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The Duration of Estrogen Replacement but not Estrogen Levels Correlate with Sex Hormone Binding Globulin and Fasting Insulin. Edward M. Lichten, M.D.1 , Denise Cunningham, R.N.1, David Pieper, Ph.D.2, Stephanie R. Lichten, B.A.3, Jason B. Lichten, M.D.4, S. LaDella, M.D.1, Jeffrey Lin, M.D.1, James Sowers, M.D.6 and the ALARM group. AUTHORS AFFILIATIONS 1 Providence Hospital, Departments of Obstetrics & Gynecology, Southfield, Michigan 2 Providence Hospital, Department of Family Practice, Southfield, Michigan 3 St. John's Hospital, Chairman, Department of Research, Grosse Pointe, Michigan 4 Rush Medical College, Chicago, Illinois 5 Beth Israel Hospital, New York City, New York 6 S.U.N.Y.,Director, Division of Endocrinology & Metabolism, Brooklyn, New York CORRESPONDENCE to PRINCIPLE AUTHOR Edward M. Lichten, M.D. Midwest Medical Group, P.C. 29355 Northwestern Highway Suite 120 Southfield, Michigan 48034 Phone (248)358-3433 Fax (248)358-2513 Email: [email protected] ABSTRACT: Background: Numerous observational studies support the cardioprotective effects fo Estrogen Replacement Therapy (ERT) on coronary risk factors. Likewise, hypoandrogenenia, elevated leels of Sex Hormone Binding Globulin (SHBG) and insulin sensitivity are associated with reduced risk of coronary disease. Although these factors seem unrelated, we hypothesize that there exists a stepwise direct correlation: 1) estrogen induces increases in SHBG, 2) SHBG decrease androgenicity, 3) increases in the duration of estrogen exposure increase SHBG and 4) duration of estrogen exposure and increases ni SHBG correlate with decreases in insulin levels. And since lower insulin levels correlate with decreases in cardiac risk, for women, the initial factor is the duration of estrogen exposure in the menopausal years. Objective: The purpose of this cross sectional study was to determine 1) the relative impact of duration of estrogen replacement therapy (D-ERT) and venous serum Estrogens(E) levels on SHBG and insulin levels, and 2) the influence of the increases in D-ERT and SHBG on fasting insulin (i.e. insulin sensitivity) and other coronary risk factors. Method: One hundred and sixty-three post-menopausal women who underwent routine clinic visits were evaluated by hemodynamic and anthropomorphic measures, and fasting blood sampling for plasma lipids, apoproteins, insulin, glucose, cortisol, testosterone, dehydroepiandrosterone sulfate (DHEAS), free testosterone, free estradiol, estradiol, estrone, and SHBG. Results: One hundred and seventeen women had no history of ERT and 49 were on ERT for a duration of one to 120 months. Forty percent were African-American of whom only 10.8% were on ERT, vs whites (P > .001). There were no anthropologic differences between ERT and non-ERT cohorts in age (mean 60 + 10), presence of coronary disease, tobacco use, waist to hip ratio (WHR), cholesterol, or apo B-100. ERT was associated with a lower BMI, higher HDL-C and triglycerides (p< 0.05), and a marked increase (p<.001) in E and SHBG levels. Further, ERT was associated with a markedly lower insulin level (p<.002). There were no differences in free estradiol, testosterone, or DHEAS. The duration of estrogen replacement therapy (D-ERT) was directly related to SHBG ( r= .43 , p <.001) and inversely to fasting insulin (r = -0.51, p <.044) in the 49 women on ERT. Exclusion of the six (6) individuals on concombinant progestin therapy did not change the significance of the correlation (r = .65, p < .002). In the entire group, SHBG was inversely related to BMI, WHR, insulin, and "unbound" testosterone while it was directly correlated with HDL-C (range of p < .001 to p < .025). Estradiol levels were inversely associated in regard to age in non-estrogen users (r=-.242, p <.001) and also inversely associated with WHR in estrogen users (r= -.268, p < .006). Conclusion: The duration of ERT (D-ERT), rather than the random estrogen measurement, was associated with increased SHBG and decreased fasting insulin. This shift in relative hormonal concentrations, perhaps mediated through increases in SHBG could possibly explain both lower fasting insulin levels and decreased CVD factors in women on long-term E replacement. SHBG represented an age-independent and lipidindependent factor that was both insulin and E dependent. The interaction between duration of Estrogen therapy and SHBG might have been the important link between sex hormones, insulin and CVD risk. BACKGROUND CVD is multi-factorial, and includes cholesterol, insulin and sex hormones.1 The replacement of estrogen (ERT) following menopause reduces CVD mortality by 50%2-3. Oral ERT improves risk factors for CVD including plasma lipids and fibrinogen.4 Yet, to date, researchers have been unable to relate serum estradiol levels with the presence of CVD.5-10 The duration of ERT has not been adequately researched. The androgen sex hormone, testosterone, by itself or relative to estrogen levels, may be a relative risk factor for CVD in women.11 Exogenous testosterone may negate the benefits of ERT12, and metabolic states with high testosterone or testosterone precursors are associated with increased cardiovascular risk13, However, Haffner et al14-16 does not confirm a significant CVD risk attributable to testosterone/estrogen ratios. An indirect measurement of androgenicity, sex hormone-binding globulin (SHBG) has been reported to be directly related to insulin resistance, an atherogenic lipid profile, impaired glucose tolerance, and CVD.17-19 It is not clear, though how the high SHBG effects other CVD risk factors. The purpose of this study has been to determine if there is an association between the duration of estrogen replacement (D-ERT) and known CVD risk factors including SHBG and fasting insulin. We have hypothesized that the duration of estrogen replacement (D-ERT) will be directly related to sex hormone-binding globulin (SHBG) and inversely related to fasting insulin levels, both recognized CVD risk factors.7,11 METHODS Patient and Biochemical Determinations One hundred and sixty-three postmenopausal women were identified from a multicenter CVD database in southeastern Michigan. Included for each was a comprehensive CVD risk database and anthropologic measurements of blood pressure, body mass index and waist-to-hip ratios. After documenting appropropriately informed consent, 14cc of venous blood was drawn from the antecubetal vein, spun and frozen. The serum lipid measurements were calculated at a C.D.C. approved laboratory from these specimens. A separate 2cc aliquot was used for duplicate batch hormone analysis. RAI assays were performed for estradiol, total testosterone, free testosterone, DHEAS, androstenedione, sex-hormone binding globulin (SHBG), cortisol and insulin. Estradiol, the most potent estrogen, was measured because it correlated with estrone in postmenopausal women 20 and futher because its has the strongest affinity for SHBG20. The Estradiol was measured by RAI as described previously21. The laboratory assay, technique, supplier and coefficients of variances is seen in Table I. The calculated inter- and intra-assay coefficient of variation were supplied from the supplier. The formula for calculation is C.V.= S.D./mean x 100%. Serum cholesterol and HDL cholesterol were determined by enzymatic procedure at the C.D.C. approved laboratory in Michigan. extraction technique. Insulin was measured by double Table I. Laboratory Assays LAB TESTS SOURCE Testosterone Total Testosterone Free DHEA-SO4 Cortisol INTERASSAY Coated-tube IRA Diagnostic(DPC) Product Corp DPC 2.10 ug/ml C.V.=6.4% C.V.=9.5% 0.18 pg/ml C.V.=7.3% C.V.=9.5% DPC 2.10 ug/ml C.V.=6.4% C.V.=9.5% DPC 0.20 ug/dl C.V.=4.9% Single assay 1.3 mIU/ml C.V.=4.6% Single assay 1.40 pg/ml 0.02 ng/ml C.V.=7.3% C.V.=4.5% C.V.=1.3% Single assay 3 nmol/L C.V.=7.8% Single assay Double Antibody Technique Insulin Diagnostic Systems Lab(DSL) Estradiol DSL Androstenedione DSL “Active” Sex Hormone Binding Globulin MDD Coefficients INTRAASSAY Coated-tube immunoradiometric assay (DSL) Procedures: Informed consent was obtained at the beginning of the examination which included measurements of height and weight. Anthropologic measurements were performed in triplicate for calculations of body mass index and waist-to-hip ratios. Blood pressure readings were taken in triplicate and averaged using a sphygmomanometer to the nearest digit on the right arm of the seated participant after at least a 5-minute rest period. Diabetes was defined as having a previous history of being treated with insulin or a hypoglycemic medication or having fasting serum glucose above 126 mg/ml. Heart disease was based on the physician's record of angina or myocardial infarction associated with changes in EKG or hospitalization/ heart catherization studies. Hypertension was based on the physician's record and the continued use of hypertensive medications. Smokers were removed from the co-variant analyses. Although the patient's last meal was reported as the day before the evaluation, the time of day at which the blood was drawn varied from 8:00 AM to 4:30 PM. Thus, it is unlikely that the time of assay led to any systematic bias in the association between sex hormones and cardiovascular risk factors. Statistical Analysis All statistical analyses were performed with SPSS version 6.1. In all analyzes, a two-tailed value of P<= .05 was considered significant. In the multiple regression model, the listed variables were analyzed comparing the groups of postmenopausal women with and without estrogen replacement. In the logarithmic regression used to determine the relationship of listed variables and risk factors for cardiovascular disease, all cardiovascular risk factors were grouped together and estradiol, sex hormone binding globulin, insulin and HDL cholesterol were considered independent variables. Although 90% of the estrogen22 and 98% of the testosterone23 in women are bound by SHBG, they were considered 100% bound for statistical analysis. Various ratios to sex-hormone binding globulin were also included in the analysis. To determine whether significant correlation existed between any two independent variables in the study, partial correlation coefficients were calculated by linear regression analysis after controlling for age and BMI. RESULTS: Means and standard deviations for the variables in the study appear in Table II. Frequency of race and disease states appears in Table III. Pearson Correlation coefficients comparing variables between the group with estrogen replacement and those without estrogen appear in Table IV. Cross correlation appears in Table V. Independent and dependent variables in the equation appear in Table VI. Graphic displays of these cross group correlation appear in Scattergrams. Figure 1 graphs the mean SHBG versus insulin for current estrogen users. Figure 2 graphs the mean SHBG versus duration of time on ERT (D-ERT). Figure 3 graphs the mean fasting insulin versus duration of time on ERT (D-ERT). RESULTS: The mean and standard deviations of non-estrogen users are compared to the entire group studied (Table II). There is no significant difference between the groups except in reference to the estradiol levels (E2) resulting from the supplementary estrogen replacement. The age, BMI, waist/hip ratio, systolic and diastolic blood pressure, total testosterone, free testosterone, cortisol, DHEA-sulfate, androstenedione, and various cholesterol measurements are comparable. The frequency table (Table III) compares the demographics of the non-estrogen and estrogen users based on race. There is a predominance of estrogen users within the Caucasian population, with 40 women reporting estrogen use versus only 7 AfricanAmerican women use estrogen (p < .001). The non-ERT user population is relatively equal at 63 Caucasian versus 58 African-American women. There is a predominance of diabetes, hypertension and the all-disease-group in the non-ERT group as compared to the ERT group (p < .005). Table IV lists the Pearson correlation coefficients of the 21 variables for the estrogen users (49) and the non-estrogen users (117) in respect to estradiol, insulin and SHBG. For both groups there is a significant inverse correlation with SHBG for insulin, BMI and Waist-hip ratio (p <. .02). There is a significant direct correlation with insulin for BMI and Waist-hip ratio (p < .004). HDL-cholesterol is significantly and directly correlation with SHBG (p < .001) and inversely correlation with insulin (p < .034). In non-estrogen users there exists a strong relation between SHBG and freetestosterone, triglycerides and systolic blood pressure. Triglycerides show a direct correlation and age an inverse correlation for non-estrogen users, but not in ERT users. In the cross correlation performed between the non-estrogen and estrogen replacement groups shows that estradiol and SHBG are significantly higher and that Waist-hip ration and insulin levels are lower in the ERT group (p < .002) Table 5. In the ERT group, the BMI is lower (p < .01) while the cortisol, triglycerides and HDLcholesterol are raised (p <.03) Table 6. Insulin is the independent variable that correlates with the presence of all disease states. DISCUSSION Many observational studies have shown a correlation between estrogen use and a decrease in cardiovascular disease1-3. The Framingham study1 and Nurse’s Health study2-3 showed that women who used ERT experienced dramatically less heart disease. However, measurements of random estradiol, total estrogen, and free estradiol have not show significant associations with cardiovascular risk parameters.5-9 One of the directives of the Women's Health Initiative begun in 1992 was to determine the role that ERT might have in reducing cardiovascular risk in menopausal women. The current investigation is the first to incorporate the parameter of duration of time on estrogen (D-ERT) within a post-menopausal data base. Previous reports have focused on the inter-correlation of three cardiovascular risk factors for post-menopausal women: SHBG, insulin, and cardiovascular disease.7,11,14-16,19 SHBG serves as the important determinant of the ratio of unbound estradiol and unbound testosterone. In biological female systems, increases in SHBG have a feminizing effect while decreases in SHBG are masculinizing.20 In addition to being directly effected by the level of various sex hormones, SHBG is also strongly influenced by states of hyperinsulinemia and obesity21. Hyperinsulinemia with and without obesity prove to be masculinizing for the polycystic female.2 SHBG and insulin are both recognized independent risk factor of cardiovascular disease,22, 23 independent of HDL cholesterol, triglycerides, Apolipoprotein-B, and HDL-C/ Cholesterol ratio. In this complex system, SHBG may serve as the primary conduit of the action of sex hormones on insulin and insulin, in turn, on sex hormones. In conclusion, the Duration of Estrogen Replacement (D-ERT), rather than any random measurement of any estrogenic component was associated with increased SHBG and decreased fasting insulin. Although the domino effect of increased D-ERT contributes to increases in SHBG and decreases in androgenicity, it is their effect on insulin that is primary to reduction in risk. For the logarithmic regression analysis confirms that insulin remains the only independent contributor to disease risk. Since D-ERT induces changes in SHBG that acts on the cell wall to facilitate transport of hormones into the cell, further research may discover a complementary effect on the cell wall action of glucose transport. We conclude that in postmenopausal women, it may well be the lack of long-term estrogen replacement and decreased SHBG that define a state of increased fasting insulin and cardiovascular risk. When future prospective studies are completed that compare estrogen preparations, SHBG, insulin and cardiovascular risk, we may have proof that decreased cardiovascular risk is observed in those individuals who remain the longest on estrogen replacement. TABLE II: POSTMENOPAUSAL WOMEN: Mean and Standard Deviations ALL WOMEN NON-ESTROGEN USERS variable Mean Standard Dev Cases Mean Standard Dev Cases Insulin 11.2334 7.7102 160 | 12.4113 8.0348 116 SHBG 143.0776 87.3985 161 | 115.0256 60.3077 117 E2 43.8444 64.6287 162 | 19.5154 41.2115 117 E2 x SHBG 8537.33 15723.9 161 | 2390.171 6193.02 117 Testosterone 0.2831 0.3604 162 | 0.2625 0.2103 117 Testosterone/SHBG 0.0027 0.0032 161 | 0.0030 0.0028 117 T-free 0.9183 0.8377 161 | 0.8991 0.6139 117 Cortisol 13.5725 5.8470 160 | 12.8276 5.0179 116 DHEA-S 101.2190 59.8350 162 | 101.862 58.369 117 Androstenedione 0.8275 0.4208 160 | 0.8492 0.4203 117 Triglycerides 127.4724 70.5147 163 | 120.0924 67.6587 119 Total Cholesterol 229.3496 39.8326 163 | 226.9747 42.8289 119 HDL Cholesterol 55.3312 14.9166 163 | 53.7563 14.1613 119 LDL/Cholesterol 153.9448 37.1552 163 | 154.4622 40.4271 119 HDL-C/ Chol 0.2480 0.0076 163 | 0.2449 0.0078 119 Apoprotein(B) 115.4662 29.1764 163 | 115.0420 30.7341 119 BP- Systolic 132.5195 18.6205 145 | 133.0777 18.4576 103 BP- Diastolic 80.8069 9.7616 145 | 81.4401 10.1131 103 Age 59.96 10.96 163 | 60.38 11.36 125 BMI 30.3031 6.8116 160 | 31.1058 11.36 115 Waist/Hip Ratio 0.8220 0.0735 161 | 0.8310 0.0074 125 ================================================================ Table III. Women Frequency Table Population ERT (172) 49 non-ERT 117 p value ** Race ~White 40 (38.8%) 63 (61.2%) ~Black 7 (10.8%) 58 (89.2%) 0.001** Diabetes (172) 1 ( 2.1%) 19 (15.6%) 0.005** Smoker (171) 7 (15.0%) 13 (10.5%) n.s. Angina (169) 3 ( 6.4%) 17 (13.9%) n.s. Hypertension (169) 15 (31.9%) 61 (50.0%) 0.025* 1 ( 2.1%) 4 ( 3.3%) n.s. 16 (34.0%) 72 (59.0%) MI All diseases (169) (169) **Power .80 @ .05 Alpha 0.003** Table V. Pearson Correlation coefficients: Cross Groups ERT No ERT Number of 49 117 women Age 57.8 9.7 60.4 11.4 p value n.s. Race ~White 40 (38.8%) 63 (61.2%) ~Black 7 (10.8%) 58 (89.2%) SHBG (49) 217 + 104 Estradiol 107 + 72 Insulin Cortisol BMI Triglycerides HDL Cholesterol DHEAS Testosterone Free Estradiol Total Cholesterol Chol/HDL ratio 8.12 + 15.5 + 28.3 + 5.8 7.3 5.7 147 75 60.0 16 99.5 0.337 0.722 235 64 0.59 0.61 30 4.22 1.2 115 + 60 19.5 + 41.2 .001 .001 .001 12.4 12.8 31.1 120 53.7 + 8.0 + 5.0 + 7.0 68 14 .002 .01 .02 .03 .03 102 0.262 0.560 227 58 0.21 0.50 43 n.s. n.s. n.s. n.s. 4.46 1.3 n.s. HDL/Chol ratio 0.256 0.073 0.245 0.078 Apoprotein B 117 25 115 31 n.s. Waist to Hip 0.79 + 0.067 0.83 + 0.074 .008 n.s. VI. Dependent variable .. DISEASE (MI, HTN, DM, ANG) -2 Log likelihood 214.55939 constant is included in the model Variables entered on Step Number 1.. Insulin HDLCHOL SINAIHDL E2 Testosterone SHBG Estimation terminated at iternation number 4 because Log likelihood decreased by less than .01 percent -2 Log likelihood Goodness of fit Cox and Snell –R^2 Natgelkerke -R^2 189.698 172.253 .148 .198 Mdoel Block Step Chi Quare 24.862 24.862 24.862 dr 6 6 6 Significance .0004 .0004 .0004 Classification Table for DISEASE The cut value is .50 Observed No Observed Yes Predicted No Yes 50 24 28 53 Overall Percent correct 67.57% 65.43% 66.45% Variables in the Equation: Logrithmic Regression Variable Insulin HDL/C B S.E. 0.0898 0.0290 -1.2285 3.5175 Wald 9.5883 0.1220 df 1 1 Sig 0.0020 0.7269 R 0.1892 0.0000 Exp(B) 1.0940 0.2927 HDL Estradiol Testosterone SHBG Constants 0.0154 -0.0049 -0.7494 -0.0028 -1.0630 0.0184 0.0029 0.7129 0.0025 0.8682 0.7033 2.8997 1.1049 1.2267 1.1049 1 1 1 1 1 0.4017 0.0886 0.2932 0.2680 0.2208 0.0000 -.0658 0.0000 0.0000 1.0155 0.9981 0.4727 0.9972 KEYWORDS sex hormone binding globulin, testosterone, estradiol, insulin, Syndrome-X, cholesterol, obesity, dehydroepiandrosterone, risk factors, coronary artery disease, women, correlation Abbreviations: ApoB= BMI = CAD = ASHD= F = DHEAS= DPC = DSL = FT = TRT = HDL/Chol = HDL = LDL = MDD = Tri = RAI = SHBG = TC = TRT = TT = WHR = Apoprotein-(B) body mass index coronary artery disease atherosclerotic heart disease cortisol Dehydroepiandrosterone sulfate Diagnostic Products Corp Diagnostic Systems Lab free testosterone Testosterone Ratio Test HDL/ Cholesterol ratio high density lipoprotein cholesterol low density lipoprotein cholesterol minimal detectable dose triglycerides radioimunoassay sex-hormone-binding globulin total cholesterol Testosterone Ratio Test total testosterone waist-to-hip ratio Acknowledgments: Quest Laboratories, Capistrano, California for funding the free estradiol and total estrogen assays. Lori Mosca, M.D, Ph.D. who supplied the information from the A.L.A.R.M. database and initial support for this study. Grant supported was supplied by Providence Hospital, Research Fund. We are grateful to Kathleen Lobocki, M.T. who performed all of the non-lipid analyzes in the Research Department Laboratories of Providence Hospital, Southfield, Michigan. References 1 Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1976;85(4):447-52 2 Stampfer MJ, Colditz GA, Willett WC, Manson JE, et al. Postmenopausal estrogen therapy and cardiovascular disease: Ten year follow-up from the nurses health study. N Engl J Med1991;325(11):756-62 3 Martin KA, Freeman MW. Postmenopausal hormone replacement therapy. 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