Skip Navigation


American Journal of Epidemiology Advance Access originally published online on October 31, 2007
American Journal of Epidemiology 2007 166(12):1479-1480; doi:10.1093/aje/kwm303
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
166/12/1479    most recent
kwm303v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Dören, M.
Right arrow Articles by Greiser, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dören, M.
Right arrow Articles by Greiser, E. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

LETTERS TO THE EDITOR

RE: "INVITED COMMENTARY: HORMONE THERAPY AND RISK OF CORONARY HEART DISEASE—WHY RENEW THE FOCUS ON THE EARLY YEARS OF MENOPAUSE?"

Martina Dören1 and Eberhard M. Greiser2

1 Clinical Research Center of Women's Health, Charité-Universitätsmedizin Berlin, D-12200 Berlin, Germany
2 Institute for Public Health and Nursing Research, Faculty of Health Sciences, Bremen University, D-28259 Bremen, Germany

(e-mail: martina.doeren{at}charite.de)

The meta-analysis by Salpeter et al. (1) is ineligible to support the validity of the "timing hypothesis" discussed by Manson and Bassuk in a recent Journal article (2), because this work suffers from methodological shortcomings. The objective to disentangle associations between coronary heart disease and use of menopausal hormone therapies was obscured by including not only trials with defined coronary heart disease events, monitored and analyzed as primary or secondary outcomes, but also trials reporting adverse events. Eight of 12 included studies of women younger than age 60 years (3–10) report adverse events, not primary or secondary endpoints [(1), figure 1]. Likewise, five of 13 trials of women older than age 60 years also provide only adverse events [(11–15); (1), figure 2]. The authors (1) included studies that had zero coronary heart disease events in one group and one event in the other group, a situation not enabling relative risks to be calculated. It would also have been more suitable to report woman-years instead of numbers of women when calculating relative risks. Data on safety outcomes including adverse events are subject to bias due to selective reporting (16). Therefore, it is reasonable to perform meta-analyses based on predefined outcomes intended for comparison between groups (17). Finally, the results of a test of interaction was not reported (1), useful to examine age effects (18).

Three further recent meta-analyses (19–21) address cardiovascular risk in conjunction with menopausal hormone therapies. These analyses were based on trials with coronary heart disease events as the primary or secondary trial outcomes. One Cochrane review (19) with the objective to determine the effects of menopausal hormone therapies for the prevention of cardiovascular diseases analyzed specified cardiovascular events studied as primary or secondary outcomes. The authors concluded on the basis of 10 trials that there was no evidence for a protective effect for any outcome. However, results of subgroup analyses regarding interactions of chronological age and/or age at menopause in conjunction with initiation of menopausal hormone therapies were not reported. A second Cochrane review (20), based on inclusion of 15 randomized, placebo-controlled, double-blinded trials reporting myocardial infarction or coronary death, concluded that combined continuous menopausal hormone therapies increased the risk of coronary events after use for 1, 2, 3, and 4 years, not after a mean of 5.6 years. There was no change in coronary heart disease risk for unopposed estrogen therapy. Their analyses did not indicate any difference between menopausal hormone therapies and placebo groups regarding death from any cause or death from coronary heart disease. The authors stated that no trial focused on younger women. Obviously, analyses and conclusions of both studies (19, 20) were influenced by the relative weight of the Women's Health Initiative trials. A third meta-analysis (21) based on seven trials concluded that menopausal hormone therapies did not significantly change the risk of all-cause mortality, of coronary heart disease death, or of nonfatal acute myocardial infarction.

Manson and Bassuk (2) refer to a further meta-analysis (22) in the context of mortality reduction by menopausal hormone therapies. Unfortunately, this report also suffers from shortcomings (16–18). Additionally, we are concerned about the validity of findings because one trial, providing the relatively largest proportion of cases among younger women (32 of 53), included ovarian cancer survivors.

Finally, we wonder why the risk of stroke, apart from risks for other endpoints, was not considered when examining the appropriateness of the timing hypothesis (2). According to post-hoc analyses of Women's Health Initiative data, reporting upon the largest number of confirmed coronary endpoints and applying a uniform coding scheme for age and years since menopause (23), the risk of stroke did not vary significantly by age or time since menopause. Thus, stroke risk is of relevance and should be part of any decision making regarding use of menopausal hormone therapies in younger and older women alike.


   ACKNOWLEDGMENTS
 
Conflict of interest: none declared.


   References
TOP
 References
 

  1. Salpeter SR, Walsh JME, Greyber E, et al. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. J Gen Intern Med (2006) 21:363–6.[CrossRef][Web of Science][Medline]
  2. Manson JE, Bassuk SS. Invited commentary: hormone therapy and risk of coronary heart disease—why renew the focus on the early years of menopause? Am J Epidemiol (2007) 166:511–17.[Abstract/Free Full Text]
  3. Hall GM, Daniels M, Doyle DV, et al. Effect of hormone replacement therapy on bone mass in rheumatoid arthritis patients treated with and without steroids. Arthritis Rheum (1994) 37:1499–505.[Web of Science][Medline]
  4. Komulainen M, Kröger H, Tuppurainen MT, et al. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women. A population-based 5-year randomized trial. J Clin Endocrinol Metab (1999) 84:546–52.[Abstract/Free Full Text]
  5. Mosekilde L, Beck-Nielsen H, Sørensen OH, et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas (2000) 36:181–93.[CrossRef][Web of Science][Medline]
  6. Nachtigall LE, Nachtigall RH, Nachtigall RD, et al. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol (1979) 54:74–9.[Web of Science][Medline]
  7. Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med (1999) 131:935–42.[Abstract/Free Full Text]
  8. Samaras K, Hayward CS, Sullivan D, et al. Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolisms, and vascular factors in type 2 diabetes: a prospective study. Diabetes Care (1999) 22:1401–7.[Abstract/Free Full Text]
  9. Utian WH, Shoupe D, Bachmann G, et al. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril (2001) 75:1065–79.[CrossRef][Web of Science][Medline]
  10. Westendorp IC, de Kleijn MJ, Bots ML, et al. The effect of hormone replacement therapy on arterial distensibility and compliance in perimenopausal women: a 2-year randomised trial. Atherosclerosis (2000) 152:149–57.[CrossRef][Web of Science][Medline]
  11. Gallagher JC, Fowler SE, Detter JR, et al. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab (2001) 86:3618–28.[Abstract/Free Full Text]
  12. Maheux R, Naud F, Rioux M, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol (1994) 170:642–9.[Web of Science][Medline]
  13. Os I, Hofstad AE, Brekke M, et al. The EWA (estrogen in women with atherosclerosis) study: a randomized study of the use of hormone replacement therapy in women with angiographically verified coronary artery disease. Characteristics of the study population. Effects on lipids and lipoprotein. J Intern Med (2000) 247:433–41.[CrossRef][Web of Science][Medline]
  14. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med (1993) 329:753–6.[Abstract/Free Full Text]
  15. Recker RR, Davies KM, Dowd RM, et al. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med (1999) 130:897–904.[Abstract/Free Full Text]
  16. Williamson PR, Gamble C, Altman DG, et al. Outcome selection bias in meta-analysis. Stat Methods Med Res (2005) 14:515–24.[Abstract/Free Full Text]
  17. Chan AW, Hróbjartsson A, Haahr MT, et al. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA (2004) 291:2457–65.[Abstract/Free Full Text]
  18. Altman DG. A meta-analysis of hormone replacement therapy for fracture prevention. JAMA (2001) 286:2096–7.[Free Full Text]
  19. Gabriel-Sánchez R, Carmona L, Roque M, et al. Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev (2005) CD002229.
  20. Farquhar CM, Marjoribanks J, Lethaby A, et al. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev (2005) CD004143.
  21. Magliano DJ, Rogers SL, Abramson MJ, et al. Hormone therapy and cardiovascular disease: a systematic review and meta-analysis. BJOG (2006) 113:5–14.[Medline]
  22. Salpeter SR, Walsh JME, Greyber E, et al. Mortality associated with hormone replacement therapy in younger and older women. J Gen Intern Med (2004) 19:791–804.[CrossRef][Web of Science][Medline]
  23. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA (2007) 297:1565–77.

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur Heart JHome page
M. Doren
Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis
Eur. Heart J., April 1, 2009; 30(7): 866 - 867.
[Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
166/12/1479    most recent
kwm303v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Dören, M.
Right arrow Articles by Greiser, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dören, M.
Right arrow Articles by Greiser, E. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?