(Circulation. 1999;100:1690-1696.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Testosterone on Coronary Vasomotor Regulation in Men With Coronary Heart Disease
From Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, and Royal Brompton Hospital, London, UK (C.M.W., J.G.M., C.S.H., P.C.), and Columbia Laboratories, Paris, France (D.d.Z).
Correspondence to Dr Peter Collins, Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK. E-mail peter.collins{at}ic.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The increased incidence of coronary artery disease in men compared with premenopausal women suggests a detrimental role of male hormones on the cardiovascular system. However, testosterone has direct relaxing effects on coronary arteries in animals, as shown both in vitro and in vivo. The effect of testosterone on the human coronary circulation remains unknown.
Methods and Results—We studied 13 men (aged 61±11 years) with coronary artery disease. They underwent measurement of coronary artery diameter and blood flow after a 3-minute intracoronary infusion of vehicle control (ethanol) followed by 2-minute intracoronary infusions of acetylcholine (10-7 to 10-5 mol/L) until peak velocity response. A dose-response curve to 3-minute infusions of testosterone (10-10 to 10-7 mol/L) was then determined, and the acetylcholine infusions were repeated. Finally, an intracoronary bolus of isosorbide dinitrate (1000 µg) was given. Coronary blood flow was calculated from measurements of blood flow velocity using intracoronary Doppler and coronary artery diameter using quantitative coronary angiography. Testosterone significantly increased coronary artery diameter compared with baseline (2.78±0.74 mm versus 2.86±0.72 mm [P=0.05], 2.87±0.71 mm [P=0.038], and 2.90±0.75 mm [P=0.005] for baseline versus testosterone 10-9 to 10-7 mol/L, respectively). A significant increase in coronary blood flow occurred at all concentrations of testosterone compared with baseline (geometric mean [95% CI]: 32 [25, 42] versus 36.3 [27, 48] {P=0.006}, 35.3 [26, 47] {P=0.029}, 36.8 [28, 49] {P=0.002}, and 37 [28, 48] {P=0.002} mL/min for baseline versus testosterone 10-10 to 10-7 mol/L, respectively). No differences existed in coronary diameter or blood flow responses to acetylcholine before versus after testosterone.
Conclusions—Short-term intracoronary administration of testosterone, at physiological concentrations, induces coronary artery dilatation and increases coronary blood flow in men with established coronary artery disease.
Key Words: coronary arteries • testosterone • blood flow
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In recent years, sex hormones, particularly estrogen, have emerged as important factors for modulating cardiovascular disease.1 2 Although the incidence of coronary heart disease increases in women after menopause, postmenopausal women have a lower incidence of coronary heart disease and myocardial infarction than men of a similar age. It has been proposed that testosterone may predispose to coronary artery disease and may partially explain the sex difference. However, no direct evidence exists linking testosterone to an increased incidence of coronary heart disease and myocardial infarction.
In men without prior myocardial infarction who are referred for coronary angiography, a significant inverse correlation was found between plasma testosterone levels and extent of coronary artery disease, demonstrating that men with low testosterone levels may be at increased risk for coronary atherosclerosis.2 Some reports suggest that testosterone therapy in men has a beneficial effect on angina pectoris3 4 and on exercise-induced ST-segment depression in patients with angina pectoris.5 6 A double-blind study was performed in 50 men who had ST-segment depression after exercise.6 After 4 to 8 weeks of treatment with testosterone or placebo, a significant decrease in the exercise-induced extent of ST-segment depression occurred with testosterone when compared with placebo. The mechanism(s) by which testosterone decreased postexercise ST-segment depression was not established.
The direct effect of testosterone on coronary circulation in men is unknown. Testosterone induces relaxation in precontracted rabbit coronary arteries and aorta in vitro, with or without endothelium.7 A high-cholesterol diet and environmental tobacco smoke have detrimental effects on endothelial function in male animals; this effect was exacerbated by testosterone at physiological concentrations.8 Short-term intracoronary infusions of testosterone dilate male and female canine coronary arteries in vivo and increase coronary blood flow, partially by an endothelium-dependent mechanism. ATP-sensitive potassium channels are also involved in the dilator response.
These data suggest a beneficial effect of testosterone on the coronary circulation. We therefore investigated the effects of testosterone on the coronary circulation of men with atherosclerotic coronary artery disease.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
Men aged 35 to 70 years who had angiographically proven coronary artery disease at diagnostic angiography for investigation of stable angina pectoris were enrolled in the study. Patients with primary valvar heart disease, complete heart block, or uncorrected hypokalemia were excluded. All patients gave written informed consent in accordance with the ethical requirements of the Royal Brompton Hospital Ethics Committee.
Study Design
Cardiac medication was withheld for at least 24 hours before
cardiac catheterization, and caffeine-containing
beverages were prohibited during this time. After
diagnostic coronary angiography and full
heparinization, a 0.014-inch Doppler flow wire (Cardiometrics
Inc) was positioned in the proximal portion of an unobstructed
coronary artery (no lesion>50% occlusive) from which
continuous traces of average peak blood flow velocity were
recorded. Arterial pressure, heart rate, and ECG were
displayed continuously.
Intracoronary Infusions
A 3-minute intracoronary infusion of vehicle control
(ethanol) was given, followed by investigation of
endothelium-dependent coronary responses by
increasing concentrations of intracoronary acetylcholine
(estimated concentrations, 10-7 to
10-5 mol/L) for 2 minutes each or until peak
velocity response. After this, a dose-response curve to testosterone
was performed for 3 minutes at each concentration into the right
coronary artery with an infusion rate of 1 mL/min (estimated
concentration of testosterone: 2.3, 23, 230, and 2300 ng/min) and of
1.5 mL/min into the left coronary artery (estimated
concentration of testosterone: 3.45, 34.5, 345, and 3450 ng/min). These
doses are approximately equal to the 10-10 to
10-7 mol/L concentrations of
testosterone, respectively, achieved in the coronary
blood. Acetylcholine infusions were then repeated. All infusions were
given at a rate of 1 mL/min into the ostium of the right
coronary artery or 1.5 mL/min into the ostium of the left
coronary artery. The study protocol was completed with an
intracoronary bolus of 1000 µg of isosorbide dinitrate, a
non-endothelium–dependent vasodilator.
Coronary angiograms were performed at baseline and then
immediately after the peak velocity response to each dose of vasoactive
substance. A second baseline angiogram (baseline 2) was performed
between the first acetylcholine challenge and the commencement of the
testosterone infusions. A rest period was observed between each
infusion to allow all measured parameters to return to
baseline. At baseline 1 and at the end of each testosterone infusion,
blood sampling was performed to measure plasma testosterone
concentrations (total testosterone) using a standard radioimmunoassay
(Abbott IMX System, Abbott Diagnostics Division).
To determine the effect of vehicle control on the acetylcholine response, a 3-minute infusion of vehicle control (0.01 mL of 60% ethanol in 10 mL of blood) was given after the first acetylcholine challenge, as described above, in a similar group of 8 male patients with coronary artery disease. The acetylcholine response was then repeated.
Testosterone Dilutions
The testosterone dilutions were calculated to give a dose of
testosterone in the coronary artery of
10-10 to 10-7 mol/L
(normal range, 10-8 to
5x10-8 mol/L [3 to 10 ng/mL]) using an
assumed coronary blood flow of 80 mL/min in the left
coronary arterial tree and 40 mL/min in the right
coronary artery. Stock solutions of 2300 µg/mL testosterone
and vehicle control (ethanol) were provided by Columbia Laboratories
(Paris, France). We diluted 0.1 mL of 2300 µg/mL testosterone
in 10 mL of the patient's blood to give a 23 µg/mL
(10-6 mol/L) testosterone concentration. This
was then diluted further to give testosterone concentrations of
10-7 to 10-10 mol/L (2.3
µg/mL to 2.3 ng/mL) in the coronary blood.
Testosterone is lipid-soluble and was prepared in 60% ethanol. Vehicle control was prepared for intracoronary infusion at 1 concentration, which was equivalent to the concentration given at the greatest concentration of testosterone (0.01 mL of 60% ethanol in 10 mL of blood).
Quantitative Coronary Angiography and Calculation of
Flow
Coronary angiograms were acquired and analyzed
digitally using a real-time digital image acquisition and
analysis system (Digitron III VACI, Siemens AG), as previously
described.9 Measurement of diameter and velocity were made
at baseline and at peak velocity change. Diameter was measured
4 mm distal to the tip of the Doppler wire at the sample
volume site by an independent observer. Care was taken to measure
diameter at an identical position after each infusion. The wire
position did not change in any of the patients studied. A quantitative
estimate of coronary blood flow was calculated from Doppler
flow velocity and diameter 4 mm distal to the Doppler wire tip
using the following equation10 :
 |
In addition to measuring local changes in diameter, global diameter changes throughout the entire artery were measured by an independent observer using quantitative coronary angiography. With this analysis, changes in mean coronary diameter were measured, as were responses at the sites of defined focal narrowing and/or dilatation.
Statistical Analysis
Baseline 1 versus baseline 2 comparison was performed using a
paired t test or a Wilcoxon matched pairs test when
the data were not normally distributed. All other analyses were
performed using a 2-way ANOVA with patient and time as factors. In
Results, we present comparisons of baseline 1 versus acetylcholine
responses before testosterone, baseline 2 versus testosterone, and
baseline 2 versus acetylcholine responses after testosterone. We also
compared responses to respective doses of acetylcholine before versus
after testosterone. The following assumptions were tested: normality of
residuals by the Shapiro Francia W' test and equality of variances in
the time groups by Bartlett's test. Data are presented as
mean±SD or as geometric mean (95% confidence interval [CI]) where
data have been log-transformed to normality. P<0.05 was
considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients
Thirteen men were enrolled in the study; they had a mean age of 61±11 years. Patient characteristics are described in Table 1
. Seven patients had 1 significantly
diseased coronary artery (stenosis >70%), and 6
patients had 2-vessel disease. The study vessel of all patients was
irregular but not significantly obstructed on angiography. The left
anterior descending coronary artery was studied in 2 patients,
the left circumflex in 1 patient, and the right coronary artery
in 10 patients. Ten patients had focal narrowing in the study vessel
between 10% and 40%, with a mean lesion severity of 23±10%.
|
Plasma Hormone Concentrations
Plasma testosterone levels in the femoral artery were
significantly increased at the greater concentrations of infused
testosterone (11±6 versus 14±4, 16±5, 29±16, and 35±15
nmol/L for baseline versus 10-10 to
10-7 mol/L testosterone, respectively;
P=0.40, 0.12, <0.001, and <0.001, respectively). The mean
baseline plasma estradiol level was 188±77 pmol/L (range, 112 to 358
pmol/L).
Coronary Artery Responses to Testosterone
Testosterone (10-9 to
10-7 mol/L) significantly increased
coronary diameter (Table 2) by
3.1% (P=0.05), 3.5% (P=0.038), and 4.5%
(P=0.005), respectively, compared with baseline 2
(Figure). A significant increase occurred
in coronary blood flow at all concentrations of testosterone
compared with baseline 2 (Table 2). Blood flow was increased by
15.9% (P=0.006), 11.9% (P=0.029), 16.3%
(P=0.002), and 17.4% (P=0.002) at levels of
10-10 to 10-7 mol/L
testosterone, respectively (Figure). Velocity was not affected
by testosterone at any concentration (Table 2).
|
|
Coronary Artery Responses to Acetylcholine Before and
After Testosterone
Coronary artery diameter at the Doppler wire tip did
not change after acetylcholine infusion compared with baseline, and no
difference existed in this diameter response to acetylcholine before
and after testosterone (Table 2
). Coronary velocity and
flow were significantly increased by 10-6 and
10-5 mol/L acetylcholine compared with baseline
1 (all P<0.001; Table 2), but no difference existed
in the velocity or flow responses before and after testosterone.
Mean Coronary Artery Diameter Changes
The mean diameter of the entire study vessel was measured in
response to the maximum dose of acetylcholine infused in 11 patients.
Acetylcholine (10-5 mol/L) induced a significant
increase in mean diameter compared with baseline (3.01±0.68 versus
3.14±0.63 mm for baseline 1 versus acetylcholine
10-5 mol/L; P<0.05); however, no
difference existed in this response before and after testosterone
infusion (3.14±0.63 versus 3.07±0.64 mm). In 8 areas of focal
narrowing (mean severity, 23±10%), the diameter response to
acetylcholine (10-5 mol/L) was unchanged before
and after testosterone (2.46±0.7 mm versus 2.46±0.86 mm).
In 11 areas of dilatation to acetylcholine (10-5
mol/L), the dilator response was the same before and after infusions of
testosterone (4.01±0.82 mm versus 3.85±0.79 mm).
Coronary Artery Responses to Vehicle Control and
Isosorbide Dinitrate
Vehicle control did not change coronary artery diameter or
velocity or blood flow compared with baseline 1 or baseline 2 (Table 2). Isosorbide dinitrate significantly increased
coronary velocity, diameter and flow compared with baseline 2
(P<0.001, P=0.005, and P<0.001,
respectively; Table 2).
Systemic Hemodynamics
Table 2 shows that mean arterial pressure and
heart rate did not change significantly throughout the study.
Controls
Characteristics
Eight controls were enrolled (mean age, 57±9 years), and all had
coronary atherosclerosis (Table 1).
Three controls had 1-vessel disease, and 5 had 2-vessel disease. The
left circumflex coronary artery was studied in 1 control
patient, and in 7 controls, the right coronary artery was
studied. No differences existed between the patients and controls with
respect to age, baseline plasma testosterone concentration, or factors
that might affect endothelial function, such as lipid
profile, blood pressure, heart rate, or coronary
atherosclerosis (Table 1). Seven controls had
focal narrowing in the study vessel of between 10% and 40%, with a
mean lesion severity of 21±9%.
Coronary Artery Vasoreactivity
Vehicle control did not affect coronary velocity,
diameter, or blood flow compared with baseline (Table 3). No differences existed in the
velocity, diameter, or blood flow responses to acetylcholine before and
after vehicle control (Table 3). Mean diameter was measured in
response to the maximum dose of acetylcholine infused in 8 patients.
Acetylcholine (10-5 mol/L) did not significantly
change mean diameter compared with baseline 1 (3.22±0.56 mm
versus 3.31±0.6 mm), and no differences existed in this response
before and after infusions of vehicle control (3.31±0.6 mm versus
3.27±0.58 mm). In 7 areas of focal narrowing (mean severity,
21±9%), the diameter response to acetylcholine
(10-5 mol/L) was unchanged before and after
vehicle control (2.65±0.46 mm versus 2.58±0.48 mm). In 8
areas of dilatation to acetylcholine (10-5
mol/L), the dilator response was the same before and after infusions of
vehicle control (4.6±1.2 mm versus 4.5±1.23 mm). Systemic
blood pressure and heart rate did not change after infusion of vehicle
control compared with baseline (Table 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We demonstrated that testosterone, administered acutely at physiological (and greater) concentrations, induces coronary artery dilatation (up to 4.5%) and increases coronary blood flow (up to 17.4%) in men with coronary atherosclerosis. Testosterone did not alter acetylcholine-induced increases in coronary blood flow or areas of constriction or dilatation induced by acetylcholine, which suggests that it had no measurable effect on stimulated endothelial nitric oxide. These findings are similar to those found in vitro in which testosterone-induced coronary relaxation was shown to be independent of the endothelium,7 with the possible involvement of potassium channel modulation. The effect of testosterone on coronary artery diameter and blood flow are approximately half that demonstrated after intracoronary diltiazem administration, where diameter was increased by 10% and flow by 30%.11 Nicorandil, a potassium channel activator, exerts its vasodilator actions through a mechanism similar to that of testosterone, via activation of ATP-sensitive potassium channels. In a study in patients with normal coronary arteries and coronary artery disease, this agent increased proximal coronary artery diameter by 13%. The dose of nicorandil infused into these coronary arteries was 0.5 mg, a pharmacological dose.12
In an animal model, short-term intracoronary infusions of testosterone (10-7 and 10-6 mol/L) increased coronary blood flow, similar to the findings of the present study.13 Inhibition of nitric oxide synthase by L-NAME significantly attenuated testosterone-induced increases in blood flow (P=0.04), indicating an endothelium-dependent effect of testosterone on this calculated parameter. However, a high concentration of testosterone was used to achieve this effect (10-6 mol/L), and the attenuation of cross-sectional area and velocity were not statistically significant at the 5% level (both P=0.06). These authors13 could not distinguish between a direct effect of testosterone on nitric oxide synthase or a flow-mediated effect of testosterone on the endothelium. Testosterone-induced changes in coronary velocity and flow were significantly attenuated in resistance vessels by glibenclamide (P=0.03 and 0.02, respectively), indicating inhibition of ATP-sensitive potassium channels by testosterone. Although acetylcholine had no effect on epicardial coronary artery diameter in the present study, it did increase blood flow velocity and blood flow volume in a dose-dependent manner, suggesting that functional endothelium exists in resistance vessels. The fact that this response was not different after administration of testosterone does not preclude involvement of the endothelium in testosterone-induced increases in blood flow. In vitro7 and in vivo13 animal data would suggest that testosterone stimulates epicardial coronary dilatation, independent of the endothelium, possibly by effects on ion channels on the vascular smooth muscle plasma membrane, such as ATP-sensitive potassium channels. However, it is impossible to rule out an indirect flow-mediated endothelium-dependent effect of testosterone on blood flow response without the use of an inhibitor of nitric oxide.
We assessed the mean coronary artery diameter response to acetylcholine throughout the length of the study arteries and found no significant difference in mean diameter response to acetylcholine before versus after the testosterone infusions. Areas of focal narrowing and areas that dilated to acetylcholine before exposure to testosterone did not react differently before versus after exposure to testosterone. This reinforces our suggestion that testosterone does not enhance endothelial function in sites of constriction or dilatation to acetylcholine.
Testosterone is converted to 17ß-estradiol by the enzyme aromatase. It is possible that estradiol may account for the vascular effects of testosterone; however, the evidence to date does not support this potential mechanism. Inhibition of both the testosterone and estrogen receptors does not affect testosterone-induced coronary relaxation in vitro7 or coronary dilatation and increases in blood flow in vivo.13 Androgen receptors have been identified in ventricular and atrial myocytes, endothelial cells, and vascular smooth muscle cells of some mammalian species14 15 16 ; however, at present, no information exists regarding the presence of androgen receptors in the coronary arteries of humans. Also, it has been shown in a number of studies that estrogen does not have a direct relaxing effect on human coronary arteries in vivo.9 17
We demonstrated direct coronary effects of testosterone at
physiological concentrations (adult male normal
range is 10-9 to 10-8
mol/L)18 in humans. Previous studies (described
above) showed significant effects of testosterone at pharmacological
concentrations in vitro (10-6 and
10-5 mol/L)7 and
near-physiological concentrations in vivo
(10-7 mol/L).13 Interestingly, the
mean baseline testosterone level of the men included in the present
study was at the lower end of the normal range (mean, 11±6 nmol/L;
range, 1 to 26 nmol/L), which reinforces the observation of Phillips et
al2 that low plasma testosterone may be a risk factor for
coronary heart disease. Indeed, 7 of the 13 men had plasma
testosterone levels <11 nmol/L. Serum testosterone decreases with
age,19 and bioavailable testosterone is decreased in older
men.20 Concurrently, an apparent stimulation of
gonadotrophin release occurs, with increased levels of
follicular-stimulating hormone and luteinizing hormone in elderly
men.21 The patients in the current study demonstrated
relatively low testosterone levels for men of a younger age; therefore,
it would be plausible that, in our study group, coronary artery
disease was not simply a function of age but may also be related to
serum testosterone levels. Separate analyses of flow responses
in our subjects with normal and low baseline testosterone levels showed
no significant correlation between baseline plasma testosterone levels
and flow response to infused testosterone (data not shown). This may be
due to small numbers (n=7 and n=6, respectively) or to the fact that
the normal group had testosterone levels at the lower end of the normal
range.
Dose is an important consideration regarding long-term testosterone administration. High concentrations of testosterone have detrimental effects on atheroma progression,22 plasma lipids,23 and hemostatic factors,2 24 25 and they increase the risk of myocardial infarction and stroke.26 However, recently published data show a beneficial effect of testosterone on atheroma development in rabbits.27 The natural androgens testosterone and dehydroepiandrosterone, at physiological concentrations, produced this effect, which was only partially mediated through a beneficial effect on lipid profile. The results of the present study are important because they show the effects of low-dose, physiological levels of testosterone on coronary vasomotion in humans. The results are also important because testosterone is present in both men and women and, therefore, the results may be pertinent to both sexes. Further studies will be needed to investigate the effects of long-term, low-dose testosterone administration on coronary reactivity and risk factors for coronary artery disease in men and the role of testosterone in coronary physiology and pathophysiology in women.
Limitations
We found no effect of testosterone on acetylcholine-induced
increases in blood flow, indicating a lack of effect of testosterone on
endothelium-dependent responses. To prove a direct
effect of testosterone on nitric oxide synthase, however, experiments
inhibiting endothelium-derived nitric oxide synthesis
would need to be performed. These further experiments would still not
exclude the possibility that testosterone may affect the
endothelium indirectly via a sheer stress–mediated
effect.
Diameter responses to testosterone were compared with baseline 2, which revealed a testosterone-induced dilatation. Although the diameter did not return to the original baseline value, baseline 1 and baseline 2 were not significantly different for any measured variable. A carry-over effect of the acetylcholine may account for the decreased coronary diameter at baseline 2; however, this effect has not been reported in previous, similar studies using estrogen,9 17 and it did not affect the blood flow measurement at baseline 2 in the present study.
Due to the complexity of the study protocol, a number of statistical comparisons were performed. This could call into question statistical significance set at the 5% level. However, with particular regard to the effect of testosterone on coronary blood flow for 3 of the 4 data points, the significance levels were at the 1% level. As multiple comparisons were not performed, we did not need Bonferroni correction of data. The methodology used in the present study, including the statistical analysis, is very similar to that used in previous intracoronary studies of estrogen.9 17
Conclusions
We demonstrated, for the first time, a direct effect of
physiological doses of testosterone in human
coronary circulation, which resulted in coronary artery
dilatation and increases in coronary blood flow. This
observation may have important clinical implications if testosterone
can be shown to improve myocardial ischemia and long-term
outcomes in men with established coronary heart disease.
|
Acknowledgments |
|---|
We thank all the patients who kindly participated in this study, the staff in the daycase unit of Paul Wood Ward and the cardiac catheterization laboratory of the Royal Brompton Hospital, Glenn Sontag for technical assistance, and Amy Gosling for statistical assistance. This study was supported by a grant from the British Heart Foundation. Dr Hayward was supported by the National Heart Foundation of Australia.
Received March 5, 1999; revision received June 23, 1999; accepted July 2, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63.[Medline] [Order article via Infotrieve]
2.
Phillips GB, Pinkernell BH, Jing TY. The association
of hypotestosteronemia with coronary artery disease in men.
Arterioscler Thromb. 1994;14:701–706.
3. Levine SA, Likoff WB. The therapeutic value of testosterone propionate in angina pectoris. N Engl J Med. 1943;229:770–772.
4.
Lesser MA. Testosterone propionate therapy in one
hundred cases of angina pectoris. J Clin Endocrinol. 1946;6:549–557.
5. Webb CM, Adamson DL, de Ziegler D, Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol. 1999;83:437–439.[Medline] [Order article via Infotrieve]
6.
Jaffe MD. Effect of testosterone cypionate on
postexercise ST segment depression. Br Heart J. 1977;39:1217–1222.
7.
Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collins
P. Testosterone relaxes rabbit coronary arteries and aorta.
Circulation. 1995;91:1154–1160.
8. Hutchison SJ, Sudhir K, Chou TM, Sievers RE, Zhu BQ, Sun YP, Deedwania PC, Glantz SA, Parmley WW, Chatterjee K. Testosterone worsens endothelial dysfunction associated with hypercholesterolemia and environmental tobacco smoke exposure in male rabbit aorta. J Am Coll Cardiol. 1997;29:800–807.[Abstract]
9.
Collins P, Rosano GMC, Sarrel PM, Ulrich L,
Adamopoulos S, Beale CM, McNeill J, Poole-Wilson PA.
Estradiol-17ß attenuates acetylcholine-induced coronary
arterial constriction in women but not men with
coronary heart disease. Circulation. 1995;92:24–30.
10.
Doucette JW, Corl PD, Payne HM, Flynn AE, Goto M, Nassi
M, Segal J. Validation of a Doppler guide wire for intravascular
measurement of coronary artery flow velocity.
Circulation. 1992;85:1899–1911.
11. Vrolix MC, Sionis D, Piessens J, Van Lierde J, Willems JL, De Geest H. Changes in human coronary flow reserve after administration of intracoronary diltiazem. J Cardiovasc Pharmacol. 1991;18(suppl 9):S64–S67.
12. Haager PK, Klues HG, Schmidt M, vom Dahl J, Hanrath P. Effects of nitroglycerin and nicorandil on regional poststenotic quantitative coronary blood flow in coronary artery disease: a combined digital quantitative angiographic and intracoronary Doppler study. J Cardiovasc Pharmacol. 1999;33:126–134.[Medline] [Order article via Infotrieve]
13.
Chou TM, Sudhir K, Hutchison SJ, Ko E, Amidon TM,
Collins P, Chatterjee K. Testosterone induces dilation of canine
coronary conductance and resistance arteries in vivo.
Circulation. 1996;94:2614–2619.
14.
McGill HC Jr, Sheridan PJ. Nuclear uptake of sex
steroid hormones in the cardiovascular system of the
baboon. Circ Res. 1981;48:238–244.
15.
Lin AL, Gonzalez R Jr, Shain SA. Androgen directs
apparent cytoplasmic and nuclear distribution of rat
cardiovascular androgen receptors.
Arteriosclerosis. 1985;5:659–667.
16. Higashiura K, Mathur RS, Halushka PV. Gender-related differences in androgen regulation of thromboxane A2 receptors in rat aortic smooth-muscle cells. J Cardiovasc Pharmacol. 1997;29:311–315.[Medline] [Order article via Infotrieve]
17.
Gilligan DM, Quyyumi AA, Cannon RO III. Effects of
physiological levels of estrogen on
coronary vasomotor function in postmenopausal women.
Circulation. 1994;89:2545–2551.
18. Hassan T. A Guide to Medical Endocrinology. London: MacMillan; 1985.
19.
Gray A, Feldman HA, McKinlay JB, Longcope C. Age,
disease, and changing sex hormone levels in middle-aged men: results of
the Massachusetts Male Aging Study. J Clin Endocrinol
Metab. 1991;73:1016–1025.
20.
Nankin HR, Calkins JH. Decreased bioavailable
testosterone in aging normal and impotent men. J Clin
Endocrinol Metab. 1986;63:1418–1420.
21.
Harman SM, Tsitouras PD, Costa PT. Reproductive
hormones in aging men, II: basal pituitary gonadotropins and
gonadotropin responses to luteinizing hormone-releasing hormone.
J Clin Endocrinol Metab. 1982;54:547–551.
22.
Adams MR, Williams JK, Kaplan JR. Effects of
androgens on coronary artery atherosclerosis
and atherosclerosis-related impairment of vascular
responsiveness. Arterioscler Thromb Vasc Biol. 1995;15:562–570.
23.
Thompson PD, Cullinane EM, Sady SP, Chenevert C,
Saritelli AL, Sady MA, Herbert PN. Contrasting effects of testosterone
and stanozolol on serum lipoprotein levels. JAMA. 1989;261:1165–1168.
24.
Ajayi AA, Mathur R, Halushka PV. Testosterone increases
human platelet thromboxane A2 receptor density and
aggregation responses. Circulation. 1995;91:2742–2747.
25. Heller RF, Meade TW, Haines AP, Stirling Y, Miller NE, Lewis B. Inter-relationships between factor VII, serum testosterone and plasma lipoproteins. Thromb Res. 1982;28:423–425.[Medline] [Order article via Infotrieve]
26.
Bagatell CJ, Bremner WJ. Androgens in men: uses and
abuses. N Engl J Med. 1996;334:707–714.
27.
Alexandersen P, Haarbo J, Byrjalsen I, Lawaetz H,
Christiansen C. Natural androgens inhibit male
atherosclerosis: a study in castrated,
cholesterol-fed rabbits. Circ Res. 1999;84:813–819.
This article has been cited by other articles:
 |
|
 |
|
  A. Mathur, C. Malkin, B. Saeed, R Muthusamy, T H. Jones, and K. Channer Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men Eur. J. Endocrinol., September 1, 2009; 161(3): 443 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Tharp, I. Masseau, J. Ivey, V. K. Ganjam, and D. K. Bowles Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine Cardiovasc Res, April 1, 2009; 82(1): 152 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Carrero, A. R. Qureshi, P. Parini, S. Arver, B. Lindholm, P. Barany, O. Heimburger, and P. Stenvinkel Low Serum Testosterone Increases Mortality Risk among Male Dialysis Patients J. Am. Soc. Nephrol., March 1, 2009; 20(3): 613 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Yassin and F. Saad Testosterone and Erectile Dysfunction J Androl, November 1, 2008; 29(6): 593 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mancini, E. Leone, R. Festa, G. Grande, A. Silvestrini, L. de Marinis, A. Pontecorvi, G. Maira, G. P. Littarru, and E. Meucci Effects of Testosterone on Antioxidant Systems in Male Secondary Hypogonadism J Androl, November 1, 2008; 29(6): 622 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Montano, E. Calixto, A. Figueroa, E. Flores-Soto, V. Carbajal, and M. Perusquia Relaxation of Androgens on Rat Thoracic Aorta: Testosterone Concentration Dependent Agonist/Antagonist L-Type Ca2+ Channel Activity, and 5{beta}-Dihydrotestosterone Restricted to L-Type Ca2+ Channel Blockade Endocrinology, May 1, 2008; 149(5): 2517 - 2526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-T. Khaw, M. Dowsett, E. Folkerd, S. Bingham, N. Wareham, R. Luben, A. Welch, and N. Day Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) Prospective Population Study Circulation, December 4, 2007; 116(23): 2694 - 2701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Hydock, C.-Y. Lien, C. M. Schneider, and R. Hayward Effects of voluntary wheel running on cardiac function and myosin heavy chain in chemically gonadectomized rats Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3254 - H3264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Bowles, K. K. Maddali, V. C. Dhulipala, and D. H. Korzick PKC{delta} mediates anti-proliferative, pro-apoptic effects of testosterone on coronary smooth muscle Am J Physiol Cell Physiol, August 1, 2007; 293(2): C805 - C813. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J Pearson, C. Rait, M G. Nicholls, T. G Yandle, and J. J Evans Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II. J. Endocrinol., October 1, 2006; 191(1): 171 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Braga-Basaria, A. S. Dobs, D. C. Muller, M. A. Carducci, M. John, J. Egan, and S. Basaria Metabolic Syndrome in Men With Prostate Cancer Undergoing Long-Term Androgen-Deprivation Therapy J. Clin. Oncol., August 20, 2006; 24(24): 3979 - 3983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hall, R. D. Jones, T. H. Jones, K. S. Channer, and C. Peers Selective Inhibition of L-Type Ca2+ Channels in A7r5 Cells by Physiological Levels of Testosterone Endocrinology, June 1, 2006; 147(6): 2675 - 2680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Abularrage, A. N. Sidawy, G. Aidinian, N. Singh, J. M. Weiswasser, and S. Arora Evaluation of Macrocirculatory Endothelium-Dependent and Endothelium-Independent Vasoreactivity in Vascular Disease Perspectives in Vascular Surgery and Endovascular Therapy, September 1, 2005; 17(3): 245 - 253. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Meyer, B. P. McGrath, J. Cameron, D. Kotsopoulos, and H. J. Teede Vascular Dysfunction and Metabolic Parameters in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4630 - 4635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Gonzales, A. A. Ghaffari, S. P. Duckles, and D. N. Krause Testosterone treatment increases thromboxane function in rat cerebral arteries Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H578 - H585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G. Mishra, R. K. Hermsmeyer, K. Miyagawa, P. Sarrel, B. Uchida, F. Z. Stanczyk, K. A. Burry, D. R. Illingworth, and F. J. Nordt Medroxyprogesterone Acetate and Dihydrotestosterone Induce Coronary Hyperreactivity in Intact Male Rhesus Monkeys J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3706 - 3714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Bowles, K. K. Maddali, V. K. Ganjam, L. J. Rubin, D. L. Tharp, J. R. Turk, and C. L. Heaps Endogenous testosterone increases L-type Ca2+ channel expression in porcine coronary smooth muscle Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2091 - H2098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Nieschlag, H.M. Behre, P. Bouchard, J.J. Corrales, T.H. Jones, G.K. Stalla, S.M. Webb, and F.C.W. Wu Testosterone replacement therapy: current trends and future directions Hum. Reprod. Update, September 1, 2004; 10(5): 409 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C J Malkin, P J Pugh, P D Morris, K E Kerry, R D Jones, T H Jones, and K S Channer Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life Heart, August 1, 2004; 90(8): 871 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sierra-Ramirez, T. Morato, R. Campos, I. Rubio, C. Calzada, E. Mendez, and G. Ceballos Acute effects of testosterone on intracellular Ca2+ kinetics in rat coronary endothelial cells are exerted via aromatization to estrogens Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H63 - H71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Morgentaler A 66-Year-Old Man With Sexual Dysfunction JAMA, June 23, 2004; 291(24): 2994 - 3003. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Littleton-Kearney and P. D. Hurn Testosterone as a Modulator of Vascular Behavior Biol Res Nurs, April 1, 2004; 5(4): 276 - 285. [Abstract] [PDF]
|
|
|
|
|
|
R. J. Gonzales, D. N. Krause, and S. P. Duckles Testosterone suppresses endothelium-dependent dilation of rat middle cerebral arteries Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H552 - H560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Rhoden and A. Morgentaler Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring N. Engl. J. Med., January 29, 2004; 350(5): 482 - 492. [Full Text] [PDF]
|
|
|
|
|
|
M. Muller, Y. T. van der Schouw, J. H. H. Thijssen, and D. E. Grobbee Endogenous Sex Hormones and Cardiovascular Disease in Men J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5076 - 5086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Callies, H. Stromer, R. H. G. Schwinger, B. Bolck, K. Hu, S. Frantz, A. Leupold, S. Beer, B. Allolio, and A. W. Bonz Administration of Testosterone Is Associated with a Reduced Susceptibility to Myocardial Ischemia Endocrinology, October 1, 2003; 144(10): 4478 - 4483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Chatrath, K. L. Ronningen, S. R. Severson, P. LaBreche, M. Jayachandran, M. P. Bracamonte, and V. M. Miller Endothelium-dependent responses in coronary arteries are changed with puberty in male pigs Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1168 - H1176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.J. Malkin, P.J. Pugh, T.H. Jones, and K.S. Channer Testosterone for secondary prevention in men with ischaemic heart disease? QJM, July 1, 2003; 96(7): 521 - 529. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Y. Liu, A. K. Death, and D. J. Handelsman Androgens and Cardiovascular Disease Endocr. Rev., June 1, 2003; 24(3): 313 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fukui, Y. Kitagawa, N. Nakamura, M. Kadono, S. Mogami, C. Hirata, N. Ichio, K. Wada, G. Hasegawa, and T. Yoshikawa Association Between Serum Testosterone Concentration and Carotid Atherosclerosis in Men With Type 2 Diabetes Diabetes Care, June 1, 2003; 26(6): 1869 - 1873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. W. Wu and A. von Eckardstein Androgens and Coronary Artery Disease Endocr. Rev., April 1, 2003; 24(2): 183 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Jones, C. J. Malkin, K. S. Channer, and T. H. Jones Low Levels of Endogenous Androgens Increase the Risk of Atherosclerosis in Elderly Men: Further Supportive Data J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1403 - 1404. [Full Text]
|
|
|
|
|
|
K S Channer and T H Jones Cardiovascular effects of testosterone: implications of the "male menopause"? Heart, February 1, 2003; 89(2): 121 - 122. [Full Text] [PDF]
|
|
|
|
|
|
M. Zitzmann, M. Brune, and E. Nieschlag Vascular Reactivity in Hypogonadal Men Is Reduced by Androgen Substitution J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5030 - 5037. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Molinari, A Battaglia, E Grossini, D A S G Mary, C Vassanelli, and G Vacca The effect of testosterone on regional blood flow in prepubertal anaesthetized pigs J. Physiol., August 15, 2002; 543(1): 365 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zitzmann, R. Junker, A. Kamischke, and E. Nieschlag Contraceptive Steroids Influence the Hemostatic Activation State in Healthy Men J Androl, July 1, 2002; 23(4): 503 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Kenny, K. M. Prestwood, C. A. Gruman, G. Fabregas, B. Biskup, and G. Mansoor Effects of Transdermal Testosterone on Lipids and Vascular Reactivity in Older Men With Low Bioavailable Testosterone Levels J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2002; 57(7): M460 - 465. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. K. Mukherjee, H. Dinh, G. Chaudhuri, and L. Nathan Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis PNAS, March 19, 2002; 99(6): 4055 - 4060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Sader and D. S. Celermajer Endothelial function, vascular reactivity and gender differences in the cardiovascular system Cardiovasc Res, February 15, 2002; 53(3): 597 - 604. [Full Text] [PDF]
|
|
|
|
|
|
R. K. Dubey, S. Oparil, B. Imthurn, and E. K. Jackson Sex hormones and hypertension Cardiovasc Res, February 15, 2002; 53(3): 688 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Matsumoto Andropause: Clinical Implications of the Decline in Serum Testosterone Levels With Aging in Men J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2002; 57(2): M76 - 99. [Full Text]
|
|
|
|
 |
|
 S.-H. Yang, E. Perez, J. Cutright, R. Liu, Z. He, A. L. Day, and J. W. Simpkins Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model J Appl Physiol, January 1, 2002; 92(1): 195 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zitzmann, M. Brune, B. Kornmann, J. Gromoll, S. von Eckardstein, A. von Eckardstein, and E. Nieschlag The CAG Repeat Polymorphism in the AR Gene Affects High Density Lipoprotein Cholesterol and Arterial Vasoreactivity J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4867 - 4873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Smith, S. Bennett, L. M. Evans, H. G. Kynaston, M. Parmar, M. D. Mason, J. R. Cockcroft, M. F. Scanlon, and J. S. Davies The Effects of Induced Hypogonadism on Arterial Stiffness, Body Composition, and Metabolic Parameters in Males with Prostate Cancer J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4261 - 4267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Vermeulen Androgen Replacement Therapy in the Aging Male--A Critical Evaluation J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2380 - 2390. [Full Text] [PDF]
|
|
|
|
|
|
H. Hanke, C. Lenz, B. Hess, K.-D. Spindler, and W. Weidemann Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall Circulation, March 13, 2001; 103(10): 1382 - 1385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Dobs, P. S. Bachorik, S. Arver, A. W. Meikle, S. W. Sanders, K. E. Caramelli, and N. A. Mazer Interrelationships among Lipoprotein Levels, Sex Hormones, Anthropometric Parameters, and Age in Hypogonadal Men Treated for 1 Year with a Permeation-Enhanced Testosterone Transdermal System J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1026 - 1033. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. A. Sader, K. A. Griffiths, R. J. McCredie, D. J. Handelsman, and D. S. Celermajer Androgenic anabolic steroids and arterial structure and function in male bodybuilders J. Am. Coll. Cardiol., January 1, 2001; 37(1): 224 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Worboys, D. Kotsopoulos, H. Teede, B. McGrath, and S. R. Davis Evidence That Parenteral Testosterone Therapy May Improve Endothelium-Dependent and -Independent Vasodilation in Postmenopausal Women Already Receiving Estrogen J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 158 - 161. [Abstract] [Full Text]
|
|
|
|
|
|
K. M. English, R. P. Steeds, T. H. Jones, M. J. Diver, and K. S. Channer Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina : A Randomized, Double-Blind, Placebo-Controlled Study Circulation, October 17, 2000; 102(16): 1906 - 1911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Webb, M. A. Ghatei, J. G. McNeill, DCRR, and P. Collins 17{beta}-Estradiol Decreases Endothelin-1 Levels in the Coronary Circulation of Postmenopausal Women With Coronary Artery Disease Circulation, October 3, 2000; 102(14): 1617 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.J. Pugh, K.M. English, T.H. Jones, and K.S. Channer Testosterone: a natural tonic for the failing heart? QJM, October 1, 2000; 93(10): 689 - 694. [Full Text] [PDF]
|
|
|
|
|
|
G. G. Geary, D. N. Krause, and S. P. Duckles Gonadal hormones affect diameter of male rat cerebral arteries through endothelium-dependent mechanisms Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H610 - H618. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.M.C. Rosano Androgens and coronary artery disease. A sex-specific effect of sex hormones? Eur. Heart J., June 1, 2000; 21(11): 868 - 871. [PDF]
|
|
|
|
|
|
K.M English, O Mandour, R.P Steeds, M.J Diver, T.H Jones, and K.S Channer Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms Eur. Heart J., June 1, 2000; 21(11): 890 - 894. [Abstract] [PDF]
|
|
|
|
|
|
C. S. Hayward, R. P. Kelly, and P. Collins The roles of gender, the menopause and hormone replacement on cardiovascular function Cardiovasc Res, April 1, 2000; 46(1): 28 - 49. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||