(Circulation. 1996;94:1857-1863.)
© 1996 American Heart Association, Inc.
Articles |
No Association of Menopause and Hormone Replacement Therapy With Carotid Artery Intima-Media Thickness
the Division of Epidemiology (A.A.N., A.R.F.), School of Public Health, University of Minnesota, Minneapolis; School of Public Health (A.A.N., G.H.), Department of Epidemiology, University of North Carolina, Chapel Hill; Johns Hopkins School of Hygiene and Public Health (M.S.), Baltimore, Md; Burroughs-Wellcome Co (A.W.), Epidemiology, Surveillance, and Pharmacoeconomics Division, Research Triangle Park, NC; and Division of Epidemiology and Clinical Applications (M.H.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Azmi A. Nabulsi, MB, BCh, Abbott Laboratories, Department of Epidemiology and Outcomes Research, 100 Abbott Park Rd, D42J, AP6C-1, Abbott Park, IL 60064-3500.
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Abstract |
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Background Cardiovascular disease is the major cause of death in older women. Information on the relation of menopause and hormone replacement therapy with carotid atherosclerosis is limited.
Methods and Results We examined cross-sectionally the association of menopausal status, years since last menstruation, and hormone replacement therapy status with carotid artery intima-media thickness as determined by B-mode ultrasound. Female participants (n=5436) in the Atherosclerosis Risk in Communities Study without a history of symptomatic cardiovascular disease were included in the analyses. Menopause status in 45- to 54-year-old women who had never used hormone replacement therapy was not strongly associated with carotid intima-media thickness (mean=0.65 mm and 0.67 mm in premenopausal and postmenopausal women, respectively, adjusted for age, race, cigarette years of smoking, body mass index, sport index, systolic blood pressure, use of blood pressure medications, drinking status, diabetes, and education level). In postmenopausal women aged 55 to 64 years, women with 
5 years since last menstruation had an adjusted average intima-media thickness (0.74 mm) comparable to those with >5 years since last menstruation (0.75 mm) (P>.05). Although hormone replacement therapy use was associated with a more favorable lipid and hemostasis profile than nonuse, its use was not associated with intima-media thickness in postmenopausal women aged 55 to 64 years (adjusted average=0.74 mm for current users of estrogen alone and 
0.75 mm each for current users of estrogen plus progestin, former users, and never users).
Conclusions The data suggest that the well-known associations of hormone replacement therapy with reductions in atherosclerotic cardiovascular disease may be attributable more to acute physiological effects, such as hemodynamic changes or reduced thrombosis, than to atherosclerosis itself.
Key Words: menopause • hormones • atherosclerosis
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Introduction |
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Atherosclerotic CVD is the major cause of morbidity and mortality in older women. Although the incidence of CVD increases with age, evidence that natural menopause is an independent risk factor for CHD or stroke1 is not convincing. In contrast, several studies2 have suggested that surgical menopause (bilateral oophorectomy) increases CHD risk. HRT appears to afford protection from CHD, especially in women with bilateral oophorectomy,3 4 5 but there was little evidence that HRT prevents stroke6 until several recent studies were reported.7 8 9
Carotid atherosclerosis is associated with stroke; it is also correlated with coronary atherosclerosis.10 11 12 However, there is only limited information on the relation of menopause and HRT with carotid atherosclerosis. In the ARIC study, we had the opportunity to assess the associations of menopausal status and HRT with subclinical atherosclerosis as defined by the thickness of the intima-media of the carotid artery measured by ultrasonography.
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Methods |
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The ARIC study13 is a prospective investigation of 45- to 64-year-old men and women in four US communities. A population sample of 15 800 people was selected in Forsyth County, North Carolina; Jackson, Miss; selected suburbs of Minneapolis, Minn; and Washington County, Maryland (approximately one quarter in each location). All participants in Jackson were black; 14% in Forsyth County were black. The remaining study cohort was almost all white. Participant response rates were 37% for Jackson and
66% for the other three communities.
Participants were invited for a baseline examination in 1986 through 1989. This included measurements of sitting blood pressure, anthropometry, venipuncture (12-hour fasting), B-mode ultrasound of the carotid arteries, and a number of interviews (such as medical history, physical activity, reproductive history, medication use, and others). Three sitting blood pressure readings were recorded with the use of a random-zero sphygmomanometer. The systolic blood pressure used in the analysis was the average of the second and third readings. Serum glucose was assessed by a hexokinase/glucose-6-phosphate dehydrogenase method. Diabetic women were those who identified themselves as such, were using antidiabetic medications, or had an elevated serum glucose level (
140 mg/dL fasting, 200 mg/dL nonfasting). BMI (kg/m2) was computed with the use of measurements of weight and height. A physical activity index (sports index) ranging from 1 (low) to 5 (high) was derived by use of the Baecke questionnaire.14 We calculated cigarette years of smoking by multiplying the average number of cigarettes smoked per day by the number of years smoked. Drinking status and educational level were ascertained through interviews.
Prevalent CVD was defined as angina or intermittent claudication by the Rose questionnaire,15 a self-reported physician-diagnosed history of a heart attack or stroke, a prevalent Q wave on ECG, or a self-reported history of cardiovascular surgery or angioplasty.
Menopausal status, the number of years since last menstruation, HRT, and OC use were ascertained by a trained interviewer. To enhance the accuracy of the information pertaining to medication use, the participants were asked to bring containers of all medications used in the 2 weeks before the ARIC study clinic examination.
Premenopausal women were those who reported having menstruated in the 2 years before the ARIC study examination and who labeled themselves as premenopausal. Perimenopausal women were those who had menstruated in the 2 years before the examination but who labeled themselves as postmenopausal or as uncertain menopausal status. Women who had not menstruated in the 2 years before the examination were identified as postmenopausal.
Three groups of postmenopausal women were identified according to the cause of menopause: surgical menopause (bilateral oophorectomy), natural menopause (this group also included women who had a hysterectomy, at least one intact ovary, and were 55 years of age), and uncertain menopause status (nonmenstruating women with unknown ovarian status, such as those who had a hysterectomy and at least one intact ovary but who were <55 years of age). Three additional groups of postmenopausal women were identified according to the number of years since last menstruation (2 to 5, 6 to 9, or 10 years). Postmenopausal women were also subclassified into current users of estrogen alone, current users of estrogen plus progestin, former hormone users, and never users. Former users could not be classified accurately by the type of hormone used because of difficulty in recall.
The intima-media thicknesses of the near and far walls of the extracranial carotid arteries were measured by high-resolution B-mode ultrasound.16 Three 1.0-cm segments were scanned bilaterally: the distal portion of the common carotid artery, the carotid bifurcation, and the proximal portion of the internal carotid artery. The ultrasonic images from the six sites were recorded on high-resolution ¾-in videocassettes to be read at the Ultrasound Reading Center. Standardized protocols were used for the scanning16 and reading17 procedures. A methodology based on the technique developed by Pignoli et al18 was used to obtain measurement of the intima-media thickness of each of the six sites described above. Because the far wall was better visualized than the near wall, far-wall intima-media thickness was used in the analysis.
During the first few months of the ARIC study, the quality of ultrasound images was suboptimal; hence, the scans were unread. For the present report, we therefore excluded data collected before July 1987. (Those excluded are an approximate random sample, because ARIC recruited monthly random samples.) In addition, incomplete visualization of some arterial walls resulted in missing arterial boundaries on some scans (17% of the left common carotids, 18% of the right common carotids, 39% of the left bifurcations, 38% of the right bifurcations, 58% of the left internal carotids, and 57% of the right internal carotids). Missing data were correlated moderately with artery depth and BMI; therefore, to prevent bias in wall-thickness estimates, missing boundaries were imputed from the visualized ones. Maximum likelihood methods that used the EM (expectation maximization) algorithm were used for imputation.19 The algorithm used a multivariate linear model for the mean far-wall thickness at the above-mentioned six sites. The model was race- and sex-specific and adjusted for artery site, depth, BMI, and depthxBMI interaction with an unstructured covariance matrix. The intima-media far-wall thickness used in the analyses was the unweighted average, measured or imputed, of the six arterial wall segments. Of the 8704 female ARIC participants, 7391 had usable wall-thickness data.
The main hypotheses of interest were as follows: (1) among women 45 to 54 years of age who had never been on HRT, postmenopausal women have a greater carotid intima-media thickness than do perimenopausal and premenopausal women, and postmenopausal women with surgical menopause have a greater intima-media thickness than do women with natural menopause; (2) among postmenopausal women aged 55 to 64 years, women with 5 years since last menstruation have a greater carotid intima-media thickness than do women with 5 years since last menstruation; and (3) among postmenopausal women aged 55 to 64 years, hormone users, current and former, have smaller intima-media thickness than do never users, and these associations differ by history of OC use.
Statistical Analysis
We excluded (from all analyses) 4 women who had primary amenorrhea, 159 who could not be classified as to menopausal status or hormone-use category, 61 who were using either estrogen creams only or hormones other than estrogen alone or estrogen plus progestin, and 1313 women with unusable ultrasound data. We also excluded 967 women with prevalent CVD and 764 women with uncertain cause of menopause. A total of 5436 women aged 45 to 64 years (of whom 27% were black) were included in the analyses.
Linear least-squares regression models were used to calculate the adjusted average carotid intima-media thickness. In one model, we adjusted for age and race (black/white). In a second model, we adjusted for age, cigarette years of smoking, BMI, sport index, systolic blood pressure (all continuous); the use of blood pressure medications (yes/no); race; drinking status (yes/no); diabetes (yes/no); and education level (basic [11 years], intermediate [12 years, GED, or vocational school], and advanced [college]). In the models pertaining to the number of years since last menstruation, we also adjusted for HRT and type of menopause (natural/surgical). For the models pertaining to HRT, additional adjustment for the type of menopause (natural/surgical) was done. We did not adjust for plasma lipids because they represent a possible means by which menopause and HRT are thought to influence vascular disease. We tested the hypotheses of interest by using statistical contrasts in the linear regression models. The SAS statistical package was used.20
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Results |
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The distribution of carotid intima-media wall thickness in the ARIC study women included in this analysis (62% of total ARIC women) who were aged 45 to 64 years and free of CVD is presented in Fig 1
. The distribution was right-skewed with a mean wall thickness of 0.70 mm and a median of 0.67 mm. Most women had carotid intima-media thickness between 0.6 and 0.8 mm. Among women aged 45 to 54 years, postmenopausal women compared with premenopausal women were older, included a greater number of black women, were more likely to smoke, had slightly higher BMI, were less likely to exercise and drink alcohol, had more prevalent diabetes, had higher blood pressure, and had fewer years of education. Among women aged 55 to 64 years, HRT users compared with nonusers were younger, included fewer black women, were less likely to smoke, had lower BMI, were more likely to exercise and drink alcohol, had less prevalent diabetes, had lower blood pressure, and had more years of education.
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Menopause and Intima-Media Thickness
Table 1 shows the adjusted mean values of carotid intima-media thickness by menopausal status for women aged 45 to 54 years who had never used HRT (n=1910). Premenopausal women had the lowest mean value of wall thickness; postmenopausal women with natural menopause had the highest. In model 2, the 0.017-mm-lower carotid intima-media thickness of premenopausal women compared with postmenopausal women (natural and surgical combined) was marginally significant (P=.07). Women with surgical menopause had mean values not statistically distinguishable from those with natural menopause.
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Number of Years Since Last Menstruation and Intima-Media Thickness
The adjusted mean values of carotid intima-media thickness by the number of years since last menstruation for women aged 55 to 64 years are shown in Table 2. Women with 2 to 5 years since last menstruation had intima-media thickness at least 0.01-mm thinner (model 1) than any of the other two groups, but this was not statistically significant (P>.05) either before or after adjustment for other risk factors.
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HRT and Intima-Media Thickness
There was no statistically significant association between HRT and carotid intima-media thickness for postmenopausal women aged 55 to 64 years (n=2385) (Table 3). For model 1, the age- and race-adjusted mean wall thickness for estrogen plus progestin users was lower than that for nonusers; this difference disappeared after adjustment for other risk factors. However, among current users of estrogen alone and among former HRT users, women who had ever used OCs had higher mean wall thickness (by >0.03 mm) than those who never used OCs (Fig 2). Repetition of the above analyses for women aged 45 to 64 years yielded comparable results.
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Discussion |
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The strengths of the ARIC study are its large sample of women free of CVD, the large number of risk factors measured, and the quantitative assessment of carotid artery intima-media thickness. It is limited by its cross-sectional design, which prevents firm causal inferences. Another limitation of this cross-sectional analysis, as in all cross-sectional studies, is the possibility of selection bias. Because women were not randomized into menopausal or hormone groups, differences in their baseline characteristics may have yielded biased estimates of the associations. Although we adjusted for important baseline characteristics, the statistical adjustment may not have abolished all differences between women in the different groups. Also, details on hormone formulations and dose were not available. If associations existed for a particular formulation or dose, then the inability to stratify by formulation or dose may have obscured the true associations. Another possible study limitation is that random error in B-mode measurement of the carotid intima-media thickness and its narrow range (0.6 to 0.8 mm) could have made it difficult to demonstrate differences among menopause or HRT groups. However, the <0.03-mm differences observed between menopause or HRT groups were smaller than the 0.10-mm differences in intimal-medial thickness observed between 45- to 54-year-old women and 55- to 64-year-old women in the present study.
Approximately 15% of ARIC women could not be assessed for carotid wall thickness, mainly because of unread scans or, less often, incomplete ultrasound data. However, this should have introduced little bias, because women with unread scans were a random sample as a result of the periodic probability sampling used in the ARIC study. Imputation for the remaining missing ultrasound data (see "Methods") was performed to reduce bias in wall-thickness measures. When we repeated the analyses using only the observed wall-thickness data, the associations with HRT were virtually unchanged.
Menopause and Intima-Media Thickness
We found no overall association between menopausal status and carotid intima-media thickness in women aged 45 to 54 years, although pairwise comparisons suggested that women with natural menopause may have a slightly higher adjusted mean carotid intima-media thickness than premenopausal women (0.669 versus 0.650 mm, P=.024). Thus, our analyses offer only weak evidence that menopause and carotid atherosclerosis are associated.
Bonithon-Kopp et al21 also reported no association between menopausal status and carotid wall thickness or plaque measured by B-mode ultrasonography in women aged 45 to 54 years. Witteman et al22 reported that the relative risk of aortic atherosclerosis in women aged 45 to 54 years was 3.4 for surgical menopause and 5.5 for natural menopause compared with premenopause. In general, there is no strong evidence that natural menopause is associated with increased CHD or stroke risk.1 However, the evidence is stronger that surgical menopause (bilateral oophorectomy) is associated with an increased risk of CHD.2 Case-control studies23 24 showed no association between natural menopause and CHD. However, in both studies, bilateral oophorectomy was significantly associated with CHD. Most prospective studies25 26 showed no significant association between natural menopause and CHD. For example, the Nurses' Health Study,26 after 6 years of follow-up, found no association between natural menopause and CHD. However, among nurses who had never used estrogen replacement therapy, those with bilateral oophorectomy had double the risk of CHD compared with premenopausal nurses.
Number of Years Since Last Menstruation and Intima-Media Thickness
We found that women with 2 to 5 years since last menstruation had an adjusted average intima-media wall thickness comparable to women with <5 years since last menstruation. However, a separation of the effects of cessation of ovarian function from aging effects in relation to wall thickness is probably not fully achievable. We attempted to minimize the effects of age by limiting our analyses to narrow age groups (45 to 54 years for the analysis of menopausal status, 55 to 64 for the analyses pertaining to the number of years since last menstruation and HRT) and adjusting further for age in the statistical models.
HRT and Intima-Media Thickness
HRT is associated with a halving of CHD risk.27 An earlier ARIC report28 showed that compared with nonusers, current HRT users had higher levels of HDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, and apolipoprotein A-I and had lower LDL, apolipoprotein B, lipoprotein(a), fibrinogen, and antithrombin III levels. We also found that users of estrogen alone had higher plasma triglycerides, factor VII, and protein C levels than users of estrogen plus progesterone. In light of these results, we hypothesized that an inverse association existed between HRT and carotid intima-media thickness. However, the current analysis revealed no such association. Among current estrogen users and former users, women who had ever used OCs had greater intima-media thickness than those who had never used OCs. This suggests that women who used OCs may derive less benefit from HRT. This potential interaction merits further investigation.
A recent cross-sectional analysis29 revealed lower adjusted carotid intima-media thickness of the common and internal carotid arterial segments in current hormone users compared with past and never users. That study investigated a population of women who were relatively old (65 years), which might explain the difference from the ARIC study findings. Women who use HRT after age 64 are likely to be highly selected, although it is possible that the beneficial atherosclerotic effects of HRT are greater in older women, who would have a higher risk of CVD than women in the ARIC study. It is also possible that a longer duration of HRT use than that observed in the ARIC study may be necessary to affect carotid intima-media thickness.
Four studies30 31 32 33 have examined the association between estrogen replacement therapy and atherosclerosis as determined by angiography of the coronary arteries. The pooled estimated relative risk of atherosclerosis for these four studies combined was 0.41 (95% CI, 0.34-0.50) for current estrogen users compared with nonusers.27 These studies differ from the present report in that they examined coronary, not carotid, arteries and included women who most likely had symptoms that required assessment by a coronary angiogram; our analyses included only women who were free of CVD at the baseline visit. An issue of concern in angiographic studies is that detection bias could have been introduced if women on estrogen were selected for an angiogram for less severe symptoms in comparison with nonusers; such bias would lower the risk assigned to estrogen use. On the other hand, Gruchow et al30 reported similar rates of angina, chest pain, and dyspnea in estrogen users and nonusers who presented for angiography.
Although HRT seems to prevent the occurrence of CHD, its role in preventing stroke is less clear. The Nurses' Health Study34 showed a 50% reduction of CHD in current HRT users but did not observe an association between hormone use and stroke. However, reports from the Leisure World cohort7 and from the National Health and Nutrition Examination Survey8 reported that HRT was associated with 46% and 63% reductions in the risk of death from stroke, respectively. In a population-based Swedish cohort,9 the use of estrogen alone and the use of estrogen plus progestin were associated with 30% and 50% reductions, respectively, in myocardial infarction and 30% and 39% reductions in the risk of stroke.35 In contrast, at least two studies36 37 reported an increased risk of stroke in association with HRT. Psaty et al6 thus concluded there is no association between HRT use and stroke. Hence, it is possible that the effects of HRT in the coronary arteries are different from its effects in the carotid arteries, which we studied.
It is possible that the reduced risk of atherosclerotic coronary disease associated with HRT, at least in the first two decades after menopause, may be attributable more to the acute physiological effects of hormone replacement than to prevention of atherogenesis per se. Estrogen decreases fibrinogen28 and platelet aggregation,38 increases prostacyclin activity,39 and vasodilates.40 Estrogen receptors are found in arteries,41 and Gangar et al42 reported that estrogen increases the distensibility of the carotid arteries. Others43 44 45 have hypothesized that estrogen reduces atherosclerotic plaque via antioxidant effects; the antioxidant effects of estrogen are more active in the coronary arteries and carotid bifurcation than in other sites.46 An effect that is primarily acute is consistent with most clinical studies that show the protective association between HRT and CHD to be stronger for current users than for former users34 and not related to duration of use. On the other hand, it is possible that duration of HRT use for the majority of ARIC study participants was not long enough to produce detectable differences in carotid wall thickness between users and nonusers. In ARIC, the average duration of HRT use for women 55 to 64 years old was 3 years for past users and 9 years for current users.
In summary, we found little evidence that carotid intima-media thickness was associated with menopausal status, years since menstruation, or HRT. The data suggest that the well-known inverse association of HRT with atherosclerotic CVD may be attributable more to favorable acute physiological effects, such as hemodynamic changes or reduced thrombosis, than to reduction of atherosclerosis itself.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Support for this study was provided by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. Investigators included the following individuals and institutions: University of North Carolina, Chapel Hill: Carol Summers, Catherine Burke, Deanna Horwitz, Carmen Woody, Peter DeSaix, Mal Foley, Tom Goodwin, Richard Hayes; University of Mississippi Medical Center, Jackson: Cora Walls, Dorothy Washington, Mattye Watson, Nancy Wilson; University of Minnesota, Minneapolis: Barbara Kuehl, Anne Murrill, Bryna Lester, Jennifer Hill; The Johns Hopkins University, Baltimore, Md: Joel Hill, Patricia M. Crowley, Joyce B. Chabot, Patricia Hawbaker; University of Texas Medical School, Houston: Valerie Stinson, Pam Pfile, Hoang Pham, Teri Trevino; The Methodist Hospital, Houston, Tex: Val Creswell, Julita Samoro, Wanda Wright, Karima Ghazzaly; Bowman-Gray School of Medicine, Winston-Salem, NC: Regina Delacy, Delilah Cook, Carolyn Bell, Teresa Crotts, Suzanne Pillsbury. We would also like to thank Victoria Nabulsi and Sara Ephross for assistance in the preparation of the manuscript.
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Footnotes |
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Reprint requests to Aaron R. Folsom, MD, Division of Epidemiology, School of Public Health, University of Minnesota, 1300 S Second St, Suite 300, Minneapolis, MN 55454-1015.
Received November 21, 1995; revision received July 26, 1996; accepted August 1, 1996.
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