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Editorial |
Wake Forest University School of Medicine, Section of Comparative Medicine, Winston-Salem, North Carolina 27157
Address all correspondence and requests for reprints to: Thomas B. Clarkson, D.V.M., Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1040. E-mail: tclarkso{at}wfubmc.edu.
Few matters relating to the cardiovascular health of women at middle age and beyond have been more controversial than the question of whether estrogen therapy provides cardiovascular benefits. During the mid and late 1990s, animal model data and the results of observational studies contributed to the widely held belief that postmenopausal estrogen therapy provided major cardiovascular benefits. It was within that context of presumed understanding that three major randomized, prospective trials were planned and initiated. The first was the Heart and Estrogen/Progestin Replacement Study (1), which was followed in turn by the Estrogen Replacement Study (2) and the Women’s Health Initiative (WHI) (3). All three used oral conjugated equine estrogens (CEE), either alone or with medroxyprogesterone acetate (MPA). The Heart and Estrogen/Progestin Replacement Study enrolled older women (66.7 yr) that were symptomatic with coronary heart disease (CHD). The Estrogen Replacement Study evaluated the effect of CEE alone or in combination with MPA on women with angiographically documented CHD. Finally, the WHI enrolled women that were older than 67 yr. Taken together, those studies found no cardiovascular benefit of CEE or CEE plus MPA treatment. Each study, in fact, observed an increase in CHD events in the initial year of treatment. Unfortunately, many observers generalized those findings, which were based on older women or those with documented coronary disease, to all postmenopausal women irrespective of age or disease status.
Over the past 5 yr, reassessment of the data from the WHI and other studies has led to an emerging appreciation that some groups of peri- and postmenopausal women may in fact derive cardiovascular benefits from hormone therapy. In this regard, much interest has focused on the timing hypothesis, which states that estrogens are atheroprotective if administered during the fatty streak to uncomplicated plaque stage of atherosclerosis progression but have null or deleterious effects if administered after plaques have become complicated by necrosis and inflammation (4). The timing hypothesis is supported in part by studies of monkey models and from recent reevaluation of data from the WHI. For example, in the CEE-only arm of the WHI, the hazard ratio for CHD among women aged 50–59 yr was 0.56 with a confidence interval of 0.30–1.03, whereas the hazard ratio for women aged 60–69 yr was 0.92 with a confidence interval of 0.69–1.23 (5).
More recently, investigators assessed the effect of hormone treatment on coronary artery calcium scores among the 50- to 59-yr-old women in the CEE-only arm of the WHI (6). Specifically, coronary artery calcium scores were determined for both the placebo- and CEE-treated groups after 7.4 yr of treatment and 1.3 yr after the trial was completed. Presumably, the younger women on whom this study focused would have had minimal subclinical atherosclerosis when enrolled in the study. In fact, the coronary artery calcium scores (among the women that were at least 80% adherent to treatment) that were more than 0, 10 or more, and 100 or more had odds ratios of 0.64 (P = 0.01), 0.55 (P < 0.001), and 0.46 (P = 0.001), respectively. Generally, this finding has been interpreted as indicating that CEE inhibited atherosclerosis progression among women in the 50- to 59-yr age group. However, not all experts agree, because older age groups were not examined in the same analysis (e.g. Ref. 7).
The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the impact of unopposed oral micronized estradiol on the progression of atherosclerosis in postmenopausal women. The investigators found that subclinical atherosclerosis progression [carotid artery intima media thickness (CIMT)] was significantly reduced in postmenopausal women randomized to receive oral micronized estradiol (8). The EPAT investigators subsequently reported additional findings that helped extend our understanding of the ways in which estrogen could affect the cardiovascular health of postmenopausal women. They reported, for example, that the proportion of oral micronized estradiol therapy’s atherosclerosis inhibitory effect was due to the changes in the lipid profile (9), concluding that 30% of the estrogen-related influence on the progression of CIMT was due to the beneficial alteration in the plasma concentrations of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol.
In this issue of the Journal, the EPAT investigators offer a novel perspective, relating to individual differences in hormone response, that may significantly advance our ability to identify subsets of postmenopausal women capable of deriving cardiovascular benefits from estrogen therapy. In a finding that likely will rival the timing hypothesis in stimulating new research, Karim et al. (10) describe among both estrogen- and placebo-treated women the presence of specific hormonal milieus associated with a lack of progression, or perhaps even regression, of carotid artery atherosclerosis. They also describe a seemingly adverse hormonal milieu that was associated with a substantial increase in intima media thickness during the period of experimental observation. Specifically, among women given oral micronized estradiol, those responding with increased plasma concentrations of free estradiol and SHBG plus decreased free testosterone had reductions in CIMT (–5.45 µm/yr). In contrast, those women given estradiol and responding with increased plasma concentrations of free estradiol but with no change in SHBG and free testosterone had increased progression in CIMT (+8.53 µm/year). Notably, there was substantial hormonal variation even among the women not on therapy; estrogen, SHBG, and total testosterone were significantly inversely associated with risk of atherosclerosis progression.
The authors provide important information about the need to serially assess the hormonal milieu across time during trials of oral estrogen therapy. Among the women being administered oral micronized estradiol in this 2-yr trial, the within-subject variability of total estradiol, free estradiol, total testosterone, and free testosterone was 36, 37, 18, and 25%, respectively. The need for multiple sampling to classify a woman’s post-estradiol hormonal milieu phenotype will likely limit the clinical application of the findings.
Nonetheless, the observation has important clinical/translational implications as well as suggestions for new research directions. With respect to translation, the finding establishes the possibility of predicting from measurements of the hormonal milieu resulting from estrogen therapy whether the individual postmenopausal woman is likely, or not likely, to derive cardiovascular benefits.
Future Research Directions
The most obvious opportunity for future research involves an effort to determine whether there is a genetic contribution to variation in hormonal response to estrogen therapy. If, for example, individual differences in estrogen metabolites may be modulating SHBG in different ways, a search for epigenetic effects could be rewarding.
The composition of the putatively beneficial and adverse hormonal milieus emphasizes a complex and intertwined role of estradiol, progesterone, and testosterone in modulating cardiovascular health. Mendelsohn and Karas (11) have reviewed the importance of interactions among these sex steroid hormones and their receptors, especially the receptor signaling properties. Sex steroid hormone receptors do not act alone but interact with numerous co-regulatory proteins to signal transcription. They point out that most current research focuses on the estrogen receptors, whereas progesterone and testosterone and their receptors in specific tissues have received far less attention. Furthermore, they indicate that a more complete understanding of each of the sex steroid hormones and their receptors in the cardiovascular system will be required to understand more fully the effects of postmenopausal estrogen therapy on atherosclerosis.
That differences in hormonal milieu of both placebo- and estradiol-treated women had such robust effects on carotid artery atherosclerosis progression or lack of progression will be considered unexpected by many. It is important to extend those studies to measures of breast cancer risk, such as rates of breast cell proliferation.
It may be important to determine the role, if any, of individual differences in the gut flora’s metabolism of endogenously derived estradiol during the enterobiliary circulation in the case of women not given exogenous hormones and of women administered oral micronized estradiol. One of the most interesting by-products of research on soy isoflavones has been the finding that women’s gut flora that has the capacity to metabolize daidzein to equol also has the capacity to metabolize steroid hormones in ways different from women who lack the daidzein-metabolizing phenotype, even during times when no isoflavones are being administered (12). It seems plausible that individual differences in the production of different kinds and amounts of estradiol metabolites could modulate differences in the production of SHBG and perhaps even differences in the amounts of circulating free estradiol and testosterone. We have found recently that individual differences in equol-metabolizing capability of postmenopausal women being treated with tibolone had important cardiovascular effects. Even while not being administered any soy isoflavones, tibolone-treated women with daidzein-metabolizing phenotype had lower blood pressure (13) and better endothelial function (14).
Footnotes
Abbreviations: CEE, Conjugated equine estrogens; CHD, coronary heart disease; CIMT, carotid artery intima media thickness; EPAT, Estrogen in the Prevention of Atherosclerosis Trial; MPA, medroxyprogesterone acetate; WHI, Women’s Health Initiative.
Received November 2, 2007.
Accepted November 5, 2007.
References
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