclusively showed that estrogen therapy reduces either CHD or total mortality in younger women. Although younger women receiving estrogen appeared to have a more favorable balance of benefits and risks than did older women, interaction tests according to age showed only borderline significance.1
In addition, it remains unclear whether with prolonged treatment any coronary benefits of estrogen therapy in women under the age of 60 years would persist at older ages, when coronary events become more frequent. We do believe that the WHI findings on estrogen therapy in younger women, combined with the low absolute rates of vascular events in this age group, provide some reassurance to recently menopausal women who are considering hormone therapy for the short-term treatment of menopausal symptoms. However, in light of other risks, we believe that hormone therapy should not be used for the prevention of CHD or other chronic diseases.
We agree with Brouwer and colleagues that conclusions with regard to clinical outcomes should be drawn from trials designed and powered to address clinical events. However, we did not state that the data provide reassurance that estrogen therapy may not be harmful. Indeed, we noted explicitly that “other risks and benefits of treatment must be considered,” even though estrogen is “unlikely to have an adverse effect on the risk of coronary events among women who have recently undergone menopause.” However, coronary-artery calcium scores do appear to improve prediction of the risk of CHD, even in asymptomatic persons at relatively low risk for CHD.2
Finally, we concur with Hofbauer et al. that the mechanisms underlying the relationship between estrogen and vascular calcification, including the possible role of antiresorptive effects of estrogen, warrant further study. We do not have data on serum osteoprotegerin levels, and we have data on bone mineral density for only a small number of women, so we cannot address the correlations proposed by Hofbauer et al. Notably, a postmortem study of coronary arteries suggested that estrogen therapy was associated with both a smaller plaque area and reduced calcium content.3 Coronary-artery calcium scores in WHI-CACS were strongly correlated with traditional risk factors for CHD, including smoking, hypertension, hypercholesterolemia, and diabetes, suggesting a strong correlation with atheromatous plaque burden. We hope that future analyses of data from WHI-CACS and other studies will further elucidate the mechanistic basis for the relationships we observed.
3 ReferencesJoAnn E. Manson, M.D., Dr.P.H.
Harvard Medical School, Boston, MA 02115
jmanson@rics.bwh. harvard. edu Matthew A. Allison, M.D., M.P.H.
University of California, San Diego, La Jolla, CA 92037Jacques E. Rossouw, M.D.
National Heart, Lung, and Blood Institute, Bethesda, MD 208921
Rossouw JE ,Prentice RL ,Manson JE , et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-1477
CrossRef | Web of Science | Medline2
Budoff MJ ,Achenbach S ,Blumenthal RS , et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 2006;114:1761-1791
CrossRef | Web of Science | Medline3
Christian RC ,Harrington S ,Edwards WD ,Oberg AL ,Fitzpatrick LA . Estrogen status correlates with the calcium content of coronary atherosclerotic plaques in women. J Clin Endocrinol Metab 2002;87:1062-1067
CrossRef | Web of Science | Medline
