American Journal of Epidemiology Advance Access originally published online on November 10, 2007
American Journal of Epidemiology 2007 166(12):1480-1481; doi:10.1093/aje/kwm323
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.
RE: "INVITED COMMENTARY: HORMONE THERAPY AND RISK OF CORONARY HEART DISEASE—WHY RENEW THE FOCUS ON THE EARLY YEARS OF MENOPAUSE?"
Lynn Rosenberg
School of Medicine - Slone Epidemiology Unit, Boston University, Brookline, MA 02146
(e-mail: lrosenberg{at}slone.bu.edu)
Manson and Bassuk (1) discuss a theory, "the timing hypothesis," advanced to explain the discrepancy between the results of observational studies that have suggested a protective effect of supplemental female hormone use against coronary heart disease and the overall results of randomized trials (2, 3), which have not supported a protective effect. The timing hypothesis posits that an effect of female hormone use against coronary heart disease depends on whether atherosclerosis was present initially—specifically, that treatment must start soon after menopause, before atherosclerosis has developed, for protection to occur. Consistent with this hypothesis, the relative risks in the randomized trials of female hormone use and coronary heart disease were below 1 for women whose treatment began within 10 years after the onset of menopause, but they were 1 or greater for women treated long after the occurrence of menopause (these differences are not statistically significant) (1).
Manson and Bassuk (1) state that the results of an experiment in female cynomolgus monkeys (4) "lend credence" to the hypothesis. In the monkey experiments, female hormones prevented atherosclerosis in animals treated immediately after oophorectomy but did not prevent atherosclerosis when treatment was begun well after oophorectomy. An experience that I had some years ago brought home to me the difficulty of knowing when animal data are relevant to humans and points up the need for caution in arguing that animal data lend credence to human data. I was involved in a study of men that was mounted after experiments in male cynomolgus (5) and rhesus (6) monkeys indicated that vasectomized monkeys developed more atherosclerosis than monkeys that had not been vasectomized. These animal results led the National Institutes of Health to call for a study, which my research group conducted, to assess the relation of vasectomy to risk of coronary heart disease in men. The results of our study were null (7), and subsequent studies also failed to find an increase in coronary heart disease risk in vasectomized men (8–10). A plausible explanation for the discrepancy between the animal and human results is that the monkey models in this set of circumstances were not relevant models for men.
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ACKNOWLEDGMENTS
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Conflict of interest: none declared.
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References
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- 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]
- Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med (2003) 349:523–34.[Abstract/Free Full Text]
- Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch Intern Med (2006) 166:357–65.[Abstract/Free Full Text]
- Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res (2002) 53:605–19.[Abstract/Free Full Text]
- Alexander NJ, Clarkson TB. Vasectomy increases the severity of diet-induced atherosclerosis in Macaca fascicularis. Science (1978) 201:538–41.[Abstract/Free Full Text]
- Clarkson TB, Alexander NJ. Long-term vasectomy: effects on the occurrence and extent of atherosclerosis in rhesus monkeys. J Clin Invest (1980) 65:15–25.[Web of Science][Medline]
- Rosenberg L, Schwingl PJ, Kaufman DW, et al. The risk of myocardial infarction 10 or more years after vasectomy in men under 55 years of age. Am J Epidemiol (1986) 123:1049–56.[Abstract/Free Full Text]
- Coady SA, Sharrett AR, Zheng ZJ, et al. Vasectomy, inflammation, atherosclerosis and long-term followup for cardiovascular diseases: no associations in the Atherosclerosis Risk in Communities study. J Urol (2002) 167:204–7.[CrossRef][Web of Science][Medline]
- Goldacre MJ, Wotton CJ, Seagroatt V, et al. Cancer and cardiovascular disease after vasectomy: an epidemiological database study. Fertil Steril (2005) 84:1438–43.[CrossRef][Web of Science][Medline]
- Giovannucci E, Tosteson TD, Speizer FE, et al. A long-term study of mortality in men who have undergone vasectomy. N Engl J Med (1992) 326:1392–8.[Abstract]
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