© 1996 American Heart Association, Inc.
Articles |
Decreased Serum Testosterone in Men With Acute Ischemic Stroke
From the Departments of Clinical Chemistry, Glostrup Hospital (L.L.J.) and Kolding Hospital (K.W.), and the Departments of Neurology (H.S.J., H.N., T.S.O.) and Radiology (H.O.R.), Bispebjerg Hospital, Copenhagen, Denmark.
Correspondence to Lise Leth Jeppesen, MD, Ernest Gallo Clinic and Research Center, University of California San Francisco, San Francisco General Hospital, Bldg 1, Room 101, San Francisco, CA 94110.
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Abstract |
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Abstract Serum levels of total and free testosterone and 17ß-estradiol were determined in 144 men with acute ischemic stroke and 47 healthy male control subjects. Blood samples from patients were drawn a mean of 3 days after stroke onset and also 6 months after admission in a subgroup of 45 patients. Initial stroke severity was assessed on the Scandinavian Stroke Scale and infarct size by computed tomographic scan. Mean total serum testosterone was 13.8±0.5 nmol/L in stroke patients and 16.5±0.7 nmol/L in control subjects (P=.002); the respective values for free serum testosterone were 40.8±1.3 and 51.0±2.2 pmol/L (P=.0001). Both total and free testosterone were significantly inversely associated with stroke severity and 6-month mortality, and total testosterone was significantly inversely associated with infarct size. The differences in total and free testosterone levels between patients and control subjects could not be explained by 10 putative risk factors for stroke, including age, blood pressure, diabetes, ischemic heart disease, smoking, and atrial fibrillation. Total and free testosterone levels tended to normalize 6 months after the stroke. There was no difference between patients and control subjects in serum 17ß-estradiol levels. These results support the idea that testosterone affects the pathogenesis of ischemic stroke in men.
Key Words: risk factor • sex hormones • stroke • testosterone
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Introduction |
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Male sex is an important risk factor for stroke1 as well as ischemic heart disease.2 It is therefore conceivable that endogenous sex hormones play a role in the pathogenesis of these atherothrombotic diseases.
Epidemiological studies on the role of endogenous sex hormones and ischemic heart disease in men are conflicting. Several case-control studies have shown decreased levels of endogenous testosterone in male survivors of myocardial infarction,2 whereas in two prospective studies, testosterone levels in men who subsequently died from cardiovascular disease were normal.3 4 However, Phillips et al5 report that low serum testosterone level is associated with the degree of coronary artery disease. Endogenous estradiol is elevated in male survivors of myocardial infarction,2 but prospective studies find no association between endogenous estradiol and ischemic heart disease.3 4 6
Thrombus formation is an essential feature in stroke. Exogenous testosterone increases platelet aggregability,7 8 and in animal studies testosterone augments arterial thrombus formation.9 In contrast, endogenous testosterone is negatively associated with plasminogen activator inhibitor-1,10 11 12 fibrinogen,5 and factor VII in men,13 14 suggesting that low levels of endogenous testosterone could increase the risk of thrombosis in men. In men, exogenous estrogen promotes thrombosis,15 16 suggesting that estrogens play a role in thrombogenesis.
To study the role of endogenous sex hormones in stroke, blood levels of total and free testosterone, 17ß-estradiol, LH, and FSH were determined in men with ischemic stroke in the acute phase and after 6 months and were compared with those of healthy control subjects.
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Methods |
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Patients
Included were 167 nonselected males with acute stroke who were admitted consecutively to the Neurological Department of Bispebjerg Hospital, Copenhagen. All stroke patients were admitted, regardless of age and stroke severity, to this single department from a well-defined community within the city of Copenhagen with 239 886 inhabitants.17 Stroke was defined according to the World Health Organization: rapidly developed clinical signs of focal disturbance of cerebral function lasting more than 24 hours or leading to death with no apparent cause other than vascular origin.18 Excluded were patients with hemorrhagic strokes (n=7), since these might have a different pathogenesis from the ischemic ones. Patients with onset of stroke more than 14 days before admission (n=16) were also excluded, leaving 144 patients (age, 72.0±0.9 years [mean±SEM]; range, 35 to 92 years). None of the patients received hormone therapy. Forty-five of these patients were examined
6 months (range, 158 to 289 days) after admission;
none of these patients received hormone therapy after the acute stroke.
Thirty-four patients died before the 6-month examination, and the
rest (n=65) did not respond to our request for an examination in the
outpatient clinic. The patients joining (n=45), the patients alive but
not joining (n=65), and the patients who were dead at the 6-month
examination (n=34) were progressively older and had more severe
strokes, with mean ages of 71.0±1.4, 71.7±1.5, and 73.8±1.4 years,
respectively, and mean SSS scores on admission of 45±2, 43±2, and
26±3, respectively (for definition of SSS score, see "Clinical
Assessment").
Computed Tomographic Measurements
Computed tomographic scan was in most cases performed within 2
weeks (median, 7 days) after onset of stroke in 117 (81%) of the
patients. All scans were described by the same radiologist (H.O.R.)
with no knowledge of the relevant clinical data. The lesion size was
measured in millimeters as the largest visible diameter of the infarct
on computed tomography.
Risk Factors
In patients, these risk factors were taken into account: age,
atrial fibrillation (if present on
electrocardiogram obtained on admission), current
smoking (daily smoking of any kind of tobacco), daily alcohol
consumption, hypertension (under treatment with antihypertensive drugs
when admitted or hypertension diagnosed during the hospital stay),
diabetes (already known, diagnosed during the hospital stay, or blood
glucose on admission >11 mmol/L), ischemic heart disease
(already known or diagnosed during the hospital stay), previous stroke,
and serum cholesterol level and systolic blood
pressure on admission.
Information about risk factors was obtained from hospital records (hypertension, diabetes, ischemic heart disease, and previous stroke) or by asking the patient (smoking and alcohol consumption). If patients were not able to answer sufficiently, relatives were asked.
Clinical Assessment
The SSS, which was used to assess stroke
severity,19 20 evaluates level of consciousness; eye
movement; power in arm, hand, and leg; orientation; aphasia; facial
paresis; and gait. The total score ranges from 0 (maximal severity of
stroke) to 58 points (highest possible score).
Control Subjects
The control group consisted of 47 healthy men recruited from an
activity center for elderly people (wickerwork, weaving, etc). We
included volunteers who agreed to participate in the study and who
reported that they had never had any thromboembolic diseases. None of
the control subjects was receiving hormone therapy. Their mean age was
73.4±1.2 years (range, 46 to 90 years), ie, close to that of the
patients. Obesity was estimated by BMI (weight in kilograms/height in
meters squared).
Blood Sampling and Analyses
In patients, venous blood was obtained a mean of 2.9±0.2 days
(range, 0 to 11 days) after stroke onset. All samples were taken
between 10 AM and 4 PM. Specimens were kept at
-20°C until analysis. Total and free testosterone were
measured by radioimmunoassay (direct method) with kits manufactured by
Diagnostic Products Corp. For total testosterone,
quality controls included 3.8 and 23.3 nmol/L; for free testosterone,
quality controls included 15.0, 24.0, and 73.0 pmol/L. Patient and
control samples were assayed in the same runs.
Estradiol was measured by radioimmunoassay with a delayed addition of tracer.21 Estradiol antiserum was from BioMakor, and tritium-labeled estradiol was obtained from Amersham International. The estradiol in serum was extracted by using tert-butyl methyl ether, and the organic phase was isolated and evaporated to dryness. An aliquot of the redissolved extract was incubated with estradiol antiserum for 20 hours at 4°C. Tritium-labeled estradiol was added, and the tubes were incubated for an additional 6 hours before separation of the antibody-bound fraction with dextran-coated charcoal. Two quality control samples of 60 and 112 pmol/L were assayed in each run.
LH and FSH were measured by a microparticle enzyme immunoassays (IMx LH and IMx FSH, Abbott Laboratories).
The sensitivities of the assays were 0.20 nmol/L, 0.60 pmol/L, 0.5
mU/mL, 0.2 mU/mL, and 10 pmol/L for total testosterone, free
testosterone, LH, FSH, and 17ß-estradiol, respectively. The
intra-assay and interassay imprecision was 5% and 6%, 4% and
9%, 6% and 7%, 4% and 7%, and 4% and 14% for total testosterone,
free testosterone, LH, FSH, and 17ß-estradiol, respectively. Due
to lack of serum, not all hormones were measured in each person (Table 1
).
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Statistical Analyses
Statistical analyses were performed by using the SPSS
package.22 Since 17ß-estradiol, FSH, and LH were not
normally distributed, data were log-transformed before statistical
analysis. Student's t test was used to
analyze differences between mean values, and ANOVA was used to
analyze differences between multiple groups. Pearson's
correlation coefficient was calculated to determine associations
between continuous variables. Multiple linear regression
analysis was performed with the use of the backward procedure.
A probability value of .05 or less was considered significant. Unless
otherwise stated, values are mean±SEM.
Ethics
The study was approved by the Ethics Committee of Copenhagen,
Denmark.
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Results |
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Testosterone in Patients and Control Subjects
The total and free serum testosterone concentrations in patients with acute ischemic stroke were, on average, 18% and 20% lower, respectively, than in the healthy control subjects (Table 1
).
After adjustment for age, the total and free testosterone levels were
still significantly lower in patients than in control subjects. The
estradiol-to-testosterone ratio was increased in stroke
patients compared with control subjects (Table 1). In the subgroup of
45 patients, total and free testosterone tended to normalize after 6
months (Table 2). When patients were divided into six
groups in which blood was obtained 1 (n=27), 2 (n=43), 3 (n=22), 4
(n=13), 5 (n=6), or 6 to 14 (n=13) days after stroke onset, there was
no significant difference in total and free testosterone concentrations
between the groups (data not shown). Patients who underwent
venipuncture the first day after stroke onset had decreased
total and free testosterone concentrations compared with control
subjects (P=.08 and P=.0001, respectively).
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Testosterone and Risk Factors for Stroke
Serum free testosterone was significantly negatively associated
with age in patients and control subjects, whereas the association
between serum total testosterone and age was not significant (Table 3). In patients, serum total testosterone but not free
testosterone was borderline negatively associated with serum
cholesterol (r=-.18, P=.054);
there were no such associations in the control subjects. Patients with
diabetes (n=29) had lower levels of total and free testosterone than
nondiabetics (n=108): 11.4±1.2 versus 14.5±0.6 nmol/L,
P=.02, and 35.3±2.6 versus 42.5±1.5 pmol/L,
P=.03, respectively. Patients with atrial fibrillation
(n=16) had decreased serum free testosterone compared with patients
without atrial fibrillation (n=99): 32.6±3.0 and 41.7±1.5 pmol/L,
respectively, P=.02. In patients, free but not total
testosterone was higher in smokers (n=64) than nonsmokers (n=45):
44.6±2.0 versus 37.7±1.9 pmol/L, P=.02.
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In control subjects, mean BMI was 25.8±0.5 kg/m2,
and BMI was significantly negatively associated with serum total
testosterone (r=-.39, P=.02) and marginally
significantly associated with serum free testosterone
(r=-.31, P=.07). BMI was not measured in
stroke patients. The risk factor characteristics for all examined
stroke patients, the subgroup of patients examined after 6 months, and
the control subjects are shown in Table 4.
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Total and free testosterone levels were not associated with hypertension, alcohol consumption, previous stroke, systolic blood pressure, or ischemic heart disease.
Testosterone and Stroke Severity
In patients, both total and free testosterone levels were
significantly inversely associated with stroke severity (Table 3) and
6-month mortality (Figure). Total testosterone was
significantly inversely associated with infarct size (Table 3). In a
multiple linear regression analysis with SSS score on admission
as the dependent variable and total and free testosterone, age,
atrial fibrillation, diabetes, hypertension, ischemic heart
disease, alcohol consumption, serum cholesterol level,
systolic blood pressure, previous stroke, and smoking as
independent variables, free testosterone and atrial fibrillation
were significantly associated with SSS score on admission
(P<.02).
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17ß-Estradiol and Gonadotropins
Serum concentrations of 17ß-estradiol, FSH, and LH did not
differ in patients and control subjects (Table 1), and there was no
association between initial severity of the stroke, infarct size, or
6-month mortality with any of these three hormone levels (data not
shown).
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Discussion |
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The results suggest that elderly men who suffer an acute thrombotic stroke have lower circulating levels of male sex hormone than their healthy counterparts and that the lower the level of total testosterone, the greater the initial loss of neural function and size of the cerebral infarct. Although these aspects were quite closely correlated and cannot be explained by other risk factors for stroke, it cannot be automatically assumed that low testosterone level actually caused the stroke.
The other possibility is that the cerebral infarct provokes an acute stress reaction, one element of which is a fall in testosterone. This is known to occur in several forms of stress, including myocardial infarction,23 24 surgery,24 and head trauma.24 25 Consistent with this idea is the fact that both total and free testosterone concentrations tended to increase between the acute phase and the 6-month follow-up in a subgroup of patients. Notably, this increase was not statistically significant for total testosterone, which leaves unanswered the question of cause versus protracted effect of the stroke. Furthermore, the subgroup of patients examined after 6 months was self-selected, being younger and with milder strokes than the unexamined group of patients, so any conclusions from the follow-up data must be tentative.
Our data suggest that if the decrease in serum testosterone is a result of stroke, the effect is there within the first day after onset: even when blood samples were obtained the first day after stroke, total and free testosterone levels were lower than in the control group. This implies that even if the decreased testosterone is a stress reaction, an acute lowering could be important for progression of the stroke, eg, by lowering fibrinolytic activity,10 11 12 which would delay lysis of a preformed thrombus.
On the basis of these speculations, it is tempting to hypothesize that men with acute stroke and low serum testosterone levels could benefit from treatment with exogenous testosterone. Although testosterone treatment increases the aggregability of human platelets7 and enhances thrombosis in animal models,8 9 treatment with the anabolic steroid Stanozolol improves fibrinolytic activity,26 27 and testosterone treatment decreases blood pressure and serum cholesterol levels.28 29 The anabolic effects of testosterone, which has been used for stimulation of wound healing,30 could also promote tissue repair after ischemic injury.
Serum testosterone may be negatively associated with blood pressure,4 6 31 diabetes,32 33 visceral adiposity,34 35 and prevalent ischemic heart disease5 36 37 38 as well as plasma concentrations of triglycerides,35 39 fibrinogen,5 LDL,35 40 and total cholesterol.36 40 Additionally, high serum testosterone is associated with smoking3 13 41 and HDL cholesterol.5 35 In accordance with these observations, in the present patient group, diabetics had lower levels of both total and free testosterone than nondiabetics, total testosterone was negatively associated with serum cholesterol in the patients, and there was a positive association between free testosterone and smoking. All this supports the validity of the present study. The finding that the estradiol-to-testosterone ratio was higher in stroke patients than healthy control subjects is consistent with observations in patients with myocardial infarction.36 That we found no association between serum testosterone and systolic blood pressure could be due to fluctuations in blood pressure on the day of admission. The advanced age of the patients could also play a role.
Importantly, the differences in total and free testosterone between patients and control subjects could not be explained by associations with other risk factors for stroke. Compared with control subjects, patients who smoked and patients without atrial fibrillation had decreased levels of free testosterone, and patients without diabetes had lower levels of total and free testosterone. The difference in total testosterone between patients and control subjects remained after adjustment for serum cholesterol.
We are aware that some potential limitations in our experimental design could affect the findings. Some studies have found a decline in both total and free testosterone with age,41 42 43 whereas others could not confirm this.31 44 45 Our control group was slightly older than the patient group (73.4 versus 72.0 years), and free testosterone but not total testosterone was significantly negatively associated with age in both patients and control subjects. Notably, bioavailable testosterone includes both free testosterone and testosterone bound to proteins other than sex hormone–binding globulin (mainly albumin).44 However, both total and free testosterone levels were significantly lower in patients than in control subjects, even after adjusting for age.
Low testosterone level is associated with a high BMI.32 35 38 39 This finding is in accordance with the significant inverse association between BMI and total serum testosterone in the control subjects of the present study. A larger BMI in stroke patients than in control subjects may therefore have contributed to the observed difference in serum testosterone level between the two groups. Unfortunately, BMI was not measured in the stroke patients. In the control group, the slope of the regression line for total testosterone as a function of BMI was -0.5 nmol·L-1·kg · m-2, which is very similar to the corresponding slope reported on BMI and serum testosterone in a study that included 985 men.32 With the use of this slope, it may be extrapolated that if the observed difference in mean values of serum total testosterone between patients and control subjects of 2.7 nmol/L was to be explained fully by a difference in BMI between the two groups, the mean BMI of the stroke patients may have been as high as 31 kg/m2, which corresponds to the 95th percentile of BMI in healthy Danes of the same age.46 It is therefore unlikely that a difference in BMI can explain the difference in serum testosterone between stroke patients and control subjects. These speculations, however, are based on the assumption of a similar linear relationship between BMI and serum testosterone level in patients and control subjects, which has not been documented.
There is a well-known diurnal variation in serum testosterone level in young47 48 49 but not elderly men.43 50 51 All our blood samples were taken between 10 AM and 4 PM, and no association between serum testosterone and time of blood sampling was found. Nor was there any variation with time of year, in contrast to findings in young men.52 53 So it is unlikely that the difference in total and free testosterone between patients and control subjects can be attributed to time of blood sampling. Fasting in the patient group due to acute illness apparently could not explain the difference between patients and control subjects. Additionally, patients who had not fasted on the day of blood sampling had lower serum testosterone than the control group (data not shown).
To probe the mechanism by which testosterone is decreased, we also measured FSH and LH. There were no differences in the serum levels of these hormones between patients and control subjects. These results are in accordance with the hypothesis that gonadotropins correlate poorly with testicular function in elderly men.54 Thus, it is unlikely that changes in these regulating hormones could explain the observed differences in serum testosterone between patients and control subjects.
It cannot be excluded that chronic hypotestosteronemia is a causative factor of stroke in men. Low testosterone levels are correlated with the degree of coronary artery disease,5 which may predispose to stroke,1 and men with low serum testosterone have a low fibrinolytic activity,10 11 12 which could also increase the stroke risk. Whether the lower testosterone levels in the stroke patients are the result or the cause of the disease cannot be established by the present study. However, since testosterone has potent effects on thrombosis, fibrinolysis, and tissue repair, the present study warrants further research on its role in acute ischemic stroke.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Danish Health Foundation, the Danish Heart Foundation, the European Organization for the Control of Circulatory Diseases, "Carl and Ellen Hertz's Legater," "Kajsings Legat," and "Asta Florida Bolding's Mindelegat." The authors want to thank Jørgen Hilden for statistical advice and technician Oda Troest for excellent technical assistance.
Received August 16, 1995; accepted January 19, 1996.
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