Special Feature

Opposition to the Timing Hypothesis

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

The Timing Hypothesis argues that estrogen can reduce the risk of coronary heart disease when administered to relatively young postmenopausal women before atherosclerosis has developed to the stage of unstable plaques (plaques with necrosis and inflammation). Elizabeth Barrett-Connor from the Division of Epidemiology at the University of California School of Medicine in San Diego concludes that the hypothesis is stronger than the evidence.1

Barrett-Connor first reviews 3 clinical trials—the HERS trial and the two canceled arms of the WHI—that failed to find an overall beneficial impact of hormone therapy on cardiac events. She further points out that subgroup analyses of HERS and WHI were problematic. In the HERS secondary prevention trial, multiple tests for interactions failed to definitely explain the results. Barrett-Connor argues that the power of the WHI to examine the timing hypothesis was limited by a relatively small number of women under age 60 and rare cardiac events in the young age group. She emphasizes that the tests for interaction with age or years since menopause in the initial publications failed to find any significant relationships. The basic problem was that clinical trials are powered to test primary outcomes, not secondary results in subgroups.

Barrett-Connor dismisses the WHI coronary-artery calcium study2 because coronary artery calcium was measured only in women under age 60 and not measured in older women for comparison. You will recall that the calcification in the coronary arteries is located in atheromas and is correlated with the degree of atherosclerosis. The average calcium score in the women treated with estrogen in the WHI estrogen-only arm was lower than that in the placebo arm, consistent with a lower prevalence of coronary artery disease. Barrett-Connor argues that this result does not test the timing hypothesis because it could not be compared to calcium scores in women over age 60.

Barrett-Connor claims that the timing hypothesis is being marketed, and that the hypothesis remains unproven until evidence becomes available from randomized, controlled clinical trials. She concludes that those who have been seeking "flaws" in the WHI are motivated by a reluctance to give up old ideas about the long-term benefits of hormone therapy.

One might turn Barrett-Connor's conclusion around and argue that her rebuttal represents a reluctance to accept a new idea that explains the limitations of the HERS and WHI trials. Her commentary was accepted for publication on December 21, 2006. Thus she did not have available the WHI analysis of cardiovascular risk by age and years since menopause which was published in April 2007.3 The WHI conducted a secondary analysis combining the two canceled arms that revealed an increased risk for coronary heart disease only in the oldest women in the trials. Furthermore, when women with prior cardiovascular disease or those older than 60 years were excluded, there was no increase in the risk of stroke. But Barrett-Connor is correct in saying that the number of women and the number of cardiac events under age 60 were too small to help us answer the question: can hormone therapy given to young postmenopausal women prevent coronary heart disease?

A meta-analysis of 23 randomized hormone therapy trials concluded that hormone treatment reduced the risk of coronary heart disease in younger postmenopausal women compared to older women (OD-0.68; CI=0.48-0.96).4 Another meta-analysis by the same authors concluded that hormone therapy reduced overall mortality in women under the age of 60.5 But I hasten to add, most of these trials were not designed to measure a cardiovascular endpoint. The meta-analyses are reassuring but they surely do not meet Barrett-Connor's plea for evidence.

The timing hypothesis originated in the hormone trials conducted in monkeys by the Wake-Forest group headed by Tom Clarkson. This is randomized trial evidence, albeit in monkeys, and we should place the results at the head of the list of observations that support the timing hypothesis:

  1. Estrogen treatment initiated immediately after menopause in monkeys inhibits progression of coronary artery atherosclerosis by about 70%. When treatment is delayed by 2 years (equivalent to about 6 years in women), there is no effect.6
  2. Next in line, according to strength of evidence in my view, would be the recent WHI reports of reduced coronary artery calcium in estrogen-treated women and an increase in cardiac events only in the oldest women in the trials.2,3 In the last report from the WHI estrogen-only arm, the problem of low event rates in younger women was addressed by lumping together, in one hazard ratio, myocardial infarction, coronary death, coronary revascularization, and confirmed angina—the risk in women aged 50 to 59 years for all of these events was significantly reduced (HR-0.66; CI=0.45-0.96).7
  3. Every woman has a trajectory of atherosclerosis development, the slope of which determines the age of onset for clinical events. Premenopausal women with lower estrogen levels have higher cardiovascular risk factors and develop more coronary heart disease.8 This includes suppressed ovarian function associated with stress, depression, or athletic activity. The importance of premenopausal estrogen is also supported by Clarkson's monkey studies. Premenopausal monkeys with normal ovarian function have less progression of coronary artery atherosclerosis as compared with monkeys with impaired ovarian function.8
  4. The results in observational studies strongly indicate that hormone treatment of young postmenopausal women reduces the risk of coronary heart disease. In the Nurses' Health Study, the reduction was approximately 50%.9 The women in the Nurses' Health Study who were under age 60 when hormone treatment was initiated had a significant reduction in coronary heart disease risk compared with no effect in women over age 60.10 A similar reduction was present in the observational arm of the WHI.11 In fact, after adjustment for confounding influences such as behavioral, dietary, physical activity, and cardiovascular risk factors, the relative risks for cardiovascular events were 30% to 38% lower than in the clinical trials. These data were derived from populations of women usually treated with postmenopausal hormone therapy, women close to their age of menopause.
  5. In a primary prevention trial using ultrasound measurement of carotid artery intima-media thickness, estradiol-treated women had slower progression of atherosclerosis.12 These same investigators demonstrated no effect of estrogen treatment in older women who had angiographic evidence of coronary atherosclerosis.13

The message from multiple secondary prevention trials is clear: we should not prescribe estrogen to women with coronary heart disease in the expectation that treatment will reduce subsequent cardiac events. The evidence is also convincing that progestational agents do not produce adverse cardiovascular effects. It remains very possible, indeed likely, that primary prevention of coronary heart disease can be achieved with estrogen administered at the right time of life. We await the results of two ongoing primary prevention trials, measuring carotid intima-media thickness with ultrasound, the KEEPS trial and the ELITE trial.

A reasonable goal is to maintain a healthy level of estrogen during the premenopausal years and in the early postmenopausal period. Although as Barrett-Connor points out, the timing hypothesis has not been proven by randomized, clinical trials, the overall evidence is impressive, and in my view, sufficient to conclude that hormone therapy in the early postmenopausal years can provide primary prevention of clinical coronary disease. Clinical decisions reflect all of our knowledge (our education, the medical literature, and our experience), not just the data from randomized, clinical trials.

The most important message is that 6 years after the initial WHI publications, it is increasingly apparent that the WHI results agree with over 20 years of research, contrary to the WHI communications first presented to the public. It is time to convince our colleagues of this conclusion and present this story to our patients.


  1. Barrett-Connor E. Hormones and heart disease in women: the timing hypothesis. Am J Epidemiol. 2007;166:506-510.
  2. Manson JE, et al. Estrogen therapy and coronary-artery calcification. New Engl J Med. 2007;356:2591-1602.
  3. Rossouw JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.
  4. Salpeter SR, et al. Brief Report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006;21:363-366.
  5. Salpeter SR, et al. Mortality associated with hormone replacement therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2004;19:791-804.
  6. Clarkson TB. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause. 2007;14:373-384.
  7. Hsia J, et al. Conjugated equine estrogens and coronary heart disease. The Women's Health Initiative. Arch Intern Med. 2006;166:357-365.
  8. Speroff L. Gonads are the heart of the matter. Menopause. 2007;14:385-390.
  9. Grodstein F, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941.
  10. Grodstein F, et al. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health. 2006;15:35-44.
  11. Prentice RL, et al. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemiol. 2005;162:404-414.
  12. Hodis HN, et al. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939-953.
  13. Hodis HN, et al. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. New Engl J Med. 2003;349:535-545.