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(Circulation. 1995;91:1952-1958.)
© 1995 American Heart Association, Inc.

Articles

Association Between Increased Estrogen Status and Increased Fibrinolytic Potential in the Framingham Offspring Study

Otavio C. E. Gebara, MD; Murray A. Mittleman, MDCM, DrPH; Patrice Sutherland, BS; Izabela Lipinska, PhD; Travis Matheney, BS; Ping Xu, MD; Francine K. Welty, MD, PhD; Peter W. F. Wilson, MD; Daniel Levy, MD; James E. Muller, MD; Geoffrey H. Tofler, MD

From the Institute for Prevention of Cardiovascular Disease, Cardiovascular Division, Deaconess Hospital, and Harvard Medical School, Boston, Mass (O.C.E.G., M.A.M., P.S., I.L., T.M., P.X., F.W., J.E.M., G.H.T.), and the Framingham Heart Study, Framingham, Mass (P.W.F.W., D.L.).

Correspondence to Geoffrey H. Tofler, MD, Institute for Prevention of Cardiovascular Disease, Deaconess Hospital, One Autumn St, 5th Floor, Boston, MA 02215.

	Abstract

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Background Although extensive evidence indicates that estrogen is responsible for the markedly decreased cardiovascular risk of premenopausal women, the mechanism through which estrogen might exert its protective effect has not been adequately explained. Since thrombosis is now recognized to play an important role in the onset of cardiovascular disease, we investigated the relation between estrogen status and fibrinolytic potential, a determinant of thrombotic risk.

Methods and Results We determined levels of plasminogen activator inhibitor (PAI-1) antigen and tissue plasminogen activator (TPA) antigen in 1431 subjects from the Framingham Offspring Study. Fibrinolytic potential was compared between subjects with high estrogen status (premenopausal women and postmenopausal women receiving hormone replacement therapy) and low estrogen status (men and postmenopausal women not receiving hormone replacement therapy). In all comparisons, subjects with high estrogen status had greater fibrinolytic potential (lower PAI-1 levels) than subjects with low estrogen status. First, postmenopausal women receiving estrogen replacement therapy had lower levels of PAI-1 than those not receiving therapy (13.0±0.5 versus 19.5±1.0 ng/mL, P<.001). Second, premenopausal women had lower levels of PAI-1 than men of a similar age (14.8±0.6 versus 20.3±0.8 ng/mL, P<.001); this sex difference diminished when postmenopausal women not receiving hormone replacement therapy were compared with men of a similar age (19.6±0.7 versus 21.1±0.7 ng/mL, P=.089). Third, premenopausal women had markedly lower levels of PAI-1 antigen than postmenopausal women not receiving estrogen therapy (14.8±0.6 versus 19.5±1.0 ng/mL, P<.001). The between-group differences observed for TPA antigen were similar to those for PAI-1 antigen.

Conclusions Each of these comparisons indicates that the cardioprotective effect of estrogen may be mediated, in part, by an increase in fibrinolytic potential. These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.

Key Words: hormones • fibrinolysis • cardiovascular diseases

	Introduction

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Despite extensive evidence that estrogen protects against coronary heart disease,^{1 2 3 4 5 6 7} the mechanisms through which a protective effect might be mediated have not been explained adequately. Exogenous estrogen has been reported to improve plasma lipid profiles,^{8 9 10} carbohydrate metabolism,^{11 12} and vascular reactivity,^{4 13 14} but the benefits expected from these changes do not fully account for the marked decrease in cardiovascular disease that has been observed.

Given the importance of thrombosis in causation of acute coronary syndromes, it is also possible that estrogen exerts a beneficial effect on risk by lowering thrombotic tendency. Recent reports demonstrated that high estrogen status is associated with a favorable decrease in fibrinogen and factors promoting coagulation,^{15 16} but the effect on the countervailing portion of the hemostatic balance, the fibrinolytic system, has not been clarified. The importance of determining the effect of estrogen on the fibrinolytic system is increased by recent studies demonstrating that impaired fibrinolytic capacity is associated with increased cardiovascular risk.^{17 18 19 20} Most studies of fibrinolytic capacity have measured levels of plasminogen activator inhibitor (PAI-1),^{21 22 23 24 25} a plasma protein controlling activity of tissue plasminogen activator (TPA) and the fibrinolytic system. High levels of PAI-1^{21 22 23 24 25 26} or TPA antigen^{27 28} have been associated with increased risk of coronary artery disease. While high levels of TPA activity indicate increased fibrinolytic potential, antigen levels reflect both free TPA and TPA bound to PAI-1.

We measured PAI-1 and TPA antigen levels in 1431 participants in the Framingham Offspring Study to examine the relation between estrogen status and fibrinolytic potential.

	Methods

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Study Population
The study subjects were members of the Framingham Offspring Study, a long-term, prospective evaluation of risk factors of cardiovascular disease. The design and methodology of the Framingham Offspring Study have been reported.²⁹ The participants are either natural or adopted children of the original Framingham Heart Study subjects or spouses of participating children. For this cross-sectional analysis, we collected data from 1624 consecutive subjects examined between April 1, 1991, and December 31, 1992, during the fifth Offspring Study examination cycle.

Data were collected from each subject during a visit to the Framingham Heart Study clinic. Menopausal status was determined by a standardized medical history questionnaire administered by the examining physician. Menopause was defined as the cessation of menses for at least 1 year. The postmenopausal women were further classified according to whether menopause was natural or surgically induced (bilateral oophorectomy). Women who had undergone hysterectomy but who had at least one ovary intact and were 51 years of age were classified as having undergone natural menopause. The use of hormone replacement therapy (estrogen with or without progestin) or oral contraceptives was ascertained by the examining physician. Individuals who regularly smoked at least one cigarette per day during the year before the index examination were classified as current smokers. Alcohol consumption was assessed as the reported number of drinks per day of beer (12 oz), wine (4 oz), and spirits (1 oz). Body mass index was computed by dividing the weight (kilograms) by the square of the height (meters).

Subjects were excluded from the analysis for the following reasons: (1) history of coronary artery disease or stroke, as previously described²⁹ (n=127), (2) current use of oral contraceptives (n=10), (3) missing information regarding menopausal status or hormone therapy (n=22), and (4) missing data for PAI-1 or TPA (n=34). After these exclusions, a total of 1431 subjects (749 women, 682 men) met entry criteria and form the basis for the present report.

Blood Sampling and Analysis
Blood samples were collected from an antecubital vein between 8:00 and 9:00 AM, with subjects in the supine position after an overnight fast. For determination of plasma levels of PAI-1 and TPA antigen, blood was anticoagulated with 3.8% trisodium citrate (9:1, vol/vol) and kept on crushed ice until centrifugation. Plasma was separated by centrifugation at 2500g for 30 minutes at 4°C. Plasma aliquots were quickly frozen and stored at -70°C for subsequent analysis. PAI-1 antigen levels were determined by a commercially available sandwich enzyme-linked immunosorbent assay according to the description of Declerck et al³⁰ (TintElize PAI-1, Biopool AB). Levels of TPA antigen also were obtained using an enzyme-linked immunosorbent assay (TintElize TPA, Biopool), following a procedure described by Ranby et al.³¹ The intra-assay coefficient of variation in our laboratory was 8.1% for PAI-1 and 5.5% for TPA.

Lipid Analysis
For determination of lipids, blood was anticoagulated with EDTA at a final concentration of 1 mg/mL. Plasma was separated by centrifugation at 2500g for 30 minutes at 4°C, and lipid measurements were made in fresh specimens. HDL cholesterol was measured after precipitation of LDL and very- low-density lipoprotein (VLDL) cholesterol with dextran-magnesium.³² Plasma levels of total cholesterol, HDL cholesterol, and triglycerides were measured by automated enzymatic methods with an Abbot Diagnostics ABA-200 bichromatic analyzer and Abbot A-Gent enzymatic reagents.³³ The level of LDL cholesterol was calculated with the Friedewald equation³⁴ in all cases with triglyceride levels <500 mg/dL. The laboratory participates in the Centers for Disease Control (Atlanta, Ga) lipid standardization program.

Statistical Analysis
For variables that were not normally distributed (PAI-1, TPA, and triglyceride levels), logarithmic transformation was performed and geometric means were presented. Linear regression models were used to evaluate PAI-1 levels for the following comparisons: (1) hormone users versus nonusers among the postmenopausal women, (2) men versus women, (3) premenopausal women versus postmenopausal women not receiving hormone therapy, and (4) users of estrogen alone versus users of estrogen-progestin combinations. For a comparison between sexes, the male population was divided into individuals <50 and 50 years of age since 50 was the median age of menopause of the women in the study.

Results are presented first as unadjusted comparisons between groups and second, after adjustment for the following covariates: age, body mass index, number of alcohol-containing drinks per day, use of antihypertensive medication, diabetes mellitus, and smoking. Adjustment for age was included in all comparisons except for the comparison between premenopausal and postmenopausal women because in this comparison, there was little overlap in the age distributions. Since increased plasma triglyceride levels have been associated previously with increased PAI-1 levels,^{35 36} a final analysis was performed adjusting for triglyceride levels in addition to the other covariates. Baseline clinical characteristics were compared using the unpaired t test and Pearson's ² test for continuous and discrete variables, respectively. All data are presented as mean±SEM. Two-tailed P values <.05 were considered statistically significant.

	Results

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The clinical characteristics and lipid levels of the women are shown in Table 1. A total of 749 women met the entry criteria, of whom 293 were premenopausal and 456 were postmenopausal. Eighty-two postmenopausal women were receiving hormone replacement therapy: 52 were taking estrogen alone, and 30 were taking an estrogen-progestin combination. The premenopausal women reported less use of antihypertensive medication than the postmenopausal women not receiving hormone replacement therapy and had a lower prevalence of diabetes mellitus, a lower body mass index, and lower levels of total cholesterol, LDL cholesterol, and triglycerides. Postmenopausal women receiving hormone replacement therapy were younger than postmenopausal women not receiving hormone therapy and also had a lower body mass index and lower levels of total and LDL cholesterol and higher HDL cholesterol. Among the 374 postmenopausal women not receiving hormone therapy, menopause occurred naturally in 256 and surgically in 86. In 32, the cause of menopause was not stated.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of the Female Population

Estrogen Use Versus Non–Estrogen Use in Postmenopausal Women
Fig 1 shows the PAI-1 antigen levels for postmenopausal women stratified by estrogen therapy. The women receiving therapy had 35% lower levels of PAI-1 than postmenopausal women not receiving hormones, with an unadjusted difference of 6.7 ng/mL (95% confidence interval from 4.8 to 8.5 ng/mL, P<.001) and a difference of 3.7 ng/mL (95% confidence interval from 1.9 to 5.5 ng/mL, P<.001) after adjustment for the covariates.

View larger version (16K): [in this window] [in a new window]   Figure 1. Bar graphs show plasminogen activator inhibitor (PAI-1) antigen levels for postmenopausal women based on hormone replacement therapy (HRT). The women receiving HRT had 35% lower levels of PAI-1 antigen than those not receiving hormones. The difference remained significant after adjustment for covariates (see text).

Women receiving estrogen alone and those receiving an estrogen-progestin combination did not differ with regard to baseline characteristics except for type of menopause (Table 2). Unadjusted PAI-1 levels also did not differ between the two groups (12.1±1.0 versus 14.3±1.8 ng/mL, estrogen alone and combined therapy, respectively, P=.241), although the difference between the two groups was of borderline significance after adjustment for the covariates (11.3±1.2 versus 15.4±2.1 ng/mL, estrogen and combined therapy, respectively, P=.041), suggesting that combination therapy may not be associated with as great an increase in fibrinolytic potential as estrogen therapy alone.

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics of the Postmenopausal Women Receiving Estrogen Versus Estrogen-Progestin Hormone Replacement Therapy

Comparison of Women Versus Men
Table 3 shows the differences in clinical characteristics between men and women of similar age. Premenopausal women had a lower mean level of PAI-1 than men of comparable age (14.8±0.6 versus 20.3±0.8 ng/mL unadjusted, P<.001, and 14.1±0.5 versus 17.1±0.8 ng/mL after adjustment, P=.001). In contrast to the findings in the younger age group, PAI-1 levels in postmenopausal women not receiving hormone replacement therapy did not differ from those observed in older men (19.6±0.7 versus 21.1±0.7 ng/mL unadjusted, P=.089, and 17.1±0.8 versus 17.1±0.6 ng/mL adjusted, P=.678).

View this table: [in this window] [in a new window]   Table 3. Clinical Characteristics of the Female Population Not Receiving Hormones and the Male Population of Similar Age

Premenopausal Women Versus Postmenopausal Women
While the PAI-1 antigen levels were not significantly different between the younger and older men, premenopausal women had 25% lower levels than postmenopausal women not receiving hormones, with an average unadjusted difference of 4.8 ng/mL (95% confidence interval from 3.6 to 5.9 ng/mL, P<.001) (Fig 2). This difference was attenuated to 2.9 ng/mL (95% confidence interval from 1.8 to 4.0 ng/mL) after adjustment for the covariates (P<.001). PAI-1 levels were similar for women who had natural or surgical menopause (19.6±0.8 versus 21.2±1.4 ng/mL, respectively, P=.324).

View larger version (18K): [in this window] [in a new window]   Figure 2. Bar graphs show plasminogen activator inhibitor (PAI-1) antigen levels in premenopausal women and postmenopausal women not receiving hormone replacement therapy (HRT). Premenopausal women had 25% lower levels of PAI-1 antigen. The difference remained significant after adjustment for covariates (see text).

TPA Antigen
The between-group differences observed for TPA antigen were similar to those for PAI-1 antigen (Table 4). Postmenopausal women receiving hormones had lower levels than those not receiving hormones. Premenopausal women had lower levels of TPA than men of similar age. Premenopausal women had lower levels of TPA than postmenopausal women not receiving hormones. Adjustment for the covariates did not account for the differences between these groups. Although postmenopausal women had lower unadjusted levels of TPA antigen than men in the same age group (P=.001), this difference became nonsignificant after adjustment for covariates (P=.104). Postmenopausal women receiving estrogen alone did not differ from those receiving combined estrogen-progestin (5.9±0.4 versus 5.9±0.5 ng/mL, respectively, P=.964). TPA antigen levels were significantly correlated with PAI-1 levels (r=.66, P<.001).

View this table: [in this window] [in a new window]   Table 4. Values of Tissue Plasminogen Activator Antigen

Plasma triglyceride levels were significantly correlated with PAI-1 (r=.47, P<.001) and TPA antigen (r=.49, P<.001) levels; however, addition of plasma triglyceride levels to the regression model did not significantly change the results for either PAI-1 or TPA antigen. Fig 3 summarizes findings that subjects with high estrogen status had higher fibrinolytic potential (lower PAI-1 levels) than subjects with low estrogen status.

View larger version (27K): [in this window] [in a new window]   Figure 3. Bar graph shows summary of comparisons of levels of plasminogen activator inhibitor (PAI-1) antigen between subjects with high estrogen status (premenopausal women and postmenopausal women receiving hormone replacement therapy [HRT]) versus levels in those with low estrogen status (men and postmenopausal women not receiving estrogen therapy). PAI-1 levels are significantly lower (indicating increased fibrinolytic potential) in the subjects with high estrogen status.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Each of the three major comparisons of the present study indicates that the protective effect of estrogen against coronary heart disease^{2 3 4 5 6 7 37} may be due in part to a beneficial effect on fibrinolysis. First, postmenopausal women receiving estrogen replacement therapy had lower levels of PAI-1, an important index of fibrinolytic potential, than postmenopausal women not receiving therapy. Second, premenopausal women had lower levels of PAI-1 than men of comparable age, whereas the sex difference disappeared after menopause. Third, premenopausal women had markedly lower levels of PAI-1 antigen than postmenopausal women not receiving hormone replacement therapy. Our findings for TPA antigen paralleled those for PAI-1 antigen and are compatible with decreased fibrinolytic potential in low estrogen states.

Estrogen and Coronary Heart Disease
Epidemiological data suggest that postmenopausal women receiving estrogen replacement therapy experience a cardiovascular risk reduction of approximately 40% to 50%.^{3 4 5 6 7 38} Potential mechanisms for this marked clinical benefit include a favorable reduction in total and LDL cholesterol, an increase of HDL cholesterol,^{8 9 10} and a decrease in LDL uptake by the arterial wall.¹⁴ Estrogen also has beneficial effects on carbohydrate metabolism, decreasing glucose and insulin levels and improving body fat distribution.^{11 12} In addition, a reduction of plasma fibrinogen levels¹⁵ and improvement of endothelium-dependent vasomotion via a direct vascular effect^{4 13} may lessen the risk of thrombosis and coronary occlusion. However, these multiple potential mechanisms do not fully explain the marked protective effect associated with high estrogen levels.

Impaired Fibrinolysis and Coronary Heart Disease
The observation that coronary artery thrombosis and myocardial infarction often occur in the absence of severe coronary stenosis has stimulated interest in the role of impaired fibrinolysis in onset of coronary heart disease.³⁹ The activity of the endogenous fibrinolytic system is dependent on the balance between plasminogen activators (mainly TPA and urokinase-type plasminogen activators) and plasminogen activator inhibitors, of which PAI-1 is considered the most important. Since most of the TPA antigen measured is complexed with PAI-1 and is inactive, high levels of TPA antigen, in association with high levels of PAI-1, reflect impairment of the fibrinolytic system.^{40 41 42 43}

Elevated PAI-1 levels are associated with thromboembolic disease, although a cause-and-effect relation remains to be proven. Most but not all^{35 44 45} cross-sectional studies of patients with angina pectoris or previous myocardial infarction have demonstrated decreased fibrinolytic activity in patients compared with control subjects.^{17 18 19 20 40} Increased levels of PAI-1 have been found in patients with angina and myocardial infarction.^{21 22 23 24} Additionally, there is a temporal association between the increased morning risk of myocardial infarction⁴⁶ and high PAI-1 levels.⁴⁷ Supportive prospective data that increased plasma PAI-1 levels are important in the development of myocardial infarction come from a study in which high PAI-1 levels after infarction were associated with an increased risk of reinfarction.²⁵ In addition to these findings for PAI-1, recent evidence links elevated levels of TPA antigen to increased risk of future myocardial infarction in asymptomatic men²⁷ and increased mortality in patients with known coronary artery disease.²⁸

Estrogen and Fibrinolysis
Our study shows that the presence of estrogen, either naturally in premenopausal women or as a result of replacement therapy in postmenopausal women, was associated with lower levels of PAI-1 and TPA antigen compared with those observed in subjects expected to have low estrogen levels. Prior studies of small numbers of postmenopausal women receiving estrogen^{48 49} or a combination of estrogen and progestin¹⁶ have demonstrated improvement in fibrinolytic potential consistent with our findings. The present report is the first, to our knowledge, to examine the relation between estrogen status and fibrinolytic potential in a comprehensive manner in a large population-based study.

Activation of the coagulation system has been reported in postmenopausal women receiving estrogen therapy⁵⁰ and in premenopausal women using oral contraceptives,⁵¹ suggesting that an increase in fibrinolytic potential may counterbalance a harmful effect on coagulation. Findings that current estrogen users had a greater cardiovascular risk reduction than former users³⁸ are consistent with an acute effect of estrogen on coagulation, in addition to a possible long-term effect on atherosclerosis.

The mechanism by which estrogen may decrease PAI-1 is not clear. Despite the previously described correlation between PAI-1 and triglyceride levels,^{35 36} lowering of triglyceride levels cannot explain the effect of estrogen on PAI-1 because the women receiving estrogen therapy had higher triglyceride levels after age adjustment but lower levels of PAI-1. Estrogen may directly decrease PAI-1 biosynthesis and secretion, since the production of PAI-1 is influenced by several hormones.⁵² However, incubation of endothelial cells with estrogen did not decrease PAI-1 production.^{51 53} Our finding that menopausal women receiving estrogen alone tended to have lower levels of PAI-1 than women receiving combined estrogen-progestin suggests that progestin may diminish the beneficial effect of estrogen on fibrinolysis. However, the number of women available for this comparison in our study was small, and further investigation on this issue is necessary.

Study Limitations
A limitation of this cross-sectional study is that confounding caused by unrecognized factors may remain despite statistical adjustment for known confounders. Randomized clinical trials, such as the Women's Health Initiative, in which women are randomly assigned to estrogen replacement or placebo, are required to demonstrate with certainty that estrogen therapy decreases PAI-1 levels and that this effect translates into decreased cardiovascular risk. Since studies of the role of PAI-1 in the development of coronary heart disease have been conducted almost exclusively in men, the importance of PAI-1 as a potential risk factor in women requires further investigation. Our sample size, while adequate for the primary analysis, was too small to analyze the effect of different types, dosage, and duration of use of hormone preparations on PAI-1 levels. As noted, we were unable to standardize the timing of blood sampling during the menstrual cycle for the premenopausal women or the pill-taking cycle for the postmenopausal women, and menopausal status was determined by history rather than by measurement of hormonal levels. However, any cycle-related variability would tend to increase the observed variability within groups and decrease the power to detect a true difference between groups. Misclassification of menopausal status would have a similar effect.

Conclusions
Our finding that high estrogen status is associated with increased fibrinolytic potential may provide a partial explanation for the cardioprotective effects of estrogen. In addition, the finding provides a stimulus to the design of agents that can reduce PAI-1 without causing other undesirable estrogen effects. This possibility may lead to new approaches to reduce PAI-1 that may be of value not only for postmenopausal women but for men as well.

	Acknowledgments

 
This work was supported by a Grant-in-Aid from the American Heart Association (92011960) and the National Institutes of Health (ROI-HL-48157). We are grateful for the assistance of Kathleen Carney in the manuscript preparation.

Received July 21, 1994; revision received November 1, 1994; accepted November 14, 1994.

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