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Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:695-701

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:695-701.)
© 1997 American Heart Association, Inc.

Articles

Relationship Between Serum Sex Hormones and Coronary Artery Disease in Postmenopausal Women

Gerald B. Phillips; Bruce H. Pinkernell; ; Tian-Yi Jing

From the Department of Medicine, Columbia University College of Physicians and Surgeons, St Luke's–Roosevelt Hospital Center, New York, NY.


*    Abstract
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 *Abstract
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Abstract Although sex hormones appear to be importantly involved in the development of coronary heart disease, apparently no study has yet reported an alteration in an endogenous sex hormone level in relation to coronary heart disease in women. In an attempt to determine whether any sex hormone abnormality might be a factor in the development of myocardial infarction in women, estradiol and testosterone, as well as sex hormone–binding globulin, insulin, dehydroepiandrosterone sulfate, and risk factors for myocardial infarction, were measured in relation to the degree of coronary artery disease (CAD) in 60 postmenopausal women undergoing coronary angiography. In a multiple-regression analysis with the degree of CAD as the dependent variable and free testosterone (FT), estradiol, age, body mass index, systolic blood pressure, cholesterol, smoking, and insulin as independent variables in the model, only FT (P<.008) and cholesterol (P=.01) were significantly related to the degree of CAD, both positively. To exclude a possible confounding effect due to prior myocardial infarction, the multiple-regression analysis was repeated for the subgroup of 49 patients remaining after excluding the 11 patients who had ever had a myocardial infarction; again only FT (P<.04) and cholesterol (P=.05) were significantly related to the degree of CAD. Neither total testosterone in place of FT nor HDL cholesterol in place of total cholesterol in the model was significantly related to CAD. Sex hormone–binding globulin and dehydroepiandrosterone sulfate, added individually to the model, showed no significant relationship to CAD. These results raise the possibility that in women an elevated FT level may be a risk factor for coronary atherosclerosis.


Key Words: testosterone • estradiol • coronary artery disease • cholesterol • myocardial infarction • risk factors for coronary heart disease • smoking


*    Introduction
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 *Introduction
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The strikingly lower prevalence of MI in premenopausal women than in men of similar age,1 the progressive narrowing of that difference with age after menopause,2 and an inability to explain the difference by known risk factors for MI other than gender3 4 suggest an important role for sex hormones in the development of MI. While numerous cross-sectional and prospective studies on plasma sex hormone levels in relation to CHD have been performed in men,5 few data are available on sex hormones in relation to CHD in women.6 7 8 In a recent study in men,5 we measured serum sex hormone levels in relation to the degree of CAD on the rationale that any factor associated with CAD, a strong prospective factor for MI, might be a prospective factor for MI. We found a strong, inverse correlation between serum FT level and the degree of CAD. In the present investigation, a similar study was carried out in women. Because of the marked fluctuation in serum estradiol levels with the menstrual cycle and the infrequency of CAD in premenopausal women, we studied postmenopausal women. The serum levels of estradiol, testosterone, FT, SHBG, insulin, and DHEAS and major risk factors for MI were measured in relation to the degree of CAD in 60 postmenopausal women.


*    Methods
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 *Methods
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Patients
Sixty female patients undergoing diagnostic coronary angiography were studied. The patients had been referred to the cardiac catheterization laboratory of the Roosevelt Hospital for evaluation of chest pain syndromes and/or abnormal stress tests and were consecutive except for those patients who were excluded if they (1) were <56 years old, at which age essentially all women would be expected to be postmenopausal9 ; (2) had a major noncardiovascular disorder; (3) were taking estrogen, thyroid hormone, insulin, or any other hormone; (4) were taking digitalis, which has been reported to affect the estradiol and testosterone levels10 11 ; or (5) had undergone a hysterectomy. All data analyses were performed for this group of 60 patients and for the remaining 49 after excluding the 11 patients who had ever had an MI. Patients were classified as having had an MI if they had had any previous episode of characteristic chest pain, electrocardiographic changes, and serum enzyme elevations indicative of an MI or gave a history of MI. All 60 patients were on medication, with an average of 2.62 drugs per patient. Drugs or classes of drugs taken by >3 patients included ß-blockers, calcium channel blockers, aspirin, angiotensin-converting enzyme inhibitors, diuretics, isordil, anticholesterol agents, antiulcer agents, and nitroglycerin.

Coronary Angiography, Blood Sampling, and Assay Methods
Coronary angiography was performed via the femoral artery with preformed catheters, and angiograms were taken by use of the Judkins technique12 with multiple views. One of the authors (Dr Pinkernell) visually estimated the maximum percent reduction in luminal diameter of the main left, left anterior descending, left circumflex, and right coronary arteries in each patient without knowledge of the laboratory results.

Before heparin administration, blood samples were withdrawn through the needle inserted into the femoral artery for angiography. All samples were taken before noon after an overnight fast. All measurements were performed on sera that had been stored airtight at -20°C. Hormones were measured by RIA. Although essentially all of the estrogen in postmenopausal women appears to be derived from the conversion of androstenedione to estrone,13 we measured estradiol, since it is the more potent estrogen14 and is derived mainly from and correlates with estrone in postmenopausal women.15 Estradiol, testosterone, and FT levels were measured in sera that had been stored for <7 months. The method for measuring estradiol has been described previously.16 Materials for the RIA of estradiol were obtained from ICN Biomedicals, Inc and those for the RIAs of total testosterone (nonextraction coated-tube method), FT (non–protein bound testosterone), insulin, and DHEAS from Diagnostic Products Corp. The minimal detection limit for estradiol was 3.0 pg/mL, for testosterone 0.04 ng/mL, and for FT 0.10 pg/mL. None of the values obtained were below these limits. The interassay coefficient of variation of the quality control sample for estradiol was 7.5%, for testosterone 6.3%, and for FT 6.1%. Materials for the immunoradiometric assay of SHBG were from Farmos Diagnostica. TC was measured enzymatically, as was the cholesterol in the supernatant after phosphotungstic acid precipitation of serum in the measurement of HDL-C (DMA, Inc).

Statistical Analysis
All statistical analyses were performed with SPSS version 6.1 on a Macintosh Performa 6300 CD computer. In all analyses, a two-tailed value of P<=.05 was considered significant. In the multiple-regression model used to determine the relationship of sex hormones and risk factors for MI to CAD, CAD was the dependent variable and sex hormones and major risk factors for MI the independent variables. The value used for the degree of CAD in each patient was the mean of the four values of the estimated maximum percent reduction in luminal diameter of the coronary artery segments examined (see above). The sex hormones included were estradiol and FT. Even though essentially all of the estrogen13 and much of the testosterone17 in women is derived from androstenedione, both estradiol and FT were included in the model because they appear to relate oppositely to risk factors for MI.18 19 TC was included as the lipid or lipoprotein risk factor. Since CAD appears unlikely to regress after cessation of smoking,20 smoking was included in the model as an indicator variable coded as 1 for present or past smoking and 0 for never smoked. Although insulin has not been established as a risk factor for MI,21 it was included as an independent variable instead of diabetes because it has been strongly implicated in MI,22 23 24 can be quantified, and has been reported to correlate with FT in women.25 26 Total testosterone in place of FT, HDL-C in place of TC, and diabetes in place of insulin were also tested in the model. To determine whether significant correlations existed between any two independent variables in the model, partial correlation coefficients were calculated after controlling for age and BMI.

To determine whether any drug might have affected the level of any variable in the model, the mean value for each variable was compared by using the unpaired Student t test in patients on or off each of the 9 drugs taken by >3 patients. This comparison was performed only for the group of 49 patients to avoid a possible confounding effect of previous MI. In addition, all 9 drugs were added to the multiple-regression model as indicator variables (coded as 1 for yes and 0 for no) to determine whether there was a drug effect on the relationship between the independent variables and CAD.


*    Results
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The mean±SEMs for the variables measured in the group of 60 women and in the subgroup group of 49 remaining after excluding the 11 patients who had ever had an MI are shown in Table 1Down. The relationship of the measured variables to the degree of CAD was determined by multiple-regression analysis (Table 2Down). In addition to estradiol and FT, independent variables in the model were age, BMI, TC, systolic blood pressure, smoking, and insulin. The significant correlations (controlled for age and BMI) that were found among the independent variables are shown in Table 3Down. In a nonparametric test (Kolmogorov-Smirnov), the significance of the standardized residuals (P=.94) and Studentized deleted residuals (P=.90) showed that the residuals of the multiple regression were normally distributed. A test for collinearity in the multiple-regression model showed no evidence of near dependency among the independent variables, since none of >=2 independent variables had high variance proportions for the same eigenvalues.


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  		Table 1. Mean±SEM of Variables in Women Undergoing Angiography


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  		Table 2. Multiple-Regression Analysis of Relationship Between CAD and Sex Hormones and Risk Factors for MI


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  		Table 3. Significant Partial Correlation Coefficients Between Variables Controlled for Age and BMI

Only FT and TC were significantly related to CAD in both the group of 60 and the subgroup of 49 (Table 2Up). Total testosterone, when substituted for FT in the model, was not significantly related to CAD in the group of 60 (P<.08) or the group of 49 (P=.27). When FT was removed from the model, estradiol did not become significantly related to CAD in either group; when estradiol was removed, however, FT remained significantly related to CAD in both groups. HDL-C when substituted for TC was not significantly related to CAD in either group. When smoking was entered into the model as 1 for present smoking (24.4% of 60 patients) and 0 for present nonsmoking, it was still not significantly related to CAD in either group, while FT and TC remained significantly related to CAD in both groups. SHBG or DHEAS added individually to the multiple-regression model (Table 4Down), SHBG substituted for FT in the model, DHEAS substituted for FT and/or estradiol in the model, or diabetes substituted for insulin in the model showed no significant relationship to CAD in either group.


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  		Table 4. Multiple-Regression Analysis of Relationship Between CAD and Sex Hormones, Risk Factors for MI, SHBG, and DHEAS in 49 Patients With No History of MI

None of the variables showed a significant difference between the patients on or off any of the 9 drugs tested. When all 9 drugs were added to the multiple-regression model, FT remained significantly related to the degree of CAD in the group of 60 (P<.001) and the subgroup of 49 (P=.036).

In support of the validity of these measurements were the significant correlations found that have been reported previously by this and other laboratories (Table 3Up). Previously reported significant Pearson correlations with age or BMI in the groups of 60 and 49, respectively, were DHEAS-age (r=-.32, P=.012 and r=-.36, P=.011), SHBG-BMI (r=-.36, P=.004 and r=-.34, P=.018), estradiol-BMI (r=.32, P=.012 and r=.32, P=.027), and FT-BMI (r=.36, P=.005 and r=.26, P=.075).


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In the multiple-regression model used in the present study, wherein the degree of CAD was used as the dependent variable and the levels of serum sex hormones and risk factors for MI as independent variables, only FT and TC were significantly related (positively) to the degree of CAD in the 60 postmenopausal women. Because of the possible confounding effect of a previous MI on the FT-CAD relationship, the data were recalculated after excluding the 11 patients who had ever had an MI, leaving 49 patients. Again, only FT and TC were significantly related to the degree of CAD but less strongly than in the group of 60, possibly owing to less statistical power with the smaller number of patients. None of these relationships could be attributed to drug intake. Total testosterone, when substituted for FT in the model, showed no significant relationship to the degree of CAD. That FT and not testosterone was related to CAD implicates SHBG, whose concentration appears to affect the ratio of FT to testosterone.27 SHBG, however, showed no significant relationship to CAD when added to the model or when substituted for FT in the model. A previous study that compared testosterone, calculated FT, and SHBG levels in women with and without CAD reported no significant differences.7 A positive relationship between cholesterol level and the degree of CAD has been observed previously in women.28 29 The present study appears to be the first to find a relationship between an endogenous sex hormone level and CHD in women.

The estradiol level, as in the previous study in men,5 was not significantly related to the degree of CAD. In a previous study of estrone levels and degree of CAD in postmenopausal women, no relationship was observed.6 However, in the present study, the relationship between estradiol and CAD was in the negative direction, an observation consistent with the evidence that estrogen administration to postmenopausal women may prevent CAD.30 The possibility arises that statistical significance might have been achieved with the greater statistical power of a larger number of patients. Also, because FT but not testosterone was related to CAD and in the study on men FT was more strongly related to CAD than was testosterone,5 it is also possible that a significant relationship between estradiol and CAD might have been found if free estradiol, which may be the biologically active component, had been measured.

The positive FT-CAD relationship found in the present study is consistent with previous studies that have suggested a relationship between androgenicity and CHD in women.7 31 32 33 34 35 36 37 38 An androgenic pattern of obesity,31 now quantified in terms of an increase in waist-to-hip ratio, has been reported in women to be associated with an increase in FT,26 39 40 41 42 CHD,31 32 34 CAD,7 36 37 38 and risk factors for MI.7 31 32 34 35 38 40 43 Hirsutism, another indicator of androgenicity in women, has been reported in association with an increased waist-to-hip ratio40 and CAD in women.36 Polycystic ovary syndrome, a hyperandrogenic syndrome, has been reported to be associated with risk factors for MI.44 45 46 None of these studies, however, measured sex hormones in relation to CHD. The positive FT-CAD relationship found in the present study is also consistent with the positive association reported in women between FT or testosterone and diabetes,26 hypertension,47 and smoking,48 risk factors for MI. In the present study, FT or testosterone correlated positively with BMI, insulin, and systolic blood pressure.

In both our previous study on sex hormones and CAD in men5 and in the present study in women, the variable that had the strongest relationship to CAD was FT. Of particular interest is that this relationship in men was in the direction opposite to that in women. Why this relationship is in opposite directions between the sexes and whether it is a cause-and-effect relationship is not clear. Among the possible explanations for the relationship are that (1) increased FT levels in women and decreased FT levels in men lead to CAD, either indirectly, through expression of risk factors for MI, or directly, in which case risk factors could be incidental to the development of CAD; (2) FT underlies abdominal obesity that in turn leads to other risk factors that cause CAD; or (3) certain risk factors, such as diabetes, smoking, and abdominal obesity, lead to decreased FT levels in men, increased FT levels in women, and also to CAD, in which case the FT levels could be incidental to the development of CAD.

If the findings of the present study on women and the previous study on men are confirmed, then the evidence would appear to favor FT as relating to CAD independently of risk factors, while at the same time underlying the expression of risk factors, such as diabetes, hypertension, hypercholesterolemia, and increased waist-to-hip ratio or BMI. In the present study in women and the previous study in men,5 FT was significantly related to CAD independently of BMI and other major risk factors. The only risk factors found to be related to CAD independently of FT were cholesterol in the women and HDL-C and age in the men.5 These findings suggest that FT could lead directly to CAD and that risk factors could be linked to CAD through the sex hormones.

There is evidence to suggest that sex hormones could underlie risk factors such as diabetes, hypertension, hypercholesterolemia, increased waist-to-hip ratio, and perhaps even smoking. Women with diabetes, for example, have been reported to have an elevated FT level26 and men with diabetes a decreased testosterone level49 50 51 and an increased estradiol-to-testosterone ratio.52 In addition, testosterone has been observed to correlate positively with insulin in women,25 26 as in the present study, and negatively with insulin in men.53 That insulin resistance and/or hyperinsulinemia may raise the testosterone level in women is suggested by the association in premenopausal women of hypertestosteronemia and various syndromes with marked hyperinsulinemia.54 Alleviation of insulin resistance and hyperinsulinemia in women with the polycystic ovary syndrome, moreover, may result in lower androgen levels.55 56 57 However, insulin administration does not appear to raise the testosterone level in women58 59 or lower it in men,59 whereas testosterone administration has been reported to decrease insulin sensitivity in women60 and increase it in men.61 Furthermore, the occurrence of the polycystic ovary syndrome has been reported in the absence of insulin resistance or hyperinsulinemia,62 63 an indication that insulin resistance or hyperinsulinemia may not cause the hypertestosteronemia. Although the lowering of androgen levels in women with the polycystic ovary syndrome has been reported not to affect insulin resistance,64 65 such lowering has also been reported to decrease insulin resistance.66 Thus, while marked insulin resistance and/or hyperinsulinemia may induce hypertestosteronemia in women, it appears that a sex hormone alteration may contribute to insulin resistance, hyperinsulinemia, and diabetes in both sexes.

Hypertension and hypercholesterolemia would not be expected to affect the testosterone level, but there is evidence that testosterone could affect blood pressure and cholesterol levels. Hypertension has been reported to be associated with a low FT level in men67 and a high FT level in women.68 69 A positive correlation between systolic blood pressure and FT was found in the present study. In addition, testosterone administration to men has been reported to decrease diastolic blood pressure.61 In the present study, the cholesterol level was independently related to CAD; however, the cholesterol level has been found to be inversely correlated with the testosterone level in men,70 71 and testosterone administration to men has been found to lower TC61 72 and low density lipoprotein cholesterol levels.72 Thus, while hypercholesterolemia may lead independently to CAD, the level of cholesterol in serum may be affected by the testosterone level.

The relationship between waist-to-hip ratio or BMI and FT appears to be a more complex one; here there is evidence that the risk factor affects the FT level as well as being affected by it.73 An increased waist-to-hip ratio has been reported to be associated with an increase in FT in women,26 39 40 41 42 with a decrease in FT with weight reduction,74 while an increased waist-to-hip ratio in men has been reported to be associated with a decrease in total testosterone and FT,16 75 76 with a rise in testosterone with weight reduction.77 However, that sex hormones may affect adipose distribution is suggested by the observations that testosterone administration to men decreased visceral adipose,61 whereas androgen administration to postmenopausal women increased visceral adipose.78 Thus, hypotestosteronemia may direct adipose to the abdomen in men and hypertestosteronemia may direct adipose to the abdomen in women. Waist-to-hip ratio, therefore, may both affect and be affected by sex hormones. An increase in waist-to-hip ratio appears to cause the expression of risk factors for MI.79 Thus, an androgenic milieu in women and a hypoandrogenic milieu in men leading to an increase in waist-to-hip ratio could account for risk factors for MI being related positively to FT in women and negatively to FT in men. On the other hand, if sex hormone levels both determine the adipose distribution, by diverting adipose to the abdomen, and cause the expression of risk factors, then adipose distribution could be incidental to the expression of risk factors but be a marker for them.

Smoking has been reported to be associated in women with increased testosterone,48 androstenedione80 (a strong, positive correlate of FT in women81 ), and waist-to-hip ratio82 and in men with increased estradiol83 84 85 and waist-to-hip ratio.82 86 An apparent dose-response relationship and the effect of smoking cessation suggest that hormonal changes may be secondary to the smoking.83 85 86 The smoking studies, however, were not randomized, prospective studies. Thus, rather than smoking's producing an androgenic effect in women and an estrogenic effect in men, it is also possible that an androgenic milieu in women and an estrogenic milieu in men, possibly through induction of depression,87 may increase the propensity to smoking and difficulty in stopping.88 A low testosterone and a high estradiol level with a favorable response to androgen administration has been found in men with depression, and high testosterone and estradiol levels with a favorable response to estrogen administration have been found in premenopausal women with depression.87 Testosterone administration to healthy men61 72 and estrogen administration to postmenopausal women89 have also been reported to induce a feeling of well-being.

In summary, the present study provides evidence of a positive relationship between the serum FT level and the degree of CAD in women. This appears to be the first finding of a relationship in women between an endogenous sex hormone level and CHD. As had been the case in our previous study in men, FT appeared to be related to CAD independently of risk factors for MI. It is not known whether the relationship between FT and CAD is cause and effect; however, evidence suggests that an increased FT level in women and a decreased FT level in men may provoke the expression of risk factors for MI. The evidence, therefore, appears to support the possibility that the FT level underlies CAD in both women and men. We have no explanation as to why the relationship between FT and CAD was found to be in opposite directions in women and men; however, this opposite relationship is consistent with evidence that the relationship of FT to risk factors for MI other than CAD also appears to be opposite in women and men.


*    Selected Abbreviations and Acronyms
 
BMI = body mass index
CAD = coronary artery disease
CHD = coronary heart disease
DHEAS = dehydroepiandrosterone sulfate
FT = free testosterone
HDL-C = HDL cholesterol
MI = myocardial infarction
RIA = radioimmunoassay
SHBG = sex hormone–binding globulin
TC = total cholesterol


*    Acknowledgments
 
This study was supported in part by the Myron C. Patterson, MD, Fund. We are also grateful to the staff of the Cardiac Catheterization Laboratory for their excellent assistance.


*    Footnotes
 
Reprint requests to Dr Gerald B. Phillips, Roosevelt Hospital, 1000 Tenth Ave, New York, NY 10019.

Received May 29, 1996; accepted December 12, 1996.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
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 *References
 

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