GB Phillips, BH Pinkernell and TY Jing 1994;14;701-706 Arterioscler. Thromb. Vasc. Biol.

GB Phillips, BH Pinkernell and TY Jing 1994;14;701-706 Arterioscler. Thromb. Vasc. Biol.

The association of hypotestosteronemia with coronary artery disease in men
GB Phillips, BH Pinkernell and TY Jing
Arterioscler. Thromb. Vasc. Biol. 1994;14;701-706
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701
The Association of Hypotestosteronemia With
Coronary Artery Disease in Men
Gerald B. Phillips, Bruce H. Pinkernell, Tian-Yi Jing
Abstract Hyperestrogenemia and hypotestosteronemia
have been observed in association with myocardial infarction
(MI) and its risk factors. To determine whether these abnormalities may be prospective for MI, estradiol and testosterone,
as well as risk factors for MI, were measured in 55 men
undergoing angiography who had not previously had an MI.
Testosterone ( r = - . 3 6 , /"=.008) and free testosterone
(r=-A9, P<.001) correlated negatively with the degree of
coronary artery disease after controlling for age and body
mass index. When the patient group was successively reduced
to a final study group of 34 men by excluding the patients with
other major disorders, the testosterone and free testosterone
correlations persisted (r=-.43, P<.02 and r=-.62, /><.001,
respectively). Neither estradiol nor the risk factors, except for
high-density lipoprotein cholesterol, correlated with the degree of coronary artery disease in the final group. Testosterone correlated negatively with the risk factors fibrinogen,
plasminogen activator inhibitor—1, and insulin and positively
with high-density lipoprotein cholesterol. The correlations
found in this study between testosterone and the degree of
coronary artery disease and between testosterone and other
risk factors for MI raise the possibility that in men hypotestosteronemia may be a risk factor for coronary atherosclerosis.
T
tion of chest pain syndromes and/or abnormal stress tests and
were consecutive except that those with any previous episode
of characteristic chest pain, electrocardiographic changes, and
serum enzyme elevations of MI, or who gave a history of MI,
were excluded from the study. The patients were separated
into four groups for statistical analysis. Group 1 consisted of all
55 patients. Group 2 (53 patients) excluded the 2 patients
whose testosterone values were outliers. Group 3 (46 patients)
further excluded 2 of the 3 patients with insulin-dependent
diabetes (the third was also one of the testosterone outliers)
and the 5 patients with major medical disorders other than
non-insulin-dependent diabetes or hypertension. Group 4 (34
patients) excluded, in addition to the above, the 8 patients with
hypertension, the 2 with non-insulin-dependent diabetes, and
the 2 with both disorders. All 55 patients were on medication,
with an average of three drugs per patient (not including the
diazepam or pentobarbital given before sampling). Group 4
patients took an average of two drugs per patient.
he observations in men of hyperestrogenemia
after myocardial infarction (MI),1 of an association of sex hormones with risk factors for MI,2'3
and of a concurrence of risk factors for MI in clinical
states other than MI and in populations 24 led to the
hypothesis that an elevation in the estradiol-to-testosterone ratio or some closely related hormonal alteration
may underlie risk factors and that hyperestrogenemia
may lead to MI in men.2'3 Most laboratories studying sex
hormones and MI in men have reported a high estradiol
level after MI, both acutely59 and months to years
later. 612 Other laboratories have observed a low testosterone level,1316 and yet others have observed both
abnormalities17'20 after MI. Prospective studies for MI,
however, have thus far failed to show an abnormality in
the level of either estradiol2125 or testosterone.2123'25
The present study investigated whether a hormonal
abnormality might be prospective for MI by determining the sex hormone levels in relation to the degree of
coronary artery disease (CAD) in men who had not had
an MI. The serum estradiol and testosterone levels as
well as the levels of risk factors for MI were measured in
55 men undergoing coronary angiography who had not
had an MI.
Methods
Patients
Fifty-five male patients undergoing coronary angiography
were studied. The patients had been referred to the Cardiac
Catheterization Laboratory of Roosevelt Hospital for evaluaReceived September 23, 1993; revision accepted February 10,
1994.
From the Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital
Center, New York, NY.
Reprint requests to Dr Gerald B. Phillips, Roosevelt Hospital,
428 W 59th St, New York, NY 10019.
(Arterioscler Thromb. 1994;14:701-706.)
Key Words • testosterone • estradiol • coronary artery
disease • HDL • hemostatic risk factors • myocardial
infarction • risk factors for coronary heart disease
Coronary Angiography and Blood Sampling
Coronary angiography was performed via the femoral artery
using preformed catheters, and angiograms were taken using
the Judkins technique26 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 artery
in each patient without knowledge of the laboratory results.
The mean of these four values was used as the estimate of the
degree of CAD for each patient in the statistical analyses.
Blood samples were obtained through the needle inserted in
the femoral artery for angiography before heparin administration. All samples were taken before noon with the patient
fasting. The methods for sampling, storage, and measurement
of the plasma hemostatic factors, ie, fibrinogen, factor VII, and
plasminogen activator inhibitor-1 (PAI-1), have been described.27 All other measurements were performed on serum
that had been stored airtight at -20°C. Hormones were
measured by radioimmunoassay (RIA). Estradiol and testosterone were measured28 on serum stored less than 7 months.
Materials for the RIA of estradiol were obtained from ICN
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702
Arteriosclerosis and Thrombosis
Vol 14, No 5 May 1994
Biomedicals, Inc, and those for the RIA of testosterone, free
testosterone (FT), insulin, and dehydroepiandrosterone sulfate (DHEAS) from Diagnostic Products Corp. Cholesterol
was measured enzymatically, as was the cholesterol in the
supernatant after phosphotungstic acid precipitation of serum
in the measurement of high-density lipoprotein cholesterol
(HDL-C) (Sherwood Medical Co).
Statistical Analysis
Means, SDs, Pearson and partial correlation coefficients,
unpaired Student's t tests (for drug and smoking analyses), and
outliers (using box plots) were calculated with SPSS programs
on a Macintosh SE/30 computer.
Results
Although atherosclerosis of only a single vessel occurred in these 55 patients, the degree of occlusion in
one vessel correlated with that in each of the other
vessels (/->.33, PsS.01) and with the mean degree of
occlusion (r>.60, /><.001) of all four vessels. Thus, the
mean percent occlusion of the four vessels appeared to
be a representative measure of the degree of occlusion
of the coronary system. The correlation between the
percent occlusion of each of the four vessels with age
(r>.39, .P5S.003) and the strong degree of correlation
between mean percent occlusion and age (r=.6O,
P<.001) support the validity of the mean percent occlusion as a measure of the degree of atherosclerosis of the
coronary system.
Because group 4 had the fewest confounding factors,
the mean values with SDs and ranges of the variables
measured are shown for this subset of 34 patients in
Table 1.
Table 2 shows the correlation coefficients, controlled
for age and body mass index (BMI), of the degree of
CAD (mean percent occlusion) with hormone and risk
factor levels in the four groups of patients. Testosterone
correlated negatively with CAD in each of the four
groups. FT correlated similarly but more strongly. The
correlation of FT with CAD in groups 1 and 4 is
depicted in Fig 1. The exclusion of the two testosterone
outliers from group 1 (group 2) had almost no effect on
the degree of any of the correlations. CAD correlated
negatively with HDL-C (Fig 2) in all groups and positively with PAI-1 in groups 1 and 2. CAD did not
correlate with estradiol, insulin, fibrinogen, factor VII,
cholesterol, systolic blood pressure, diastolic blood pressure, or DHEAS. When the one testosterone outlier,
who had no other disorders, was added back to groups
3 and 4, all of the significant correlations in groups 3 and
4 remained essentially unchanged. The Pearson correlations of FT and HDL-C with CAD were stronger than
the controlled correlations in all four groups except
between FT and CAD in group 4 (-.55, /><.001 compared with -.62, P<.001).
Table 3 shows the correlation coefficients, controlled
for age and BMI, between sex hormones and risk factors
in group 4. Testosterone correlated negatively with fibrinogen and PAI-1; testosterone and FT correlated
negatively with insulin. Testosterone correlated positively
with HDL-C in group 4 as well as in groups 1 through 3
(r> .48, P< .001); FT correlated positively with HDL-C in
groups 1 through 3 (r>.32, .P^.02) and with marginal
significance in group 4. The correlations of testosterone
and FT with HDL-C are depicted in Fig 3 for group 1;
TABLE 1. Mean Values, SDs, and Range of Variables in
34 Men Undergoing Angiography
Variable
Mean
SD
Range
Age, y
60.7
12.9
39-89
Body mass index, kg/m2
26.9
3.5
23.1-37.2
Estradiol, pg/mL
25.6
4.3
16.4-32.3
Testosterone, ng/mL
5.86
1.66
1.83-9.40
En-
4.72
1.54
2.60-9.95
5.2
5.2-31.5
Free testosterone, pg/mL
Insulin, /nU/mL
17.5
15.1
8.0
Fibrinogen, mg/dL
292
104
Factor VII, %
104
36
PAI-1, AU/mL
Cholesterol, mg/dL
HDL-C, mg/dL
Systolic BP, mm Hg
12.9
230
29.3
134
4.5
53
6.5
5.4-42.2
132-610
48-176
4.4-23.0
157-392
20.4-47.1
22
100-190
74
14
50-110
123
83
20-420
Main, % occlusion
14
24
0-75
LAD, % occlusion
47
36
0-100
Circ, % occlusion
43
41
0-100
RCA, % occlusion
38
37
0-100
CAD, % occlusion
35
25
0-84
Diastolic BP, mm Hg
DHEAS, figldL
E/T indicates estradiol-to-testosterone ratio; PAI-1, plasminogen activator inhibitor—1; AU, arbitrary units; HDL-C, high-density
lipoprotein cholesterol; BP, blood pressure; DHEAS, dehydroepiandrosterone sulfate; Main, main artery; LAD, left anterior
descending artery; Circ, circumflex artery; RCA, right coronary
artery; and CAD, coronary artery disease. Group 4 comprised
the 34 men; see "Methods" for definition of groups.
after controlling for age and BMI, the correlation coefficients were .52 (P<.001) and .38 (P<.003), respectively.
Previously unreported correlations were observed between PAI-1 and fibrinogen (r=.47, P=.OO7) and PAI-1
and HDL-C (r=-A6, P=.008) (both controlled for age
and BMI). Correlations controlled for age and BMI were
also found between cholesterol and PAI-1 (r=.43,
P<.02) and HDL-C (r=-.45, P=.0l).
Patients taking calcium-channel blockers had a significantly lower mean HDL-C level than patients not taking
them in groups 1 (F<.008) and 2 (/><.009); however,
HDL-C correlated with CAD, testosterone, and FT
more strongly in the patients not taking these drugs than
in those taking them. Patients taking aspirin had a
significantly higher mean fibrinogen level than patients
not taking it in groups 1, 3, and 4 (P=S.O5), but again,
none of the correlations could be attributed to an aspirin
effect in any of the groups. Where four or more patients
on any one drug were compared with the patients not on
that drug in groups 1 through 4, no significant effect of
any drug on the level of estradiol, testosterone, FT,
insulin, or PAI-1 could be demonstrated.
Comparing current smokers with nonsmokers or current plus past smokers with nonsmokers showed no
significant difference in the mean levels of CAD, estradiol, testosterone, FT, insulin, PAI-1, or HDL-C in any
of the groups.
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Phillips et al
Hypotestosteronemia and CAD in Men
703
TABLE 2. Correlation Coefficients Controlled for Age
and Body Mass Index Between Variables and Degree
of CAD in Men
Variable
Group 1
(n=55)
Estradiol
-.03
.06
Testosterone
-.36
P=.OO8
E/T
Group 2
(n=53)
Group 3
(n=46)
Group 4
(n=34)
c
.10
-.07
[
-.36
-.32
-.43
K
P=.01
P=.O3
P<.02
<
.30
.31
.34
.34
P<.03
P=.01
P<.03
-.49
-.49
-.52
-.62
P<.001
P<.001
P<.001
P<.001
-.06
-.06
-.20
.19
Fibrinogen
.08
.05
.04
.02
Factor VII
.06
.06
-.02
-.15
.31
.30
.21
.15
P=.O2
P=.O3
FT
Insulin
PAI-1
Cholesterol
HDL-C
SBP
DBP
DHEAS
.11
.12
.07
.08
-.50
-.49
-.46
-.37
P<.001
P<.001
P=.OO2
.09
.07
.04
P<.04
0
I
y_-
•
£
.07
.08
.10
.27
-.04
.06
-.02
CAD indicates coronary artery disease; E/T, estradiol-to-testosterone ratio; FT, free testosterone; PAI-1, plasminogen activator inhibitor—1; HDL-C, high-density lipoprotein cholesterol;
SBP, systolic blood pressure; DBP, diastolic blood pressure;
and DHEAS, dehydroepiandrosterone sulfate.
P>.05 where no probability value is given.
Discussion
The present study is the first to find a correlation
between testosterone and a measure of the degree of
CAD. This negative correlation was stronger with FT,
which may be the biologically active form of testosterone. The correlations persisted after controlling both
for age and BMI and could not be attributed to drug
intake or smoking. Furthermore, the testosterone and
FT correlations with CAD were found not only in the
original group of 55 men but also after successively
excluding the two patients whose testosterone values
were outliers and then the patients with diabetes,
hypertension, and other major disorders, which resulted
in a final group of 34 men. Two previous studies
measured testosterone in men with and without CAD
who had not had an MI; one found the mean level of
testosterone low in the men with CAD29 and one found
it normal.30 It appears that no previous studies have
measured testosterone in relation to the degree of CAD
in men who had not had an MI.
Because of the striking prevalence of MI in men,
testosterone has heretofore been implicated as a causative factor. However, the finding of hypotestosteronemia in relation to CAD in men who had not had an MI
suggests that hypotestosteronemia may be a prospective
factor for MI. More importantly, that the relation of
testosterone and FT levels to the degree of CAD found
in the present study was continuous throughout the
10 20 30 40 50 60 70 80 90 100
CAD, %
.07
-.04
30-
0
10 20 30 40 50 60 70 80 90 100
CAD, %
FIG 1. Scatterplots showing correlations between free testosterone (Free T) and degree (mean percent occlusion) of coronary artery disease (CAD) in group 1 (55 patients; top) and
group 4 (34 patients; bottom).
range of values suggests not only that a low testosterone
level may be prospective for MI but also that it may lead
to atherosclerosis and that testosterone, rather than
being a causative factor, may protect against atherosclerosis in men. The declining testosterone level and
increasing atherosclerosis with age in men is consistent
with this concept. Of interest, administration of testosterone to men has been reported to decrease risk factors
for MI.31'32 That the administration of testosterone may
be protective for men while administration of estrogen
appears to be protective for women against MI33'34 may
seem contradictory. However, based on the differing
relations in men and women of sex hormones to MI and
its risk factors as well as other evidence, it has been
suggested that sex hormones may have opposite effects
in men and women.35'36
The present study also showed correlations, controlled for age and BMI, between testosterone and risk
factors for MI. These correlations further support the
possibility that hypotestosteronemia may be a prospective factor for MI as well as the hypothesis that risk
factors for MI may be linked by an underlying alteration
in the sex hormone milieu.2-3 In the present study and as
found previously, testosterone correlated negatively
with PAI-127'37 and insulin2'28 and positively with HDL-
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704
Arteriosclerosis and Thrombosis
Vol 14, No 5 May 1994
ou r = - 0.58
p < 0 001
n = 55
50 -
TABLE 3. Correlation Coefficients Controlled for Age
and Body Mass Index Between Sex Hormones and
Risk Factors for Myocardial Infarction in 34 Men
Estradiol
IP:
40-
..
Fibrinogen
-c,
O>
Q
X
30 -
•—^—^.
'
-.32
*
-.46
P=.OO8
Factor VII
20 -
Testosterone
0
.08
-.18
.13
-.01
-.42
.47
-.11
Cholesterol
-.14
.21
10 20 30 40 50 60 70 80 90 100
CAD, %
-.13
P=.01
-.06
HDL-C
0-
.45
FT
PAI-1
P<.02
10 -
E/T
P=.OO7
-.13
-.02
.49
-.24
P=.OO5
Insulin
-.23
DHEAS
-.32
.06
.34
P=.O6
-.40
.41
-.38
P=.O2
P=.O2
P=.O3
.05
-.18
.06
E/T indicates estradiol-to-testosterone ratio; FT, free testosterone; PAI-1, plasminogen activator inhibitor—1; HDL-C, highdensity lipoprotein cholesterol; and DHEAS, dehydroepiandrosterone sulfate. Group 4 comprised the 34 men; see "Methods"
for definition of groups.
P>.05 where no probability value is given.
10 20 30 40 50 60 70 80 90 100
CAD, %
FIG 2. Scatterplots showing correlations between high-density
lipoprotein cholesterol (HDL-C) and degree (mean percent occlusion) of coronary artery disease (CAD) in group 1 (55 patients; top) and group 4 (34 patients; bottom).
Q38-41 Testosterone also correlated negatively with the
fibrinogen level. Associations between hypotestosteronemia and the risk factors diabetes, hyperglycemia,
hypercholesterolemia, hypertriglyceridemia, hypertension, obesity, increased waist-to-hip ratio, and increased
factor VII level in men who had not had an MI have been
reported.28 Moreover, as stated above, administration of
testosterone to men has been reported to decrease risk
factors for MI. 3132 Of particular interest are the negative correlations between testosterone and the hemostatic risk factors PAI-1, 2737 factor VII, 4243 and in this
study fibrinogen as well, which suggest that hypotestosteronemia, if it does underlie these risk factors for
MI, could be a factor leading to thrombosis in men.
Since these studies were carried out on men who were
undergoing angiography and who had not had an MI,
the results may not be representative of the population
at large. For example, a possible explanation for the
testosterone and CAD correlation is that a high testosterone level may induce angina (eg, through spasm or
other mechanisms), and hence lead to angiography,
before CAD develops. However, testosterone administration has not been reported to induce angina in men.
Furthermore, the possibility of a low testosterone level
leading to CAD is supported by the continuous correlation of testosterone with CAD throughout the range
of values observed in the present study and by the
negative correlations reported in men between testosterone and risk factors for MI.28
The absence of a correlation between estradiol and
CAD in the present study may indicate that hyperestrogenemia is not prospective for MI. However, none of
the prospective factors for MI measured in this study
correlated with CAD except HDL-C and PAI-1. Intervention may have confounded the correlations of estradiol and these prospective factors with CAD.23-44 It
appears that no previous studies have measured the
estradiol level in relation to the degree of CAD in men
who had not had an MI. The association of hyperestrogenemia with diabetes, hypercholesterolemia, hypertriglyceridemia, hypertension, obesity, and smoking in
men who had not had an MI,28 however, suggests that
hyperestrogenemia may be prospective for MI. The
possibility arises that hyperestrogenemia may be prospective for MI but not for CAD. The increased incidence of venous thrombosis as well as MI in men to
whom estrogens have been administered45 and evidence
that estrogens may induce coronary spasm46 support
this hypothesis. Thus, in men hypotestosteronemia may
lead to atherosclerosis (and perhaps thrombosis), while
hyperestrogenemia may lead to thrombosis.
The only risk factors that correlated with CAD were
HDL-C, which correlated in all of the groups, and
PAI-1, which correlated in groups 1 and 2. Results of
previous studies correlating HDL-C with the degree of
CAD have been conflicting.47 The positive correlation of
testosterone with HDL-C found in this study and previously3841 suggests that testosterone might protect
against atherosclerosis through an effect on lipoproteins. It is possible that certain risk factors may be
related to CAD and/or MI only through correlations
with sex hormones and may be incidental to their
development. It is also possible that the sex hormones
are related to the risk factors and to CAD and/or MI
through another factor(s). One factor suggested as
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Phillips et al Hypotestosteronemia and CAD in Men
References
18
r = 0 51
p < 0.001
n = 55
16 14 12 10 •
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10
20
30
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60
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60
r = 0.44
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n = 55
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I
705
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0-
10
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30
HDL-C,
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60
mg/dl
FIG 3. Scatterplots showing correlations of testosterone (top)
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men for the relation between testosterone level and
degree of CAD and for the reported correlations between testosterone levels and risk factors for MI remains to be determined.
Acknowledgments
This study was supported in part by the Myron C. Patterson,
MD, Fund. We are grateful to Dr Joseph L. Fleiss, Professor
of Biostatistics, Columbia University, for reviewing the statistics. We are also grateful to the staff of the Cardiac Catheterization Laboratory for their excellent assistance.
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