Published online before print July 11, 2002, doi: 10.1161/01.ATV.0000029226.45915.A7
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Effects of Continuous Combined Hormone Replacement Therapy on Inflammation in Hypertensive and/or Overweight Postmenopausal Women
From the Departments of Cardiology (K.K.K., K.K.J., M.-S. S., J.W.S., I.S.C., E.K.S.), Clinical Pathology (J.Y.A.), Obstetrics and Gynecology (B.K.Y.) (Samsung Medical Center, Sungkyunkwan University), Radiology (H.S.K.), and Preventive Medicine (Biostatistics) (D.S.K.), Gachon Medical School, Incheon, Korea
Address correspondence to Kwang Kon Koh, MD, FACC, FAHA, Professor of Medicine, Director, Vascular Medicine and Atherosclerosis Unit, Division of Cardiology, Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, Korea 405-760. E-mail kwangk{at}ghil.com
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Abstract |
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Objective— We observed that estrogen did not show cardioprotective benefits in type 2 diabetic postmenopausal women. We hypothesized that hypertensive and/or overweight women may be less likely to realize cardiovascular benefits from estrogen.
Methods and Results— We administered micronized progesterone (MP) 100 mg or medroxyprogesterone acetate (MPA) 2.5 mg with conjugated equine estrogen (CEE) 0.625 mg daily during 2 months to 35 hypertensive and/or overweight postmenopausal women with a randomized, double-blind, crossover design. With significant changes of lipoproteins, CEE+MP or MPA significantly improved flow-mediated dilation and reduced plasma E-selectin, intercellular adhesion molecule type-1, monocyte chemoattractant protein-1, and tumor necrosis factor-
levels (P<0.001, P<0.001, P=0.021, P<0.001, and P<0.001 by ANOVA, respectively), but not C-reactive protein and fibrinogen levels. Of note, there were no significant differences between each therapy regarding these effects. However, the magnitude of improvement of flow-mediated dilation in these women was less than in healthy postmenopausal women and more than in diabetic postmenopausal women reported by our previous studies. The effects of CEE+MP or MPA on inflammatory markers were comparable to healthy postmenopausal women, but not comparable to diabetic postmenopausal women.
Conclusions— Estrogen combined with synthetic progestin significantly improved flow-mediated brachial artery dilator response and reduced inflammation markers in hypertensive and/or overweight women, comparable to estrogen combined with natural progesterone.
Key Words: synthetic progestin • inflammation • hypertension • overweight • menopause
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Introduction |
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Vascular inflammation plays an important role in the pathogenesis of atherosclerosis. The vessel wall in patients with coronary heart disease (CHD) or risk factors for CHD may promote inflammation, which may contribute to development and clinical expression of atherosclerosis including myocardial infarction and stroke.1
Prospective cohort surveys suggest that hormone replacement therapy (HRT) decreases the risk of coronary artery disease in relatively young and healthy postmenopausal women.2,3 In contrast, two recent, randomized studies for secondary prevention, the Heart and Estrogen/progestin Replacement Study4 and Estrogen Replacement and Atherosclerosis trial,5 reported that there were no significant differences between HRT and placebo groups in postmenopausal women with established coronary artery disease. The effects of synthetic progestin, proinflammatory effects of estrogen, increased age, or multiple risk factors of CHD are theorized as the causes of these negative observations.
Estrogen has both anti-inflammatory and pro-inflammatory effects. Estrogen blocks monocyte/macrophage production of tumor necrosis factor (TNF)-,6 and was found to reduce expression of the cell adhesion molecules in endothelial cells activated by interleukin-1.7 We and others have found that HRT decreases serum levels of the cell adhesion molecules.8,9 However, Cid et al10 reported that estradiol enhanced expression of these same cell adhesion molecules in endothelial cells activated with TNF-. Further, estrogen increased C-reactive protein (CRP),8 which stimulates the expression of cell adhesion molecules and monocyte chemoattractant protein (MCP)-1 in endothelial cells.11,12
Meanwhile, the concept that the loss of a healthy endothelium may prevent patients from deriving pronounced cardioprotective benefits from HRT is supported by observational and clinical studies. This concept holds that many of the antiatherogenic and other favorable vascular effects of estrogen are receptor mediated and endothelium dependent. Consequently, endothelial injury13 or declines in vascular estrogen receptor (ER) populations14 can diminish the anti-inflammatory, antithrombotic, and other cardioprotective benefits of this reproductive hormone. In this regard, we observed that HRT increased brachial artery flow-mediated dilator by more than 100% in healthy postmenopausal women (mean body mass index was 22.1±0.3) compared with baseline.15 In contrast, we observed that compared with placebo, estrogen did not significantly improve the percent flow-mediated dilator response to hyperemia in type 2 diabetic postmenopausal women.16 Furthermore, we recently reported that HRT did not significantly decrease plasminogen activator inhibitor type-1 antigen levels and, rather, tended to increase prothrombin fragment 1+2 levels from baseline in 20 hypertensive and/or overweight postmenopausal women,17 which is consistent with the Heart and Estrogen/progestin Replacement Study.
Because hypertension and obesity are associated with endothelial dysfunction, these women may be less likely to realize cardiovascular benefits from estrogen. In this regard, two recent articles reported that HRT did not improve endothelial function in postmenopausal women with risk factors, compared with postmenopausal women without risk factors.18,19 In contrast, the Estrogen in the Prevention of Atherosclerosis Trial reported the opposite.20 Thus, the purpose of this study is to determine 1) whether HRT improves NO bioactivity and reduces serological markers of inflammation potentially affected by NO-potentiating properties in hypertensive and/or overweight postmenopausal women, 2) whether HRT-induced reduction in markers of inflammation is mediated by improvement in NO bioactivity or lipoprotein changes, and 3) the mechanism of CRP and other cytokines regulation because CRP induces the synthesis of cell adhesion molecules and MCP-1 in monocytes and endothelial cells.11,12
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Methods |
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Study Population and Design
Thirty-five postmenopausal women (mean±SEM, 58±1 years) participated in this study, all with plasma 17ß-estradiol levels <50 pg/mL and cessation of menses for at least 1 year. No subject had taken any cholesterol-lowering agent, estrogen therapy, antioxidant vitamin supplements, or angiotensin-converting enzyme inhibitors during the preceding 2 months. Baseline 17ß-estradiol and lipoprotein levels are shown in the Table. We used the National Heart, Lung, and Blood Institute’s definitions21 for overweight and obesity as the cutoff points, body mass index
25.0 and 30.0 kg/m2, respectively. We used World Health Organization/International Society of Hypertension definitions22 for hypertension, defined as systolic and diastolic blood pressure 140 or 90 mm Hg, respectively. Severe hypertension was excluded. Eight, 5, and 22 women were overweight, hypertensive, and both, respectively. Four of 30 were obese. Mean body mass index was 27.3±0.5. The diagnosis of diabetes was based on a history of diabetes or criteria according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.23 None were diabetic, smoked, or had previous angina. This study was randomized, double-blind, crossover in design. Study participants received micronized progesterone (MP) 100 mg or medroxyprogesterone acetate (MPA) 2.5 mg with conjugated equine estrogen (CEE) 0.625 mg daily during 2 months with the second treatment period initiated on completion of the first treatment period. The study was approved by the Gil Hospital Institute Review Board, and all participants gave written, informed consent.
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Laboratory Assays
Blood samples for laboratory assays and vascular studies were obtained at approximately 8:00 AM after overnight fasting except hormone replacement, at baseline, and at the end of each treatment period, and the samples were immediately coded so that investigators performing laboratory assays were blinded to subject identity or study sequence. Assays for lipids, plasma E-selectin, intercellular adhesion molecule type-1 (ICAM-1), vascular cell adhesion molecule type-1 (VCAM-1), MCP-1, and TNF- were performed in duplicate by ELISA (R & D Systems) as previously described.9,15,16,24 In all patients, serum was collected for the measurement of CRP levels, which were determined with an immunonephelometry system according to methods described by the manufacturer (Rate Nephelometry, IMMAGE®, Beckman Coulter). The measurement range is 0.1 to 98 mg/dL. All samples from the same patient (batch samples) were measured in blinded pairs on the same ELISA kit to minimize run-to-run variability.
Vascular Studies
Imaging studies of the right brachial artery were performed with an ATL HDI 3000 ultrasound machine equipped with a 10-MHz linear array transducer, based on a previously published technique.15,16,24 All images were transmitted to a personal computer via Ethernet with DICOM format (Digital Imaging and Communication in Medicine) and then saved on the hard disk of personal computer as a BMP format. Arterial diameters were measured with Image Tool® for Windows version 2.0 (University of Texas Health Science Center, San Antonio, Tex). Measurements were performed by two independent investigators (D.K.J. and H.S.K.) blinded to the subjects’ identity and medication status. Measurements of maximum diameter and percent flow-mediated dilation were made in 10 studies selected at random. The interobserver and intraobserver variability for repeated measurement of maximum diameter were 0.004±0.039 mm and 0.005±0.089 mm, respectively. The interobserver and intraobserver variability for repeated measurement of percent flow-mediated dilation were 0.07±1.27% and 0.15±1.24%, respectively.
Statistical Analysis
Data are expressed as mean±SEM or median (range, 25% to 75%). After testing data for normality, we used the Student paired t test or Wilcoxon signed rank test to compare values at baseline and after each therapy, as reported in the Table. We presumed that the second baseline after the washout was not different from the first baseline, because we determined no carryover effect of CEE and progestogen for 6 to 8 weeks from our previous studies15,16,24,25 and thus, we decided 2 months as treatment period without washout and the second baseline. Indeed, we found no carryover effect in this study (see Results). The effects of the two therapies on vascular function and markers of inflammation relative to baseline values were analyzed by one-way repeated measures ANOVA or Friedman’s repeated ANOVA on ranks. After demonstration of significant differences among therapies by ANOVA, post hoc comparisons between treatment pairs were made by use of the Student-Newman-Keuls multiple comparison procedures. Pearson correlation coefficient analysis was used to assess associations between measured parameters. We calculated that 30 subjects would provide 80% power for detecting difference of absolute increase, 2.1% flow-mediated dilation of the brachial artery between CEE+MP and CEE+MPA, with =0.05 based on our previous studies15,24 and others.26 The comparison of endothelium-dependent dilation among the two treatment schemes was prospectively designated as the primary end point. All other comparisons were considered secondary. Therefore, probability values less than the Bonferroni-adjusted of 0.05/7=0.007 were deemed as statistically significant for the secondary end points.
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Results |
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To assess the possibility of a carryover effect from the initial treatment periods to the next treatment period, we compared the percent changes of 1) the first treatment CEE+MP and the first treatment CEE+MPA after 2 months, 2) the cumulative effect of both therapies after 4 months, 3) the first treatment CEE+MP and the second treatment CEE+MP, and 4) the first treatment CEE+MPA and the second treatment CEE+MPA, relative to baseline values. There were no significant differences in age and baseline values, vascular function (diameter and flow), and markers of inflammation between each group. No significant differences were found in above four comparisons. (data not shown) After 2 months of CEE combined with natural or synthetic progestogen, plasma levels of 17ß-estradiol significantly increased from baseline values and to a similar degree (P<0.001 by ANOVA, Table.)
Effects of Therapies on Lipids
The effects of therapies on lipids are shown in the Table. CEE+MP and CEE+MPA therapies significantly decreased total cholesterol by 5±11% and 7±11%, respectively from baseline values (P<0.001 by ANOVA) and LDL cholesterol levels by 15±20% and 16±20%, respectively from baseline values (P<0.001 by ANOVA). CEE+MP and CEE+MPA therapies significantly increased HDL cholesterol levels by 10±15% and 8±18%, respectively from baseline values (P=0.002 by ANOVA). Thus, both therapies significantly decreased the ratio of LDL to HDL cholesterol levels by 22±20% and 20±22%, respectively from baseline values (P<0.001 by ANOVA). However, there were no significant differences in lipoprotein levels between each therapy.
Effects of Therapies on Vasomotor Function
Basal brachial artery diameter and forearm blood flows were similar during the two treatment periods as were the peak brachial artery diameters and forearm blood flows during reactive hyperemia and the percent increase in flow during hyperemia (data not shown). Both therapies significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P<0.001 by ANOVA, Figure 1) by a similar degree (P=0.674). The brachial artery dilator response to nitroglycerin between each therapy was not significantly changed from baseline measurements (P=0.269 by ANOVA).
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Effects of Therapies on Markers of Inflammation
The therapies decreased plasma levels of E-selectin by 11±18% and 14±18% from baseline values (P<0.001 by ANOVA; Figure 2A) and ICAM-1 levels by 8±16% and 12±25% from baseline values (P=0.021 by ANOVA; Figure 2B). There were no significant differences between each therapy in E-selectin and ICAM-1 levels (P=0.342 and P=0.296, respectively). However, both therapies did not significantly decrease VCAM-1 levels from baseline values (P=0.570 by ANOVA).
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CEE+MP and CEE+MPA therapies significantly decreased plasma levels of MCP-1 by 12±19% and 16±19%, respectively, from baseline values (P<0.001 by ANOVA; Figure 3A) and TNF- levels by 19±31% and 25±32%, respectively, from baseline values (P<0.001 by ANOVA; Figure 3B). However, both therapies did not significantly change serum levels of CRP from 0.13 mg/dL (0.10 to 0.43) to 0.23 mg/dL (0.10 to 0.43) or 0.21 mg/dL (0.10 to 0.39) and fibrinogen from 275±11 mg/dL to 267±12 mg/dL or 275±10 mg/dL (P=0.361 and P=0.724 by ANOVA, respectively). There were no significant differences between each therapy in MCP-1, TNF-, CRP, or fibrinogen levels (P=0.077, P=0.340, P=0.419, and P=0.554, respectively).
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There were significant inverse correlations between pretreatment MCP-1 levels and the degree of change in those levels (r=-0.392, P=0.002) and between pretreatment TNF- levels and the degree of change in those levels (r=-0.327, P=0.011) after CEE+MP and CEE+MPA.
To identify a mechanism for the regulation of E-selectin, ICAM-1, MCP-1, or TNF- levels, we assessed correlations between percent changes of lipoprotein levels or flow-mediated dilation and percent changes of E-selectin, ICAM-1, MCP-1, or TNF- levels on CEE+MP and CEE+MPA. There were significant inverse correlations between the degree of change in flow-mediated dilation and the degree of change in ICAM-1 levels (r=-0.366, P=0.002; Figure 4) after CEE+MP and CEE+MPA. Further, to identify a mechanism for the regulation of CRP, E-selectin, ICAM-1, VCAM-1, and MCP-1 levels, suggested by experimental studies,11,12 we assessed correlations between absolute levels or percent changes of CRP levels and absolute levels or percent changes of E-selectin, ICAM-1, VCAM-1, or MCP-1 levels on CEE+MP and CEE+MPA. There were no significant correlations (all r
0.155) after CEE+MP and CEE+MPA.
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Discussion |
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We observed that estrogen combined with synthetic progestin significantly improved flow-mediated brachial artery dilator response and reduced inflammation markers in hypertensive and/or overweight women, comparable to estrogen combined with natural progesterone. Herrington et al27 reported that hormone therapy with MPA 2.5 mg combined with CEE 0.625 mg daily significantly improved flow-mediated dilation of brachial artery in postmenopausal women. In contrast, Sorensen and coworkers28 reported that cyclical estradiol and norethisterone administered for 2.9 years did not improve endothelial function. Gerhard et al29 demonstrated that progesterone added to estradiol therapy did not significantly attenuate the improvement in flow-mediated dilation that was observed with estradiol administered alone. In the present study, we observed that CEE+MPA increased HDL cholesterol levels less than CEE+MP; nonetheless, both HRTs improved brachial artery endothelium-dependent vasodilatation, which was consistent with other groups.27,29 Even myocardial blood flows were similar for women on estrogen alone or estrogen plus a progestogen.19
The average magnitude of improvement, 51% to 55%, in hypertensive and/or overweight women was less than 105% to 117% in healthy postmenopausal women and more than 17% in diabetic postmenopausal women reported by our previous studies.15,16 Most our participants were mildly hypertensive and/or overweight. The Estrogen in the Prevention of Atherosclerosis Trial subjects were similar to ours regarding demographic characteristics including age and weight. That study demonstrated that the average rate of progression of subclinical atherosclerosis was slower in 17ß-estradiol users compared with non-users.20 Previous work had established a link between endothelial injury or lack of expression of the ER gene and atheroslceorsis.13,14 Indeed, a recent ex vivo study conducted by Post and colleagues30 demonstrated that the promoter region of the ER gene exhibited age-related rises in methylation and, hence, inactivation. In addition, endothelial cells explanted from coronary atheromata in patients displayed significant increases in ER gene methylation as compared with grossly normal segments of the proximal aorta. Of interest, Williams and coworkers31 observed that aging inhibited E2 effects on both smooth muscle– and endothelium-mediated vascular reactivity, and furthermore, impaired E2-mediated vascular reactivity may be associated with aging effects on ER-ß function. This observation was confirmed by another preliminary study.32 One recent article observed that HRT did not improve endothelium-dependent vasodilation in women more than 80 years old.18
To gain insight as to mechanisms of potential vasculoprotective effects of HRT, we measured markers of inflammation. Both HRTs showed average percent changes of E-selectin (-11% to -14%), ICAM-1 (-8% to -12%), and MCP-1 (-12% to -16%) in hypertensive and/or overweight postmenopausal women and E-selectin (-13% to -21%), ICAM-1 (-8% to -8%), and MCP-1 (-7% to -13%) in healthy postmenopausal women, and E-selectin (+1%), ICAM-1 (+8%), and MCP-1 (-4%) in diabetic postmenopausal women by our previous studies.16,17 The changes in E-selectin, ICAM-1, and MCP-1 levels in hypertensive and/or overweight postmenopausal women were comparable to healthy postmenopausal women, but not comparable to diabetic postmenopausal women. Of note, there were no significant differences between CEE+MPA and CEE+MP regarding these effects in the present study, comparable to healthy postmenopausal women using the same regimen, dosages, and duration.15
As to the clinical relevance of MCP-1, restenotic patients had statistically significant (P<0.0001) elevated levels of MCP-1 compared with nonrestenotic patients after coronary angioplasty,33 and stable and unstable angina patients had statistically significant (P<0.001) elevated levels of MCP-1 compared with controls, particularly higher levels in unstable angina than in stable angina.34 Ridker et al35 observed that plasma levels of TNF- were persistently elevated among postmyocardial infarct patients at increased risk for recurrent coronary events.
With regard to proinflammatory effects of estrogen, an epidemiologic study36 and a clinical trial8 reported significantly higher levels of CRP in western women using HRT. The Postmenopausal Estrogen/Progestin Interventions study demonstrated that HRT regimens increased CRP levels with a decrease in E-selectin levels.8 Accordingly, the effect of HRT on serum markers of inflammation in postmenopausal women seems to be divergent. In the present study, we observed that oral HRT showed a trend toward an increase in CRP levels in Asian women.
Increases in CRP with oral estrogen therapy may result in part from a direct stimulatory effect on hepatic CRP synthesis or release during the first pass through the liver estrogen absorbed from the intestines, as transdermal application of estrogen does not increase CRP levels.37Although likely a first pass effect of orally administered estrogen on the hepatic synthesis of CRP, elevated CRP could have deleterious effects on vascular inflammation. CRP induced the synthesis of chemokines and cell adhesion molecule in endothelial cells.11,12 However, we did not observe any correlations between absolute levels or the degree of change in CRP levels and absolute levels or the degree of change in cell adhesion molecules or MCP-1 after HRT. Walsh et al38 also observed no consistent correlations between cytokines and CRP after HRT. Recently, a cross-sectional study reported that forearm blood flow responses to acetylcholine were inversely correlated with CRP serum levels, suggesting an independent predictor of a blunted endothelial vasodilator capacity in patients with coronary artery disease.39 However, we did not observe any correlations between flow-mediated dilation response of brachial artery to reactive hyperemia and CRP serum levels on CEE+MP and CEE+MPA (-0.047r 0.502).
Plasma levels of inflammatory markers were increased and correlated with the extent of disease in patients with atherosclerosis of the coronary and peripheral arteries.40 Hingorani et al41 demonstrated that acute systemic inflammation with Salmonella typhi vaccine impaired endothelium-dependent dilation in humans. Of interest, Raza et al42 reported flow-mediated dilation was significantly impaired in adults with primary systemic necrotizing vasculitis. Further, suppression of inflammation restored and normalized impaired endothelial function in these patients. We observed significant inverse correlations between the degree of change in ICAM-1 levels and the degree of change in flow-mediated dilation after HRT.
There are several limitations in the present study. We did not have a placebo group and an estrogen-alone group. It is possible that each of the progestagens tested blunted the effects of estrogen alone. We did not directly compare the effects of HRT in mild hypertensive and/or overweight postmenopausal women and type II diabetes, and thus, another prospective study should be conducted to obtain the concrete conclusion.
In summary, we observed that estrogen combined with synthetic progestin significantly improved flow-mediated brachial artery dilator response and reduced inflammation markers in hypertensive and/or overweight women, comparable to estrogen combined with natural progesterone. The potential benefit of HRT, however, should be tested in prospective clinical trials.
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Acknowledgments |
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This study was supported by grants from Korea Research Foundation Grant (KRF-2000-F00159). We are very greatly in debt regarding his critical and devoted review to Richard O. Cannon III, MD (Head, Clinical Cardiology Section, Cardiovascular Branch, National Heart, Lung, and Blood Institute, Bethesda, Md). We express our gratitude to Sang Kyoon Kwon, MT, Hee Young Chae, BA, and Soo Jin Kim for their technical assistance.
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Footnotes |
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We administered micronized progesterone 100 mg or medroxyprogesterone acetate 2.5 mg with conjugated equine estrogen 0.625 mg daily during 2 months to 35 hypertensive and/or overweight postmenopausal women. Estrogen combined with synthetic progestin significantly improved flow-mediated brachial artery dilator response and reduced inflammation markers in these women, comparable to estrogen combined with natural progesterone.
Received March 12, 2002; accepted June 25, 2002.
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