Download Sex Hormone Bind ing Globulin: The Connection between

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.
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