doi: 10.1161/hq1201.100241
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Estrogen Replacement and Brachial Artery Flow-Mediated Vasodilation in Older Women
From the Department of Internal Medicine, Sections on Cardiology (D.M.H.) and Endocrinology/Metabolism (J.R.C.), Department of Public Health Sciences (D.M.H., M.A.E., J.R.C., J.R., G.L.B.), and Department of Neurology (W.A.R.), Wake Forest University School of Medicine, Winston-Salem, NC, and the Public Access Defibrillation Trial (M.A.M.), University of Washington, Seattle, Wash.
Reprint requests to David M. Herrington, MD, MHS, Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail dherring{at}wfubmc.edu
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Abstract |
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It remains unclear whether estrogen therapy (with or without progestin) improves endothelial function in older postmenopausal women with or at risk for coronary heart disease. To address this issue, we analyzed brachial artery flow-mediated vasodilation in the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in subjects over 65 years of age. At the tenth annual Cardiovascular Health Study examination, 1662 women returned for follow-up. Eighteen percent (n=291) were current users of estrogen replacement, most of whom (75.9%, n=221) took unopposed estrogen. Brachial artery ultrasound examinations measuring vasodilation in response to a flow stimulus (hyperemia) were performed on 1636 women. There were no statistical differences in brachial flow-mediated vasodilator responses between users and nonusers, even after adjustment for potential confounders. Absence of an effect was most notable in women over 80 years old and in those with established cardiovascular disease. However, among women without clinical or subclinical cardiovascular disease or its risk factors, there was a significant association between hormone replacement therapy use and flow-mediated vasodilator responses (P=0.01). Among older postmenopausal women, favorable vascular effects of estrogen may be limited to those who have not yet developed atherosclerotic vascular disease. These data emphasize the importance of ongoing efforts to determine the role of hormone replacement therapy for primary prevention of cardiovascular disease.
Key Words: atherosclerosis • epidemiology • ultrasonics • vasodilation • women
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Introduction |
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There are ample in vitro,1 animal model,2 and human data3 demonstrating that estrogen markedly improves endothelium-dependent vasodilator responses to various physiological stimuli. This effect is likely mediated through activation of endothelial nitric oxide synthase4 and possibly an antioxidant effect of estrogen,5 resulting in greater availability of endothelial nitric oxide to act on vascular smooth muscle. Estrogen inhibits LDL uptake, vascular inflammation, smooth muscle cell proliferation, and platelet aggregation,6 effects that may occur through activation of the nitric oxide pathway.
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However, there are reasons to question whether the favorable effects of estrogen on endothelial function will occur in older women with or at risk for heart disease who are using conventional hormone replacement therapy (HRT). First, most in vivo vascular studies of estrogen have been done in surgically postmenopausal animals or in relatively young postmenopausal women. Second, the most frequently used progestin in the United States, medroxyprogesterone acetate (MPA), may attenuate effects of estrogen on endothelium-dependent vasodilator responses7 and on other vascular effects.8 Finally, clinical trials in older women with established coronary disease have shown that HRT does not slow progression of clinical9 or angiographic10 coronary disease. Thus, it remains unclear to what extent estrogen with and without progestin therapy may be expected to favorably influence vascular function in older postmenopausal women with and without heart disease or its risk factors. To address this question, we analyzed brachial flow-mediated vasodilation using 2-dimensional ultrasound during the tenth annual examination of women in the Cardiovascular Health Study (CHS).
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Methods |
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Study Population
The CHS is a National Heart, Lung, and Blood Institute–sponsored longitudinal study of cardiovascular risk factors in older subjects. The original cohort consisted of men and women over 65 years old (n=5201) recruited from 4 US communities from 1989 to 1990.11 A cohort of black subjects (n=687) was recruited from 3 sites from 1992 to 1993.12 During annual follow-up examinations, standardized and year-specific interviews and examinations were performed. For the tenth examination cycle (1997 to 1998), participants who were willing and eligible underwent ultrasound assessment of brachial artery flow-mediated vasodilator responses (see below).
Of the 1662 women who returned for the tenth examination, complete ultrasound evaluation of brachial flow-mediated vasodilation was obtained in 1636 subjects (98.4%). Reasons for not participating or completing the examination included discomfort during cuff inflation (n=16), subject refusal (n=5), and equipment or other technical problems (n=5).
Estrogen Exposure, Risk Factor Assessment, and Cardiovascular Disease Status
When enrolled in CHS, each woman was asked about past use of estrogen and progestin therapy. In addition, at each follow-up visit, all subjects were asked to bring in currently used prescription and over-the-counter medications. For the present study, current estrogen and progestin use was based on the list of medications documented by the clinic staff at the tenth examination. Past use of estrogen and progestin was based on medication lists from each of the preceding examination cycles during active follow-up plus the self-reported use of estrogen (with or without progestins) before enrollment in CHS. Current or past use of estrogen vaginal cream was not counted as estrogen exposure. Clinically defined coronary heart disease was based on validated self-report and standardized clinician consensus-based review of ECGs and records from hospitalizations during the period of follow-up. Subjects were classified as having subclinical disease if they had an ankle-brachial index of <0.9, carotid stenosis of >25%, intimal-medial thickness of the common or internal carotid arteries in the 80th percentile for the entire study population, major abnormalities on an ECG, or a Rose questionnaire positive for claudication or angina. Reports of diabetes (World Health Organization criteria) and hypertension were based on self-report of physician diagnosis, concurrent medications, and laboratory testing.11 Smoking status, income, and education were defined on the basis of data from standardized questionnaires. Plasma lipids were not measured during the tenth examination cycle.
Measurement of Brachial Flow-Mediated Vasodilation
Methods used for image acquisition and analysis and reproducibility of the technique have been described elsewhere.13 Briefly, all subjects were examined in the fasting state after a minimum of 15 minutes of rest in the supine position. Blood pressure and heart rate were measured at 5-minute intervals throughout the procedure with an automated sphygmomanometer on the left arm. A standard pediatric cuff was placed 2 inches below the right antecubital fossa. The right brachial artery was identified 
7 cm proximal to the brachial bifurcation with a 10-MHz Biosound Phase 2 ultrasound system. The transducer position was adjusted to allow simultaneous viewing of both the blood-intimal and medial-adventitial interfaces on the near and far walls. Cursors were placed in the lumen and on distinct perivascular anatomic landmarks to help maintain the imaging geometry throughout the procedure.
Once the transducer position was established, 2 minutes of baseline data were obtained. After baseline imaging, the cuff was inflated to 50 mm Hg greater than systolic blood pressure for 4 minutes. The brachial artery was continuously imaged for the 4 minutes of cuff occlusion and for 2 minutes immediately after cuff release. Nitroglycerin was not administered to avoid headaches and hypotension in these older, fasting, mostly nitroglycerin-naïve women.
The ultrasound images were recorded on Super VHS videotape and sent to the Wake Forest University Cardiology Image Processing Core Laboratory for analysis with a previously validated analysis system.13 This system determines the diameter of the brachial artery for the entire 2 minutes after the flow stimulus. Baseline and maximum diameter, percent change in diameter, and area under the diameter versus time curve were automatically determined and stored in a database for analysis. Baseline diameter, absolute change in diameter (maximum minus baseline), and percent change in diameter ([absolute change/baseline]x 100) are presented in this report. Sonographers at the individual clinics and core laboratory technicians were unaware of HRT status for individual women. The reproducibility of the method, including cuff placement below the antecubital fossa and the automated analyses, was tested with repeat examinations <1 week apart among a subset of 127 CHS participants. The mean±SD difference in percent change in diameter was 0.02±1.54%, and the R2 was 0.7. This same technique has been used previously to demonstrate favorable effects of estrogen and droloxifene in younger postmenopausal women.14
Statistical Analysis
Continuous data are presented as mean±SE. Differences in the distribution of sociodemographic and cardiovascular risk factors according to current use of estrogen and progestin were tested with 
2 tests. ANCOVA was used to examine the relationships between estrogen exposure and brachial responses. In these linear models, brachial measures were adjusted for variables that differed significantly among users of unopposed estrogen, estrogen and progestin, and nonusers. These variables included age (70 to 74 years old, 75 to 79 years old, or 80+ years old), race (black or other), income (<$12 000/year, $12 000 to 24 000/year, or $25 000+/year), education (<8th grade, <high school, or >high school), clinic (Hagerstown, Md; Pittsburgh, Pa; Sacramento, Calif; or Winston-Salem, NC), and body mass index (treated as a continuous variable). The models were also adjusted for diabetes, hypertension, smoking, and concurrent use of ACE inhibitors, ß-blockers, nitrates, or statins. The models of baseline diameter and percent change were adjusted for height and fasting status as well. Pairwise contrasts of group means were made with F tests with adjustment for multiple comparisons by the Scheffé method.15 Analyses of the percent change data were performed after log transformation [log (% change+3)] because the raw data were highly skewed. However, the reported means and standard errors were transformed back to the original scale. Adjusted brachial responses were also examined among subgroups of women defined by the presence or absence of cardiovascular disease risk factors or subclinical/clinical cardiovascular disease.
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Results |
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Forty-seven percent of the women (n=780) had used hormone replacement, although only 18% (n=291) were current users at the tenth examination. Among current users, most (75.9%, n=221) were using unopposed estrogen. Only 70 women (24.1%) were using estrogen plus progestin.
Several demographic and cardiovascular risk factors were differentially distributed among women taking no hormone therapy, estrogen alone, or estrogen plus progestin (Table 1). Women taking some form of estrogen replacement were younger, more likely to be white and from the Sacramento or Winston-Salem clinics, and more likely to have greater than high school education, annual income >$25 000, and a body mass index <27.5 (P<0.001 for each).
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Current Estrogen Use
There were significant differences in raw baseline brachial artery diameter (P=0.001) according to estrogen status, with women taking unopposed estrogen having the smallest diameters (Table 2). However, these differences were no longer significant after adjustment for height and other potential confounders. There were no significant differences among users and nonusers of estrogen with respect to absolute or relative change in diameter after the flow stimulus. When these measures were adjusted for sociodemographic and cardiovascular risk factors, evidence of cardiovascular disease, and other factors, the minor differences with respect to percent change remained nonsignificant. In the women taking estrogen plus progestin (n=70), baseline diameter and vasodilator responses were no different from those in women taking unopposed estrogen and women not taking HRT. When the results for women taking unopposed estrogen and women taking estrogen plus progestin were combined, the results were similar to those from women taking estrogen alone.
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Nonusers of estrogen at the tenth examination included former as well as never users. A residual effect of estrogen in former users could obscure an estrogen effect when users and nonusers were compared. However, comparisons of current versus never users and current users versus former users produced virtually identical results.
Estrogen in Subgroups of Women
There was an increase in baseline diameter and reduction in absolute change with each 5-year age stratum from age 70 to 80+ years of age (data not shown). This resulted in a decrease in percent change with age (P<0.001, test for trend). In women aged 70 to 74 and those aged 75 to 79 years, the point estimates for mean percent change were greater in those taking estrogen; however, these differences were not significant (P=0.57 and 0.10, respectively; Figure 1). In women over 80 years of age, the mean percent change was numerically smaller but not significantly different in users compared with nonusers. The formal test for an interaction between users versus nonusers of HRT was 0.42.
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In women with no clinical disease or only subclinical disease, HRT use was associated with a 9% and 16% greater percent change in diameter, respectively, compared with women not taking HRT (Figure 2). Among those with subclinical disease, this difference was nominally statistically significant (P=0.03). In contrast, in women with clinical disease, the percent change in diameter was virtually identical in users and nonusers of HRT. The formal test for an interaction between HRT use and disease status was 0.01.
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Overall, women with cardiovascular risk factors (P=0.023), disease (P=0.10), or medication (P=0.08) use had less flow-mediated vasodilation than similar women without the factors in question (Table 3). In addition, among women with risk factors, disease, or cardiovascular medication use, there was no effect of HRT on vasodilator responses. In contrast, in women without hypertension (P=0.06), smoking (P=0.10), or clinical/subclinical disease (P=0.06), there were nonsignificant trends toward greater vasodilator responses among those using HRT; and in women without any risk factors or evidence of disease, HRT use was associated with significantly greater vasodilator responses (P=0.04). Similarly, in women without any cardiovascular medication use, HRT use was also associated with enhanced vasodilator responses (P=0.003).
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Figure 3 shows the adjusted percent change according to HRT use among women with no cardiovascular disease risk factors, disease, or medication use compared with all other women. In this extremely healthy subset, HRT was associated with a nearly 40% increase in vasodilator response compared with nonusers (P=0.01). In contrast, there was no significant association between HRT use and vasodilator response among the women with established cardiovascular disease, risk factors, or medication use (P=0.44). The P value for interaction was 0.01.
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Discussion |
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These data show that the effects of HRT may be significantly modified by age and presence of cardiovascular disease or its major risk factors. Among healthy women, HRT use was associated with a nearly 40% greater vasodilator response, whereas in women with cardiovascular disease or its risk factors, there was no evidence of a favorable effect.
Numerous clinical studies have found greater endothelium-dependent vasodilator responses associated with increased endogenous or exogenous estrogen. In premenopausal women, significant increases in brachial flow-mediated vasodilator responses occur during the follicular phase of the menstrual cycle16 and during pregnancy.17 Cross-sectional studies have frequently observed greater flow- or acetylcholine-mediated vasodilator responses in premenopausal versus postmenopausal women,18,19 and Pinto et al20 observed acute reductions in acetylcholine-mediated vasodilation in the forearm after oophorectomy. These data suggest that endogenous estrogen may help maintain endothelial capacity to respond to certain vasodilator stimuli.
In postmenopausal women, McCrohon et al18 found greater brachial flow-mediated vasodilation responses among those taking unopposed estrogen or estrogen plus progestin (n=55) than in women of similar age not taking HRT (n=40). In addition, numerous small clinical studies have shown that acute infusions of estradiol21 or short-term treatment with conjugated estrogen with or without MPA,22 oral estradiol,23 or transdermal estradiol with and without micronized progesterone24 result in significant improvements in flow-mediated vasodilator responses. These observations are supported by animal model2 and vascular ring studies1 that conclusively demonstrate that estrogen has the capacity to enhance endothelium-dependent, nitric oxide–mediated vasodilation. In tissue culture, this effect appears to occur as a result of nongenomic activation of nitric oxide synthase,4 resulting in increased nitric oxide production and possibly an antioxidant effect of estrogen25 and thus less inactivation of nitric oxide. These effects on endothelial nitric oxide have been presumed to be clinically important because of the ability of nitric oxide to inhibit several critical steps in atherogenesis, including monocyte adhesion to vascular endothelium, LDL uptake, smooth muscle cell proliferation, and platelet aggregation. In addition, statins and ACE inhibitors, therapies known to have favorable effects on coronary heart disease risk, are also associated with augmented brachial flow-mediated responses in most but not all studies (see Mancini26 for a review).
Despite these data, there are questions about the extent to which these potential benefits of estrogen may be realized in older women. The women in the current study were, on average, 15 to 20 years older than subjects in previously reported studies of estrogen replacement and brachial flow-mediated vasodilation. As was demonstrated in this and other studies,19 age itself is a major determinant of brachial flow-mediated vasodilation. Celermajer et al19 found that brachial responses to nitroglycerin, an endothelium-independent vasodilator, were relatively preserved with aging, which suggests that age-related declines in flow-mediated vasodilator responses represent a primary failure of endothelial production and delivery of nitric oxide to the vascular smooth muscle. It would appear, given the current data, that estrogen has little or no ability to overcome this effect of aging on vascular function in women in their seventh and eighth decades of life. This lack of effect in older women could be related to the aging-associated methylation of the estrogen receptor gene reported by Post et al.27
The presence of atherosclerosis or its risk factors also appears to attenuate the potential effects of HRT on flow-mediated vasodilator responses. This is consistent with the accumulating body of experimental evidence in women and in animals that estrogen replacement does not slow the progression of clinical9,28 or anatomic10,29,30 evidence of coronary disease once it is well established. Losordo et al31 have reported decreased expression of estrogen receptors in atherosclerotic plaque compared with normal vascular tissues, which suggests a potential mechanism to explain the attenuation of estrogen effects in women with disease.
There are several limitations in the present study. First, we could not distinguish between oral and transdermal forms of estrogen, conjugated estrogens versus estradiol, or MPA versus other progestins. However, when the data were collected, the overwhelming majority of women in the United States taking estrogen replacement used conjugated equine estrogen with or without MPA. Furthermore, both conjugated equine estrogen and estradiol, given orally13,18,23 and transdermally,21 favorably influence endothelial function. We also have no data regarding the length of time that HRT was taken. Second, this is a nonrandomized comparison of users and nonusers of HRT. Although the analyses adjusted for many influential covariates that were differentially distributed among the estrogen-use groups and for other important cardiovascular risk factors, residual confounding remains a possibility. However, the present study has many more subjects than any previous similar study, providing a good opportunity for multivariable adjustments. The older age of the cohort, use of a shorter period of cuff inflation (4 versus 5 minutes), and lower arm placement of the blood pressure cuff resulted in a lower absolute degree of flow-mediated dilation than in other studies. Nevertheless, we were able to observe significant differences between several subgroups because of the precision of the analysis methods and the large numbers of study subjects. Finally, in large prospective cohort studies like the CHS, investigators seek to minimize participant burden to prevent drop out. This concern precluded the administration of nitroglycerin to evaluate the degree of vasodilation in response to a non–endothelium-dependent stimulus. However, recent evidence suggests that response to a single dose of sublingual nitroglycerin does not rule out the possibility of impairment in the non–endothelium-dependent response to nitric oxide.32 Thus, although we may conclude that estrogen use is not associated with a significantly augmented response to an endothelium-directed vasodilator stimulus in this group of older women, we cannot specify with certainty that the lack of response to estrogen is entirely due to impaired endothelium-dependent mechanisms.
In summary, in a large group of older postmenopausal women, there was no significant association between current use of estrogen replacement and brachial flow-mediated vasodilator responses after adjustment for age and sociodemographic and cardiovascular risk factors. The absence of an effect was most notable among women >80 years of age and in those with established cardiovascular disease. However, in the subset of women who were still free of clinical or subclinical cardiovascular disease or its risk factors, HRT was associated with significantly greater flow-mediated vasodilator responses. This suggests that estrogen may be more effective for maintenance of vascular health than it is for treatment of established vascular disease, a hypothesis that remains in need of formal testing. In the meantime, efforts should be renewed to make use of therapies that are proven to be effective for primary or secondary prevention of coronary heart disease in women.33
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Acknowledgments |
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This study was supported in part by contracts N01HC85079 and N01HC85086 and grants R01HL35129 and R01HL58020 (National Heart, Lung, and Blood Institute) and grant M01RR07122 (General Clinical Research Center; National Center for Research Resources), all from the National Institutes of Health, Bethesda, Md. The authors thank the investigators and staff at the following sites for their contributions to the study: Wake Forest University School of Medicine (clinic and ECG reading center); University of California, Davis; The Johns Hopkins University School of Medicine (clinic and MRI reading center); the University of Pittsburgh; University of California, Irvine; Georgetown University Medical Center; New England Medical Center (ultrasound reading center); University of Vermont School of Medicine (central blood analysis laboratory); University of Arizona (pulmonary reading center); University of Washington (coordinating center); and the National Heart, Lung, and Blood Institute Project Office.
Received August 14, 2001; accepted October 3, 2001.
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M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response Eur. Heart J., February 2, 2005; 26(4): 363 - 368. [Abstract] [Full Text] [PDF]
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G. V. Nair, D. Waters, W. Rogers, G. J. Kowalchuk, T. D. Stuckey, and D. M. Herrington Pulse Pressure and Coronary Atherosclerosis Progression in Postmenopausal Women Hypertension, January 1, 2005; 45(1): 53 - 57. [Abstract] [Full Text] [PDF]
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J. A. Vita, J. F. Keaney Jr, M. G. Larson, M. J. Keyes, J. M. Massaro, I. Lipinska, B. T. Lehman, S. Fan, E. Osypiuk, P. W.F. Wilson, et al. Brachial Artery Vasodilator Function and Systemic Inflammation in the Framingham Offspring Study Circulation, December 7, 2004; 110(23): 3604 - 3609. [Abstract] [Full Text] [PDF]
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 S. C. Halligan, B. Murtagh, R. J. Lennon, G. M. Pumper, V. Mathew, S. T. Higano, and A. Lerman Effect of Long-term Hormone Replacement Therapy on Coronary Endothelial Function in Postmenopausal Women Mayo Clin. Proc., December 1, 2004; 79(12): 1514 - 1520. [Abstract] [PDF]
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S. N. Kalantaridou, K. K. Naka, E. Papanikolaou, N. Kazakos, M. Kravariti, K. A. Calis, E. A. Paraskevaidis, D. A. Sideris, A. Tsatsoulis, G. P. Chrousos, et al. Impaired Endothelial Function in Young Women with Premature Ovarian Failure: Normalization with Hormone Therapy J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3907 - 3913. [Abstract] [Full Text] [PDF]
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K. K. Koh and I. Sakuma Should Progestins Be Blamed for the Failure of Hormone Replacement Therapy to Reduce Cardiovascular Events in Randomized Controlled Trials? Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1171 - 1179. [Abstract] [Full Text] [PDF]
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C. Duvernoy, J. Martin, K. Briesmiester, A. Bargardi, O. Muzik, and L. Mosca Myocardial Blood Flow and Flow Reserve in Response to Hormone Therapy in Postmenopausal Women with Risk Factors for Coronary Disease J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2783 - 2788. [Abstract] [Full Text] [PDF]
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 M. Stampfer Commentary: Hormones and heart disease: do trials and observational studies address different questions? Int. J. Epidemiol., June 1, 2004; 33(3): 454 - 455. [Full Text] [PDF]
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 F. Grodstein, J. E. Manson, M. J. Stampfer, and W. C. Willett The Discrepancy between Observational Studies and Randomized Trials of Menopausal Hormone Therapy Ann Intern Med, May 4, 2004; 140(9): 764 - 765. [Full Text] [PDF]
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L. D. Kirwan, N. J. MacLusky, H. M. Shapiro, B. L. Abramson, S. G. Thomas, and J. M. Goodman Acute and Chronic Effects of Hormone Replacement Therapy on the Cardiovascular System in Healthy Postmenopausal Women J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1618 - 1629. [Abstract] [Full Text] [PDF]
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 F. J. Nieto, D. M. Herrington, S. Redline, E. J. Benjamin, and J. A. Robbins Sleep Apnea and Markers of Vascular Endothelial Function in a Large Community Sample of Older Adults Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 354 - 360. [Abstract] [Full Text] [PDF]
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M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita The clinical implications of endothelial dysfunction J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1149 - 1160. [Abstract] [Full Text] [PDF]
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R. F. Redberg, R. A. Vogel, M. H. Criqui, D. M. Herrington, J. A. C. Lima, and M. J. Roman Task force #3--what is the spectrum of current and emerging techniques for the noninvasive measurement of atherosclerosis? J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1886 - 1898. [Full Text] [PDF]
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 F. Grodstein, T. B. Clarkson, and J. E. Manson Understanding the Divergent Data on Postmenopausal Hormone Therapy N. Engl. J. Med., February 13, 2003; 348(7): 645 - 650. [Full Text] [PDF]
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P. O. Bonetti, L. O. Lerman, and A. Lerman Endothelial Dysfunction: A Marker of Atherosclerotic Risk Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 168 - 175. [Abstract] [Full Text] [PDF]
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 L. Speroff The Impact of the Women's Health Initiative on Clinical Practice Reproductive Sciences, September 1, 2002; 9(5): 251 - 253. [PDF]
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K. K. Koh, J. Y. Ahn, D. K. Jin, B.-K. Yoon, H. S. Kim, D. S. Kim, M.-S. Shin, J. W. Son, I. S. Choi, and E. K. Shin Effects of Continuous Combined Hormone Replacement Therapy on Inflammation in Hypertensive and/or Overweight Postmenopausal Women Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1459 - 1464. [Abstract] [Full Text] [PDF]
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J. A. Vita and J. F. Keaney Jr Hormone Replacement Therapy and Endothelial Function: The Exception That Proves the Rule? Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1867 - 1869. [Full Text] [PDF]
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