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The length of estrogen exposure throughout a woman’s lifetime and the risk of coronary heart disease (CHD) have been previously investigated with conflicting results [1]. The premise is that decreased lifetime duration of estrogen exposure increases the incidence of CHD (atherosclerosis). The Framingham study has lent credence to this hypothesis since women with premature or early menopause (natural or surgical) had an increased risk of CHD compared to age-matched women with intact or normal ovarian function [2]. Surgical menopause, a bilateral oophorectomy, is associated with an early onset of CHD in women who did not use hormone therapy (HT) compared to those who used replacement estrogen [3-5]. These data favor the hypothesis that the lifetime duration of exposure to endogenous and exogenous estrogen reduces the incidence or risk of atherosclerosis. This hypothesis is modified by other factors in a woman’s life such as smoking, diet, exercise and, of course, concurrent medical disease such as hypertension or diabetes.  


The current study by Merz and colleagues is an analysis of the data from the Women’s Ischemia Syndrome Evaluation (WISE). The population consisted of 646 postmenopausal women who had symptoms that required evaluation for obstructive coronary artery disease (CAD) using angiography. CAD was defined as > 70% luminal diameter stenosis in more than one major epicardial coronary artery. They also evaluated a threshold of > 50% stenosis as an alternative definition of obstructive CAD. An overall CAD severity score was assigned based on severity of stenosis, location of stenosis, and presence of partial or complete collaterals [1]. The authors used a questionnaire that captured menstrual history, pregnancy, hormonal contraception use and HT.  


The duration of total estrogen exposure time (TET) was not related to the incidence or risk of CAD. Total estrogen exposure was the summation of the duration of estrogen exposure based on the normal menstrual cycles (menarche to menopause), plus premenopausal oral contraceptive use and pregnancy time. The authors then used sustained total estrogen exposure time (sTET), which is TET plus postmenopausal HT time, and found that there was a significant correlation, with a reduction in the occurrence of CAD. Postmenopausal HT in the highest tertile of sTET appeared to protect against CAD. Comparing across all tertiles of sTET, the women who never used HT had the highest prevalence and severity of CAD, followed by women with up to 5½ years of HT use, with the lowest prevalence and severity of CAD in the women using HT for more than 5½ years ([i]p[/i] < 0.0001, [i]p[/i] < 0.0001, [i]p[/i] = 0.002, respectively). Women in the third tertile (those with the highest number of years of estrogen exposure) had the lowest age-adjusted prevalence and severity of CAD ([i]p[/i] = 0.006, [i]p[/i] = 0.014, and [i]p[/i] = 0.016 for CAD defined as > 70% stenosis, > 50% stenosis, or as a severity score, respectively). These data indicate that women with the highest number of years of sustained estrogen exposure have a lower prevalence and severity of obstructive CAD. When the data were adjusted for the duration of HT exposure, the significance disappeared for all outcomes [1].


  • David Archer
    Professor of Obstetrics & Gynecology, Eastern Virginia Medical School, Norfolk, Virginia, USA


  1. Merz CN, Johnson BD, Berga SL, et al. Total estrogen time and obstructive coronary disease in women: insights from the NHLBI-sponsored Womens Ischemia Syndrome Evaluation (WISE). J Womens Health 2009;18:1315-22.
  2. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med 1976;85:447-52.
  3. Archer DF. Premature menopause increases cardiovascular risk. Climacteric 2009;12(Suppl 1):26-31.
  4. Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006;7:821-8.
  5. Shuster LT, Gostout BS, Grossardt BR, Rocca WA. Prophylactic oophorectomy in premenopausal women and long-term health. Menopause Int 2008;14:111-16.
  6. Pines A, Sturdee DW, Birkhauser MH, et al. HRT in the early menopause: scientific evidence and common perceptions. Climacteric 2008;11:267-72.
  7. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-77.
  8. Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N Engl J Med 2003;348:645-50.
  9. Clarkson TB, Mehaffey MH. Coronary heart disease of females: lessons learned from nonhuman primates. Am J Primatol 2009;71:785-93.
  10. Karim R, Hodis HN, Stanczyk FZ, Lobo RA, Mack WJ. Relationship between serum levels of sex hormones and progression of subclinical atherosclerosis in postmenopausal women. J Clin Endocrinol Metab 2008;93:131-8.
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