© 1997 American Heart Association, Inc.
Articles |
Androgen Deprivation Is Associated With Enhanced Endothelium-Dependent Dilatation in Adult Men
From the Departments of Cardiology (S.M.H., J.T.C.R., R.J.M., M.R.A., D.S.C.) and Medical Oncology (M.J.B.), Royal Prince Alfred Hospital, and the Heart Research Institute (J.T.C.R., R.J.M., D.S.C.), Sydney, Australia.
Correspondence to A/Prof David Celermajer, Medical Foundation Fellow, University of Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Camperdown 2050, Sydney, Australia. Email davidc{at}card.rpa.cs.nsw.gov.au
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Abstract |
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Abstract Male gender is an independent risk factor for coronary artery disease, and androgen administration has been associated with increased atherosclerosis in experimental animals. Since endothelial dysfunction is an important event in the atherogenic process, we hypothesized that androgen deprivation in adult men might be associated with enhanced arterial endothelial function. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilatation) and after nitroglycerin (an endothelium-independent dilator). We studied 30 adult males aged 40 to 70 years: 10 had had bilateral orchidectomy and/or maximal androgen blockade for
6 months for treatment of prostate
cancer, and all were in complete remission (group 1). Ten healthy
controls (group 2) and 10 controls who had remission from nonprostate
cancers (group 3) were matched for age and smoking history.
Testosterone levels were lower in men in group 1 versus groups 2 or 3
(0.8±0.1 versus 19.2±8.4 or 16.1±4.9 nmol/L, P<.001). By
contrast, endothelium-dependent dilatation was markedly
higher in group 1 than in groups 2 or 3 (6.2±3 versus 2.7±2 or
2.0±1.9%, P<.001). The nitroglycerin
response was similar in all three groups (P=.92). On
multivariate analysis, increased
endothelium-dependent dilatation was significantly
associated with low serum testosterone levels (P=.001) but
not with cholesterol levels or with a past history of
malignancy (P>.25). The withdrawal of male sex hormones may
be associated with enhanced endothelial function in
adult men. This is consistent with a deleterious effect of
physiologic levels of male sex steroids on the arterial
wall.
Key Words: endothelium • nitric oxide • testosterone • atherosclerosis
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Introduction |
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There is an important gender difference in the incidence of cardiovascular morbidity and mortality, with adult males of all ages being at higher risk than females.1 2 Much attention has focused on the possible protective effects of estrogen in epidemiologic3 4 and experimental5 6 studies. Many studies have shown that estrogen therapy improves the lipid profile7 8 and has direct arterial wall benefits, with favorable influences on endothelial9 10 11 and smooth muscle physiology.12 13
Equally plausible, but less well tested, is the possibility that androgens have a detrimental effect on the arterial wall. In recent studies, Adams et al demonstrated that testosterone administration increases atherosclerosis progression in cholesterol-fed female monkeys,14 and Hutchison et al showed that testosterone administration is associated with endothelial dysfunction in hypercholesterolemic rabbits.15 It is not known, however, whether androgenic hormones may have adverse arterial effects in humans.
Endothelial dysfunction is an important early event in atherogenesis16 and also determines dynamic plaque behavior in patients with advanced coronary disease.17 18 Recently, a noninvasive method for studying endothelial function in the systemic arteries has been described.19 To assess the vascular effects of androgens in humans, we have used this method to investigate endothelium-dependent arterial dilatation in 10 adult men who had been deprived of androgens for more than 6 months as therapy for prostate cancer, in 10 healthy age-matched controls, and in 10 control subjects with a history of other (nonprostate) malignancies.
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Methods |
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Subjects
We investigated 30 adult males (aged 40 to 70 years); none had a family history of premature vascular disease nor any known history of hypertension, diabetes mellitus, or hyperlipidemia. No subjects had clinical evidence of atherosclerosis. Resting 12 lead electrocardiograms were available from 28 of 30 subjects from the time of study or within 12 months of their study visit; in all cases, there was no evidence of myocardial ischemia or infarction. No subjects were taking any regular cardiovascular medications. All subjects gave informed consent, and the study was approved by the institutional ethics review committee.
Adult men with a history of androgen deprivation therapy
for prostate cancer were identified from hospital records, and 10
consecutive subjects who fulfilled the prospectively defined inclusion
criteria were recruited for the study (group 1). Inclusion criteria
were (1) the prospectively defined age range (40 to 70 years); (2) a
history of prostate cancer in clinical remission (defined as a
prostate-specific antigen level <4 ng/mL or three serial
prostate-specific antigen levels that had continued to decrease since
diagnosis, with each of the measurements at least 3 months apart, the
most recent level as <20 ng/mL with no clinical evidence of
disease recurrence) and (3) androgen deprivation
treatment for 6 months (orchidectomy and/or maximal antiandrogen
therapy). None had received systemic cytotoxic chemotherapy. In this
group, three subjects had undergone surgical and seven had had medical
castration. Of the three subjects who had had bilateral orchidectomy,
two were also receiving the antiandrogen cyproterone acetate, 100 to
200 mg daily. Of the seven treated medically, all had received regular
injections of gonadotrophin-releasing hormone analogs (goserelin, 3.6
mg every 28 days in six, and leuprorelin, 7.5 mg every 28 days in one;
of these subjects, two were also receiving cyproterone acetate, 100 to
300 mg daily, and two others were also receiving flutamide, 750 mg
daily). The average duration of surgical or medical castration (and
thus almost total androgen deprivation) was 18±4 (range 6
to 33) months.
Two groups of control subjects were also recruited: 10 healthy controls
(group 2) and 10 control subjects who were in remission after treatment
of a nonprostate malignancy in the previous 5 years (group 3). For each
subject in group 1 (androgen-deprived), a healthy control and a cancer
control were matched for age (±5 years), smoking history (duration and
intensity of current or former smoking), and history of dietary
antioxidant supplementation. Healthy controls were drawn from community
volunteers, and cancer controls were recruited from hospital databases;
the latter were selected from lists of subjects who had surgically
curable malignancies and who had not received anticancer chemotherapy.
Two subjects had undergone hemicolectomy for Dukes' A or B cancer of
the colon; none had clinical recurrence, and both had normal
carcinoembryonic antigen levels 12 months after operation. Three
subjects had been treated with lobectomy for non-small cell lung
cancer, and five had had wide surgical excision of malignant melanoma;
none had evidence of locally recurrent or metastatic disease 12
months after their operations.
Study Design
Each patient had one visit, when a history was taken, supine
resting blood pressure was measured, fasting blood sample was taken for
lipid, hormone, and prostate-specific antigen assays, and the vascular
reactivity of the brachial artery was assessed. The blood samples were
analyzed for total cholesterol,
triglycerides, and high density lipoprotein
cholesterol levels (the latter after phosphotungstate
magnesium precipitation) using a Hitachi 747 autoanalyzer. The
low density lipoprotein cholesterol was calculated using
the Friedwald formula (in no patient was the triglyceride
level 4 mmol/L).20 Testosterone levels were
measured by radioimmunoassay, sex hormone binding globulin by
immunoradiometric assay, and free testosterone index calculated as
100 x (testosterone/sex hormone binding globulin).
Prostate-specific antigen was also measured by immunoradiometric assay
(Immulite, Diagnostic Products Corporation).
The ultrasound method for assessing endothelium-dependent and independent dilatation was performed as described previously.19 21 Brachial artery diameter was measured from B-mode ultrasound images using a 7.0-MHz linear array transducer and a standard Acuson 128 XP/10 system (Mountain View, Calif). In all studies, scans were obtained at rest, during reactive hyperemia (with increased flow leading to endothelium-dependent dilatation (EDD)), again at rest, and after sublingual nitroglycerin (glyceryl trinitrate (GTN), an endothelium-independent dilator). The brachial artery was scanned in longitudinal section above the elbow, and the center of the artery was identified when the clearest picture of the anterior and posterior intimal layers was obtained. Depth and gain settings were set to optimize images of the lumen/arterial wall interface, images were magnified using a resolution box function (leading to a video line width of approximately 0.065 mm), and machine operating parameters were not changed during any study.
When a satisfactory transducer position was found, the skin was marked, and the arm remained in the same position throughout the study. A resting scan was recorded, and arterial flow velocity was measured using Doppler techniques. Increased flow was then induced by inflation of a pneumatic tourniquet placed around the forearm (distal to the scanned part of the artery) to a pressure of 250 mm Hg for 4.5 minutes, followed by release. A second scan was taken continuously for 30 seconds before and 90 seconds after cuff deflation, including a repeat flow velocity recording for the first 15 seconds after the cuff was released. Flow measurements were derived from the Doppler flow velocity signal, and the vessel size and heart rate were measured as described and validated previously.19 22 Thereafter, 10 to 15 minutes were allowed for vessel recovery, after which an additional resting scan was obtained. Sublingual GTN spray (400 mcg) was then administered, and the last scan was performed 3 to 4 minutes later.
Ultrasound Analysis
Vessel diameter was measured in every case by two independent
observers. During analysis, using off-line videotape
recordings, arterial scans were cued on screen for
each observer in random order by another independent investigator.
Observers were "blinded" in all cases to the identity and group of
each subject and the stage of each scan by cards taped across the
monitor screen to obscure patient identification and date and time
information. We have previously shown that this ultrasound-based method
is accurate and reproducible for measurement of small changes in
arterial diameter,21 23 with low interobserver
error for measurement of flow-mediated and GTN-induced
dilatation.19
The arterial diameter was measured at a fixed distance from an anatomic marker (such as a fascial plane or a vein seen in cross-section) using ultrasonic calipers. Measurements were taken from the anterior to the posterior "m" line at end-diastole, incident with the R-wave on a continuously recorded ECG. For the reactive hyperemia scan, diameter measurements were taken 50 to 60 seconds after cuff deflation. Four cardiac cycles were analyzed for each scan, and the measurements were averaged. The vessel diameter in scans after reactive hyperemia and GTN administration was expressed as the percentage relative to the average diameter of the artery in the two resting scans (100%).
Statistics
Descriptive data are expressed as mean±standard deviation,
unless otherwise stated. The three groups of subjects were compared by
analysis of variance (ANOVA). The prospectively defined
endpoint of this study was the EDD response. All other ANOVA results
were adjusted for multiple comparisons using Hochberg's modification
of the Bonferroni procedure.24 Where statistical
significance was demonstrated, the ANOVA was followed by adjusted
pairwise comparisons between groups using the Student-Newman-Keuls
test. Due to the nonnormal distribution of lipoprotein(a) levels, these
results are given as the median with interquartile range and complete
range, and the groups of subjects were compared using the
Kruskal-Wallis ANOVA test. The influences of variables in all
analyses were considered in the whole population of subjects
available. The determinants of EDD and GTN-induced dilatation were
assessed by univariate and multivariate
linear regression analyses, with age, total or LDL
cholesterol level, vessel size, testosterone level or
history of androgen deprivation, and history of malignancy
as the independent variables. A
testosterone-cholesterol interaction was specifically
examined also by entering a (testosteronexcholesterol)
independent variable into the multivariate model
for EDD. This interaction variable was not significantly related to
EDD (P=.34), and therefore the results presented are
those from the main effects model described above. Statistical
significance was inferred at a two-sided P value
<.05.
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Results |
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Baseline Characteristics
In each group studied, five subjects had never smoked cigarettes regularly, four were former smokers, and one was a current smoker. Three of the 10 subjects in each group were currently taking supplemental vitamin C (dose 200 to 2000 mg/day) with or without other vitamins. Lp(a) levels were similar in the three groups: median 82 mg/L (interquartile range 13 to 145, range 12 to 909) in group 1; median 101 mg/L (interquartile range 57 to 355, range 52 to 1254) in group 2; and median 88 mg/L (interquartile range 52 to 251, range 12 to 531) in group 3 (P=.56 by ANOVA). There was also no significant difference between groups in age, systolic or diastolic blood pressure, total or LDL cholesterol levels, body mass index, resting vessel size, or baseline arterial flow (Table 1
). As expected,
testosterone levels and the free testosterone index were significantly
lower in the men treated by androgen deprivation (group 1)
compared with the healthy controls (group 2) and the controls with a
history of nonprostate malignancy (group 3) (P<.001).
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Arterial Reactivity Studies
The degree of reactive hyperemia after cuff
inflation and release was >500% in each of the groups studied, and
there was no significant difference between groups (Table 2). In response to this increase in flow,
EDD was markedly higher in the androgen-deprived men compared with both
groups of control subjects (6.2±3.0% versus 2.7±2.0 or 2.0±1.9%,
P<.001) (Fig 1). By contrast,
GTN responses were similar in all three groups (P=.92). On
univariate analysis, EDD was inversely correlated
with total testosterone levels (r=-.64, P<.001)
and with the free testosterone index (r=-.56,
P=.004), but not significantly correlated with total
(P=.09) or LDL cholesterol levels
(P=.14). GTN-induced dilatation was not significantly
correlated with any of these variables. On
multivariate analysis, increased EDD was
significantly associated with low testosterone levels
(P=.001) but not with total cholesterol level
(P=.68) or with a history of malignancy (P=.26).
Similar results were obtained if the free testosterone index or a
history of androgen deprivation was entered as an
independent variable, rather than total testosterone level. Similar
results were also obtained if LDL-cholesterol was used as
an independent variable, rather than total cholesterol.
Neither testosterone level, cholesterol level, nor history
of malignancy was significantly associated with GTN response.
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Discussion |
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The effects of androgens on arterial physiology in humans have not been well studied, in contrast to the large number of studies examining the vascular effects of estrogen therapy in both women9 10 11 12 13 25 26 and men.27 In this study, we demonstrate that complete androgen deprivation for
6
months is associated with significantly better arterial
endothelial function in adult men compared with
normoandrogenemic controls. These data are consistent with a
harmful effect of physiologic levels of androgens on
arterial function, compared with the largely beneficial
vascular effects associated with estrogens.9 10 11 12 Because men have a greater risk of clinical cardiovascular disease than women, many authors have suggested that women are protected by endogenous25 and/or exogenous estrogens,7 28 29 although direct evidence is lacking. Some epidemiologic data, however, support the possibility of an adverse effect of androgens. Women are at lower risk of coronary disease than men, even after the menopause1 when their estrogen levels are extremely low and nearly equivalent to those in males.30 Hyperandrogenemic women, such as those with the polycystic ovarian syndrome, have higher levels of coronary risk factors31 and a greater extent of coronary atherosclerosis32 compared with healthy female controls. In men, androgen therapy in young adults may be associated with premature vascular disease,33 34 and male-pattern baldness (an androgen-mediated condition) is associated with an increased risk of coronary events.35 Although the interaction between sex hormones and the cardiovascular system is clearly complex, it appears plausible that adverse effects of androgens, rather than simply beneficial effects of estrogens, may be contributing to the observed gender difference in the risk of atherosclerotic diseases.
Naturally occurring hyperandrogenism is rare in males, and therefore the effects of high testosterone levels on arterial physiology have been difficult to study in humans.14 In contrast, complete androgen deprivation (by orchidectomy and/or blockade of androgen synthesis or receptor binding) is commonly used in the treatment of prostate cancer. To infer whether physiologic androgen levels may be inhibiting normal arterial endothelial function, we hypothesized that withdrawal of androgens might be associated with enhanced endothelial function. We studied arterial physiology in middle-aged men in complete remission from prostate cancer after at least 6 months of maximal androgen deprivation. To exclude an effect of "cancer in remission" on endothelium-dependent or independent arterial dilatation, or an unmeasured difference between men with a history of malignancy and those without, we studied both healthy controls and a group of controls with normal androgen levels but who were in remission after treatment for nonprostate malignancy. Since age,36 cigarette smoking,37 and vitamin C supplementation38 all may influence endothelium-dependent dilatation, these variables were closely matched between case and control subjects.
Endothelial dysfunction appears to be important in atherogenesis, both as an early, initiating event16 19 and also later in the disease process.17 18 In this study, endothelium-dependent dilatation was significantly better in the arteries of the androgen-deprived men compared with either group of controls, whereas endothelium-independent responses were similar. This test of brachial artery endothelial function is accurate and reproducible,23 correlates closely with coronary endothelial responses,39 and is due mainly to endothelial release of nitric oxide.40 Our data suggest that there was greater endothelial release of nitric oxide in response to an increase in arterial flow in the androgen-deprived men compared with controls. Therefore, because nitric oxide is not only a vasodilator but also has important platelet antiadhesion, monocyte antiadhesion, and smooth muscle antiproliferative effects,41 this may be of important pathophysiologic benefit.
Previous animal and human experiments studying the arterial effects of testosterone have shown conflicting results. In rats, androgens mediate important sex differences in cardiovascular responses, with males showing impaired endothelium-dependent responses compared with females.42 In rabbits, Yue et al found that very high (supraphysiologic) doses of testosterone-relaxed preconstricted arterial rings via an endothelium-dependent mechanism43 and in dogs, Chow and colleagues reported that high-dose intracoronary testosterone also produces vasodilatation.44 In contrast, however, Hutchison et al found that physiologic concentrations of testosterone impair endothelium-dependent vasorelaxation in cholesterol-fed rabbits exposed to cigarette smoke.15 In monkeys, coronary atherosclerosis develops more rapidly in males than females.14 45 In a recent study in female cynomolgus monkeys, Adams et al found that testosterone administration increased the extent of atherosclerotic plaque formation but surprisingly, was associated with improved coronary endothelial function.14 As testosterone may influence endothelial prostanoid secretion in female but not male animals,46 it is possible that the effects of testerone in adult female monkeys differ from the effects in adult human males. In humans, high testosterone levels have been correlated with increased coronary risk factors in older women,47 and androgen-mediated baldness (due to end-organ sensitivity to testosterone) has been correlated with an increased prevalence of coronary events in men.35 However, high testosterone levels have also been associated with less angiographically evident coronary atherosclerosis in men without previous myocardial infarction.48
In the current study, the finding of significantly enhanced endothelium-dependent dilatation in androgen-deprived men is consistent with an adverse effect of androgens on vessel wall function. The mechanism whereby male sex steroids may impair endothelial function in humans is not known. Testosterone may have effects on the lipoprotein profile, although studies designed specifically to test the association between testosterone levels and lipoproteins in men have shown no significant associations with LDL cholesterol levels and inconsistent results in terms of the effect on HDL cholesterol.49 50 51 In this study, androgen-deprived men had slightly, but not significantly, lower total and LDL cholesterol levels than the control subjects. Therefore between-group differences in cholesterol levels are unlikely to have accounted for the large differences observed in endothelial function. Consistent with this, enhanced EDD was significantly associated with androgen deprivation on multivariate analysis, and this was independent of the total or LDL cholesterol measurements.
It is possible that there are direct effects of androgens on the vessel wall, as steroid receptors are known to exist in the vasculature.52 53 Alternatively, androgens might indirectly influence endothelial physiology via effects on insulin resistance54 or immune/inflammatory responses.55 Androgens may also effect handling of lipoproteins by the arterial wall, as has been recently demonstrated for other sex steroids such as estrogen and progesterone.56
A limitation of the current study is its cross-sectional, nonrandomized nature. Although the groups should have been similar since no subjects had clinical or ECG features of coronary disease, none had diabetes or hypertension and all were closely matched for age, smoking status, and antioxidant therapy, it is possible that unmeasured differences between groups were present. Furthermore, although the groups studied were relatively small, two separate control groups were investigated and compared with the androgen-deprived men, and the difference in endothelium-dependent dilatation between groups was highly significant. The arterial responses of the control groups of men, most of whom were aged >60 years and many of whom had smoked cigarettes heavily, were similar to those documented by us previously.35 36 In contrast, the androgen-deprived men (aged 40 to 70 years) had arterial responses similar to healthy young nonsmoking men, despite the well-documented adverse effects of aging35 and smoking36 on endothelial function in normoandrogenemic males. The effects of androgen deprivation in nonsmoking younger men (<40 years) or in completely healthy older men were not assessed in this study, and therefore caution must be applied about extrapolating our observations to the general population of healthy male subjects. A prospective study would allow more definitive conclusions about androgen deprivation to be made. However, this would be difficult in men with prostate cancer during treatment, since their general state of health and the extent of their cancer would change during therapy, as well as their androgen levels.
In summary, these data demonstrate that the withdrawal of male sex hormones may be associated with enhanced endothelial function in adult men. This finding is consistent with certain epidemiologic and animal data that suggest an adverse effect of male sex steroids on the arterial wall.
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Acknowledgments |
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This work is supported by grants from the National Heart Foundation of Australia (NHF), the Sylvia and Charles Viertel Charitable Foundation, and The Medical Foundation, University of Sydney (TMF). J.T.C.R. and M.R.A. are supported by the NHF and R.J.M. and D.S.C., by TMF. We thank Dr David Handelsman for his critical review of this manuscript.
Received December 18, 1996; accepted February 25, 1997.
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