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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:M827-M832 (2004)
© 2004 The Gerontological Society of America

The Effect of Different Doses of Micronized 17ß-Estradiol on C-Reactive Protein, Interleukin-6, and Lipids in Older Women

Karen M. Prestwood1,, Christine Unson1, Martin Kulldorff2 and Mary Cushman3

1 Center on Aging and the
2 Departments of Community Medicine and Statistics, University of Connecticut Health Center, Farmington.
3 Departments of Medicine and Pathology, University of Vermont, Burlington.

Address correspondence to Karen M. Prestwood, MD, Center on Aging, University of Connecticut Health Center, 265 Farmington Ave., Farmington, CT 06030-5215. E-mail: prestwood{at}uchc.edu


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Background. The authors evaluated the effect of 3 doses (0.25 mg/day, 0.5 mg/day, and 1 mg/day) of micronized 17ß-estradiol (E2) on C-reactive protein (CRP), interleukin-6 (IL-6), and lipids, compared with placebo, in healthy older women participating in an osteoporosis study.

Methods. This randomized, double-blind, placebo-controlled study was conducted in a University clinical research center. Participants were healthy, community-living women older than 65 years. The primary outcome measure of the study was bone metabolism as estimated by serum and urine markers of bone turnover. For this analysis, the authors measured serum markers of CRP, IL-6, lipids, intracellular adhesion molecule-1, and E-selectin at baseline, after 12 weeks of treatment, and after 12 weeks with no treatment.

Results. A significant dose-response effect of estrogen occurred on CRP levels. After 12 weeks of treatment, CRP decreased 59% in the 0.25 mg/day E2 group and increased 65% in the 1 mg/day E2 group, compared with placebo. The CRP level continued to be elevated (92%), compared with placebo, 12 weeks after treatment was discontinued in the 1 mg/day E2 group. High-density lipoprotein (HDL) and HDL2 cholesterol increased and low-density lipoprotein (LDL) cholesterol decreased at 12 weeks in the 1 mg/day E2 group, with a significant dose-response effect. E-selectin decreased significantly in the 1 mg/day E2 group 12 weeks after discontinuation of treatment (–7%), and there was a significant dose-response effect at this time. The 2 lower doses did not affect any of these parameters. Total and HDL3 cholesterol, triglycerides, lipoprotein(a), intracellular adhesion molecule-1, and IL-6 did not change with any dose of E2.

Conclusions. C-reactive protein, an inflammation marker associated with increased risk for cardiovascular disease, decreased in women taking the lowest estrogen dose but increased in women assigned to the highest estrogen dose, suggesting decreased inflammation with lower dose E2. However, with 3 months of treatment, 0.25 or 0.5 mg/day E2 did not have the same beneficial effects on HDL or LDL cholesterol as did 1 mg/day E2. These data suggest that estradiol doses have differential short-term effects on markers of cardiovascular disease. Low-dose E2 decreased CRP, an important marker of inflammation, but did not affect lipid parameters, whereas the highest dose increased CRP and had a beneficial effect on lipid parameters. The long-term consequences of these effects are unknown, but it is possible that estradiol dose should be considered when risk:benefit ratios are evaluated for individual women before estrogen replacement therapy is initiated.

CARDIOVASCULAR disease is the leading cause of death among women in industrialized countries. Previous epidemiologic studies have shown a lower risk for cardiovascular disease in postmenopausal women taking long-term estrogen replacement therapy (1) and that estrogen had beneficial effects on the lipid profile and vascular smooth muscle (2). However, recent prospective data suggest a transitory increase in cardiovascular risk in women with a history of cardiovascular disease who were treated with hormone replacement therapy (HRT) (3) and no benefit in long-term follow-up (4). The Women's Health Initiative discontinued the estrogen-progestin arm of the study because of an increased incidence of cardiovascular events and breast cancer in women receiving active treatment compared with placebo (5).

Estrogen may increase the risk for cardiovascular events by increasing inflammation. Previous data support the role of inflammation in the pathogenesis of cardiovascular disease. Two markers of inflammation, C-reactive protein (CRP) and interleukin-6 (IL-6), are associated with increased cardiovascular risk (6,7), and a recent study indicated that CRP is a stronger predictor of cardiovascular events than LDL cholesterol (8). The usual replacement doses of conjugated equine estrogen (0.625 mg) or estradiol (2 mg) increase CRP concentrations in postmenopausal women (9,10); however, in vivo studies in rats suggest antiinflammatory effects of estradiol (11). The different responses of CRP to estrogen in humans compared with rats may be a result of first-pass liver effects in humans, although estrogen dose may also play a role. No published studies have compared the effect of different estrogen doses on markers of inflammation in postmenopausal women. Previous studies also showed the beneficial effect of replacement-dose estrogen on markers of vascular reactivity and lipids, but the effect of low-dose estrogen on these parameters is unknown. Therefore, we evaluated the effect of three doses of 17ß-estradiol (E2) on CRP, IL-6, lipids, intracellular adhesion molecule-1 (ICAM-1), and E-selectin in older postmenopausal women participating in an osteoporosis clinical trial using serum collected during the osteoporosis trial.


   MATERIALS AND METHODS
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Women were recruited to participate in a double-blind, placebo-controlled study that evaluated the effects of 3 doses of estrogen, compared with placebo, on biochemical markers of bone turnover. Recruitment methods and a description of the population were previously published (12). Briefly, healthy, community-living women older than 65 years were recruited from the greater Hartford, Connecticut, area. Women were excluded if they had diseases or were taking medication that affected bone, if they had a contraindication to estrogen replacement therapy (breast cancer, endometrial cancer, recent thromboembolic disease), or if they had a history of symptomatic vertebral or hip fracture.

Study Protocol
The Institutional Review Board at the University of Connecticut Health Center approved the study, and all women gave written informed consent before the screening evaluation. Eligible women were stratified by racial and ethnic groups and then randomly assigned, via a computer-generated list, to a 12-week course of 1 of 4 treatment groups: 0.25 mg, 0.5 mg, or 1 mg per day micronized E2, or placebo. All women also received 1300 mg elemental calcium (given as citrate) with 1000 IU vitamin D per day throughout the study. We evaluated the effect of estrogen (0.25, 0.5, or 1 mg/day) or placebo on cardiovascular risk factors measured in serum collected at baseline, after 12 weeks of treatment, and after 12 weeks with no treatment.

Serum samples were collected between 7:00 AM and 9:30 AM after a 10–12-hour fast. The samples were divided into 0.5 ml aliquots and stored at –80°C until they were assayed. Samples were shipped frozen by overnight mail to the University of Vermont, Burlington, Vermont, or to the Lipid Research Laboratories, Washington University, St. Louis, Missouri. The technicians who completed the assays were blinded to treatment groups at all times. We measured serum CRP measured by immunoassay (antibodies and antigens from Calbiochem, San Diego, CA) using a coefficient of variation of 7.7% (13). Soluble E-selectin was measured by immunoassay (R&D Systems, Minneapolis, MN), and the coefficient of variation was 10%. The coefficient of variation was 10% for the IL-6 assay and 5% for ICAM-1, as measured by enzyme-linked immunosorbent assay (R&D Systems). Commercially available enzymatic kits were used to measure the concentrations of cholesterol (Bayer Diagnostics, Tarrytown, NY) and glycerol-blanked triglycerides (Roche Diagnostics, Indianapolis, IN) on a Hitachi 917 analyzer (Boehringer Mannheim, Germany). The concentration of high-density lipoprotein (HDL) cholesterol was measured in the supernatant after precipitation of apo B-containing lipoproteins with Mg+2-dextran sulfate (molecular weight, 50,000) (14). The HDL cholesterol was fractionated into HDL2 and HDL3 by sequential double precipitation using Mg+2 dextran sulfate (15). The Friedewald equation was used to calculate the concentration of low-density lipoprotein (LDL) cholesterol (16). The concentration of lipoprotein(a) was measured by immunoturbidimetry on the Hitachi 917 analyzer using a kit from Wako Diagnostics (Richmond, VA). The coefficient of variation was 1.5% for total cholesterol, 2.5% for HDL and triglycerides, and 5% for lipoprotein(a).

Statistical Analyses
Baseline clinical characteristics are reported using means and standard deviations stratified by treatment group. We tested for differences in baseline characteristics among the treatment groups using one-way analysis of variance or chi-square analysis. We checked all markers for normality of distribution. Absolute values of CRP were not normally distributed and are reported as the median and interquartile range; all other markers were normally distributed. For each participant, we calculated the percentage change in markers of cardiovascular risk from baseline to 12 weeks and from baseline to 24 weeks. The percentage and absolute changes for all markers were normally distributed. For each of the three treatment groups, we compared the percentage change of that group with the placebo group using one-way analysis of variance, obtaining a point estimate of the difference in the percentage change. The point estimates are reported together with 95% confidence intervals and a probability value for the test that the difference is zero. Using linear regression analysis, we also checked for a dose–response effect of estrogen on markers of cardiovascular risk. The same analyses were repeated for the absolute change from baseline to 12 weeks and from baseline to 24 weeks. In all analyses, the predetermined significance level was p <.05.


   RESULTS
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
One hundred twenty-two women were screened for the study and 107 women were randomized to treatment groups. Fourteen women who were randomized to treatment did not complete all study visits. The reasons for dropout from the bone metabolism study were previously reported (12); 2 women dropped out of the placebo and 0.25 mg/day groups, 4 out of the 0.5 mg/day group, and 6 out of the 1 mg/day group. We had sufficient serum to measure the lipid profile for 95 women and CRP, IL-6, ICAM-1, and E-selectin for 88 women. Tables 1 to 3 summarize the clinical characteristics of the women who were included in these analyses and baseline values for all markers. There were no significant differences in baseline characteristics or cardiovascular risk factors among the treatment groups; baseline characteristics of women who were not included in the current analysis did not differ from those included in this report. Ten women were taking statins at baseline and were fairly equally distributed among the groups: 3 in the 0.25 mg/day group, 5 in the 0.5 mg/day group, 2 in the 1 mg/day group, and 0 in the placebo group. The number of women taking aspirin at baseline was 6 in 0.25 mg/day group, 6 in the 0.5 mg/day group, and 4 in the 1 mg/day group. No women began either aspirin or statin therapy during the study. Thirty-four percent of women had had a hysterectomy, 28% had used estrogen replacement therapy in the distant past (>2 years), 32% had histories of fracture, and 21% and 12% were taking thiazide diuretics or thyroid hormone replacement, respectively. The overall rate of treatment compliance was 90%, and calcium supplementation was 87%, based on pill count. Compliance across treatment groups was the same.


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  		Table 1. Baseline Characteristics*.

 
After participants received E2 treatment for 12 weeks, CRP concentrations decreased significantly in the 0.25 mg/day E2 group and increased significantly in the 1 mg/day E2 group; the change in the 0.5 mg/day E2 group was intermediate (Table 4, Figure 1). Twelve weeks after treatment was discontinued, CRP concentrations remained elevated, compared with placebo, in the 1 mg/day E2 group, and we noted a significant dose-response relationship at this time. When all E2-treated groups were combined, IL-6 decreased 35% at 12 weeks compared with placebo (p <.001), but the percentage change within each E2 group was not significant and we found no dose-response effect of E2 on IL-6. The correlation between changes in CRP and IL-6 was significant when all groups were combined (R =.409; p <.001). When the correlation within each treatment group is considered separately, only the group receiving 1 mg/day E2 was significant (R =.673, p =.001). Estradiol and estrone levels increased in all E2-treated groups (12), but the change in CRP or IL-6 did not correlate with changes in estrone or estradiol levels. There was a trend toward decreased E-selectin with the highest dose, but the change was not statistically significant until 12 weeks after treatment was discontinued. Changes in E-selectin did not correlate with changes in CRP or IL-6 or estradiol and estrone levels. ICAM-1 did not change with treatment.


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  		Table 4. Point Estimates of the Difference in Percent Change in Selected Cardiovascular Risk Factors With Micronized Estradiol Treatment Compared with Placebo at 12 Weeks on Treatment and 12 weeks Post-Treatment in Older Women.

 


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  		Figure 1. Point estimates of the difference in percentage change in C-reactive protein with micronized estradiol treatment compared with placebo at 12 weeks on treatment and 12 weeks after treatment in older women. {block} = 1 mg/day 17ß-estradiol (95% confidence intervals [CI], 10.5 to 119.6 at 12 weeks and 46.8 to 138.9 at 24 weeks); {diamondsuit} = 0.5 mg/day 17ß-estradiol (95% CI, 71 to 39.8 at 12 weeks, and –46.6 to 52.3 at 24 weeks); {blacktriangleup} = 0.25 mg/day 17ß-estradiol (95% CI, –117.8 to –.33 at 12 weeks, and –100.2 to 5 at 24 weeks). *p <.05 for a difference compared with placebo

 
After 12 weeks of treatment, HDL and HDL2 levels increased significantly and LDL levels decreased significantly in the group that received 1 mg/day E2 compared with placebo; these values returned to baseline 12 weeks after treatment was discontinued (Table 4). These markers of cardiovascular risk did not change in the groups receiving 0.5 mg/day or 0.25 mg/day E2. E2 had a significant dose-response effect on HDL, HDL2, and LDL cholesterol. Total cholesterol, triglycerides, HDL3, and lipoprotein(a) levels did not change in any treatment group.


   DISCUSSION
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
We found differential dose effects of estrogen on some cardiovascular risk factors in older women after menopause. The lowest estrogen dose used in this study, 0.25 mg/day E2, decreased CRP concentrations, compared with placebo, over 12 weeks of treatment but did not affect other markers of cardiovascular risk. Conversely, 1 mg/day E2 increased CRP concentrations. CRP, a marker of inflammation, has been linked with increased risk for cardiovascular disease. In the Women's Health Study, CRP was a powerful predictor of increased cardiovascular risk, even among women with low LDL cholesterol levels. In this context, higher CRP levels probably reflect the upregulation of some aspect of inflammation involved with atherosclerosis, thrombosis, or both (6). The decrease in CRP concentrations in women receiving 0.25 mg/day E2 suggests that it may have antiinflammatory effects, similar to published results in animals.

Previous studies have shown that customary doses of HRT increase CRP concentration, and this increase may be related to the early increase in coronary risk observed with HRT, such as that seen in the HERS and WHI studies (4,5). In previous studies, estrogen users had 59% higher CRP levels than did nonusers (7) and a persistent 85% increase in CRP over 3 years, compared with placebo, in women in the early stages of menopause (17). In a short-term placebo-controlled study, van Baal and colleagues (10) found that 2 mg/day E2 or 2 mg E2 + progesterone increased CRP 110% compared with placebo after 12 weeks of treatment. However, in two open-label studies, 1 mg did not change CRP during 1 year of treatment (18,19). In recent prospective studies, transdermal estrogen did not increase CRP levels (20–22), suggesting that changes in CRP with estrogen therapy may be due to induction of hepatic synthesis with oral treatment. In our study, CRP significantly decreased in the 0.25 mg/day E2 group and increased in the 1 mg/day group, compared with placebo, suggesting that estrogen dose may be an important factor in determining the increase in cardiovascular events associated with HRT in previous studies. These findings suggest that low-dose estrogen has an antiinflammatory effect in humans, similar to that found in animal studies (11). Although other studies have not evaluated doses as low as those in the current study, in the Nurses Health study, lower dose (0.3 mg/day) conjugated equine estrogen (CEE) decreased the risk for stroke, whereas 0.625 mg/day CEE increased the risk for stroke; in that study, the risk for coronary heart disease was decreased with both doses of estrogen.

The persistent increase in CRP concentrations with 1 mg/day E2 was unexpected and may relate to changes in CRP clearance, prolonged effects on the liver, or a chance finding. This increase after discontinuation of E2 has not been previously reported, but few published studies have measured CRP concentrations after treatment.

In our study, IL-6 decreased with E2, compared with placebo, when all 3 doses were combined and the change in CRP was only associated with the change in IL-6 in the 1 mg/day group, suggesting that the CRP-raising effect of estradiol may be due to increased inflammation only in the group receiving the highest dose of E2. However, the study group was limited by a small sample size, and these findings need to be verified in a larger and longer-term study. IL-6 regulates synthesis of CRP by the liver, inhibits insulin signaling, and induces both hypertriglyceridemia and endothelial activation. In mice, exogenous IL-6 enhanced fatty lesion development in atherosclerotic-prone but not atherosclerosis-resistant animals (23). Previous prospective studies in humans have revealed both increases and decreases in serum IL-6 with estrogen treatment (24,25), and two cross-sectional studies found that women receiving HRT had lower IL-6 levels than did women who were not receiving HRT (26,27).

In this study, the group receiving 1 mg/day E2 had increases in HDL and HDL2 cholesterol levels and decreases in LDL cholesterol levels. These data are consistent with previous data regarding the effect of short-term treatment with 1 mg/day E2 on the lipid profile (28,29). Over a longer period of time, treatment with lower-dose E2 may result in similar changes in the lipid profile seen with customary doses of E2; 1 year-long study demonstrated a significant decrease in LDL concentrations and the HDL:LDL ratio in older women who received estradiol via vaginal ring, compared with women who received no treatment (30). In the Heart, Osteoporosis, Progestin, and Estrogen study, 0.3 mg/day conjugated equine estrogen (approximately equivalent to 0.5 mg/day E2) increased HDL cholesterol by 10% and decreased LDL cholesterol by 5% after 6 months of treatment; both changes were significantly different from baseline and placebo values (2).

The exact role of E-selectin is not known. It may have antiinflammatory, proinflammatory, or procoagulant effects. However, in other studies, E-selectin levels correlated with LDL levels, suggesting common regulation, and it appears that decreases in E-selectin may be a benefit for cardiovascular health. Previous studies have shown a decrease in E-selectin with 0.625 mg/day CEE and 2 mg/day E2 with short-term and long-term treatment (17,20,31,32). In the current study, E-selectin decreased only in the group receiving 1 mg/day E2, and the decrease was significant only after the women had been off treatment for 12 weeks.

In a previous study, 0.25 mg/day E2 reduced markers of bone metabolism to the same extent as 1 mg/day E2 but with fewer adverse effects (12). Here, the same dose of estrogen decreased CRP concentrations and did not affect IL-6 levels, suggesting that low-dose estrogen may have an antiinflammatory effect. If the current findings are confirmed, it is possible that 0.25 mg/day E2 may reduce cardiovascular disease through antiinflammatory or CRP-lowering effects, in a manner similar to that proposed for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (33). Furthermore, these findings, combined with those from our previous study, suggest that low-dose estradiol may prevent bone loss without adverse effects, including an increased risk for cardiovascular events. Recently completed studies will determine long-term effects of 0.25 mg/day E2 on bone density and cardiovascular risk factors in older women, but these preliminary results are promising. Given the recent data from the HERSII and the Women's Health Initiative studies related to cardiovascular adverse effects with customary doses of estrogen replacement, we must consider using lower doses of estrogen for long-term health benefits.


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  		Table 2. Baseline Values for Markers on Inflammation and Vascular Reactivity in Older Women.

 

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  		Table 3. Baseline Lipoprotein Lipid Values for Older Women on Estrogen.

 

   Acknowledgments
 
Supported in part by The Paul Beeson Physician Faculty Scholars in Aging Research program (to Dr. Prestwood), the Claude Pepper Older Americans Independence Center (grant 5P60AG13631), and the General Clinical Research Center (grant M01RR06192) at the University of Connecticut Health Center. Bristol-Myers-Squibb provided the micronized 17ß-estradiol and placebo tablets, and Mission Pharmaceuticals provided the calcium and vitamin D tablets.

The authors thank Bertha Robbins, Tom Shepherd, and Enid Zayas for help in completing this study.

Received January 2, 2003

Accepted April 30, 2003


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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