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From the Departments of Medicine for the Elderly, *
Urology, and
Oncology,
Imperial College, Hammersmith Hospital,
London, United Kingdom.
| Correspondence to: Frances Dockery, Section of Medicine for the Elderly, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom (e-mail: fdockery{at}doctors.org.uk). |
| Received for publication September 24, 2008; accepted for publication January 16, 2009. |
Endogenous testosterone and estradiol are thought to be cardio-protective
in men. We wanted to determine the effects of 2 different anti-androgen
therapies on arterial stiffness as one suppresses (goserelin—a
gonadotrophin-releasing hormone analog) while the other increases
(bicalutamide—an androgen receptor blocker) both testosterone and
estradiol. We conducted a randomized trial on 43 men (mean age, 71.2 ±
6.2 years) with localized prostate cancer. They received either goserelin or
bicalutamide for 24 weeks. Carotid-femoral (C-F) and carotid-radial (C-R)
pulse wave velocities (PWVs) were measured. Twenty age- and disease-matched
men with prostate cancer on no active treatment were studied in a similar
manner. After 12 weeks of goserelin, radial artery PWV increased significantly
from baseline and a nonsignificant increase was observed in femoral PWV
(change from baseline radial: +1.4 m/s, P = .002, femoral: +0.9 m/s,
P = .127) Both PWV measures increased significantly with bicalutamide
(change from baseline radial: +0.8, femoral: +0.9 m/s, P
.049).
PWV increased further after 24 weeks with goserelin (change from baseline
radial: +1.7, femoral: +1.3 m/s, P .049 for both) but not
bicalutamide (change from baseline radial: +0.4, femoral: +0.4 m/s, P
not significant [NS]); however, comparison of changes between the 2 drugs were
not significantly different at either 12 or 24 weeks (P 
.967 at
12 weeks and P .07 at 24 weeks). The untreated men studied in
parallel showed no changes at 12 or 24 weeks in either PWV measure.
Anti-androgen treatment in men might increase large artery stiffness, an
adverse cardiovascular risk factor; however, the effect was not maintained
with testosterone receptor blockade, in the longer term, but tended to be
sustained with suppression therapy. This could relate to the different sex
hormone effects of the 2 therapies.
Key words: Vascular, testosterone, compliance
Androgen suppression therapy is widely used in men with prostate cancer. This treatment in early prostate cancer confers no survival advantage and might even increase all-cause mortality, for unclear reasons (Iversen et al, 2004). Androgen suppression using gonadotrophin-releasing hormone (GnRH) analogs in men with prostate cancer causes an increase in arterial stiffness and hyperinsulinemia (Smith et al, 2001; Dockery et al, 2003), suggesting an adverse effect on cardiovascular risk. The measure of arterial stiffness is a useful means of noninvasively determining changes in the properties and function of the arterial wall, which cannot be detected by measuring blood pressure alone. Increased aortic stiffness is a strong independent predictor of cardiovascular mortality in a number of patient groups, including hypertensives, diabetics, and healthy older subjects, and increased radial artery stiffness is predictive of cardiovascular events (Laurent et al, 2001; Cruickshank et al, 2002; Grey et al, 2003; Sutton-Tyrrell et al, 2005).
GnRH analogs lead to a 90% fall in testosterone and a 50% fall in estradiol levels (Labrie et al, 1986). Endogenous estrogens could have cardiovascular benefits in men (Sudhir and Komesaroff, 1999), so their loss might also contribute to this seemingly adverse cardiovascular effect. The effect of bicalutamide, an androgen receptor blocker that leads to a 50% rise in both serum testosterone and estradiol levels (Verhelst et al, 1994) on arterial stiffness, has not been studied previously. Because of their different effects on the sex hormone profile, comparing the effects of the 2 drugs on vascular stiffness could shed light on the hormone–arterial effects interaction. We have previously demonstrated that anti-androgen therapy was associated with an increase in N-terminal proB-type natriuretic peptide (NT-proBNP) levels in men with prostate cancer (Dockery et al, 2008). Here, we report the data on arterial stiffness on the same group of men before and after anti-androgen therapy.
Methods
Subjects
Forty-three men with localized prostate cancer disease who were deemed as
requiring hormonal treatment by the local Urology or Oncology services were
recruited. They were randomly allocated to 6 months of either bicalutamide,
150 mg orally once daily, or goserelin depot injection, 10.8 mg 3 times
monthly (1st injection preceded by 2 weeks of flutamide, an androgen receptor
blocker, 250 mg 3 times daily, as per standard guidelines). Randomization was
computer-generated and balanced for every 6 subjects. All subjects had
arterial stiffness measures at baseline and at 12 and 24 weeks.
Additionally, 20 men who had a current or past history of prostate cancer not requiring treatment presently were studied in parallel to the 2 randomized groups for observational data. Exclusion criteria for all subjects were metastatic cancer; atrial fibrillation; severe hepatic, renal or cardiac failure; any acute illness; and any recent (in the preceding 12 months) hormone treatment.
The study was approved by the Regional Ethics Committee, and all patients gave written informed consent. Patients were asked to continue their usual medications without (unnecessary) change during the course of the study.
Arterial Stiffness Measures
All studies took place in the fasting state. An average of 3 brachial blood
pressure readings from the right arm was taken with the use of an automated
device (OMRON 705CP) after 5 minutes of lying semirecumbent and at 3-minute
intervals thereafter.
Pulse wave velocity (PWV) was measured with the "Complior" system (Colson, Paris, France), an automated recording device that calculates the time delay between 2 pulse waves recorded simultaneously (Asmar et al, 1995). Velocities from carotid to radial (C-R) and carotid to femoral (C-F) arteries were calculated, with distances given as straight lines on the body surface. The velocity was calculated as transit distance/transit time. The average of 10 recordings was calculated. Reproducibility of PWV measurement with the Complior was assessed according to methods previously described (Chaturvedi et al, 2004). The mean difference between repeated measurements was 0.06 m/s, the standard deviation of differences was 0.90 m/s. Repeatability coefficient was 1.8 m/s, which compares well with other studies (Liang et al, 1998; Chaturvedi et al, 2004).
Blood Tests
Fasting blood levels were taken at each visit for lipids, glucose, and sex
hormones. The nondiabetic cases also had a glucose tolerance test, with
glucose and insulin levels before and 2 hours after 75 g of glucose. All blood
samples were analyzed by the on-site laboratory conforming to United Kingdom
National Quality Assessment scheme. Details of all assays used, with relevant
sensitivities and specificities, are reported in the related papers (Dockery
et al, 2003,
2008).
Statistical Analysis
Independent Student's t tests or 
2 tests were
employed to compare baseline variables. The within-group change from baseline
was analyzed by paired Student's t test. Changes from baseline
between groups were compared by analysis of covariance (ANCOVA), adjusting for
baseline reading and any concomitant changes in mean arterial blood pressure
(MAP). The least significant difference post hoc tests were used to compare
each drug group with the controls. Analysis was by intention-to-treat.
Appropriate nonparametric tests were used for all skewed data not normalized
by transformation and are stated where used. All values are expressed as
± SD or median and range.
SPSS (version 12; SPSS Inc, Chicago, Illinois) was used for all analyses.
Results
One man in the bicalutamide arm dropped out after his baseline visit, leaving data from 42 subjects available for analysis. Three men discontinued bicalutamide early (1 because of impotence and 2 because of a skin reaction), and 1 man discontinued goserelin (impotence) after 3 months; however, all attended for all 3 recordings. Five men in the goserelin group and 7 men in the bicalutamide group started new vasoactive medications (antihypertensives or statins) during the study. All were included in initial intention-to-treat analysis.
Table 1 shows baseline characteristics. Differences in the type of antihypertensive medication used were not significant between the groups, although proportions were small (data not shown). Table 2 shows hemodynamic data: baseline readings were similar apart from a higher baseline C-R PWV in the bicalutamide group (P = .07 for comparison of the 2 groups).
|
|
In the randomized study, both drugs caused a significant increase in C-R PWV and C-F PWV from baseline to 12 weeks, and by 24 weeks, both radial and femoral PWV measures continued to rise in the goserelin group but had tended back toward baseline in the bicalutamide group. However, comparison of these changes from baseline were not significantly different between the 2 drug groups at either time point, but when compared with changes in the no-treatment cohort, who were studied over a similar time period, each drug group differed significantly in C-R PWV changes after 12 weeks, both with and without adjustment for any blood pressure change. The bicalutamide group also differed significantly from the no-treatment group in C-F PWV change at 12 weeks. Comparison of baseline to 24-week changes in both PWV measures tended to differ between the 3 groups, but not significantly.
Repeat per-protocol analysis excluding those who did not complete study
medication (n = 4 excluded), and again excluding those who took new vasoactive
medication (n = 13 excluded), gave a similar pattern of results: significant
P values remained so, but comparison of changes in femoral PWV were
still not significantly different between the 2 drug groups (P
.321 for all, data not shown).
Metabolic Parameters
Lipid, fasting or postprandial glucose, or insulin levels did not change
significantly with either drug at 3 or 6 months, and comparison of the changes
were not significant (Table 3).
Body mass index and waist:hip ratio did not alter significantly in any of the
3 groups, as we previously reported, and hemoglobin fell to a similar degree
in both drug groups (1 g fall in both), as would be expected with
anti-androgens (Dockery et al,
2008).
|
Discussion
This study demonstrates that men who were artificially rendered hypogonadal by either a GnRH analog (goserelin) or an androgen receptor blocker (bicalutamide) developed a significant increase in femoral and radial arterial pulse wave velocity after 3 months of treatment, although no difference was observed between the 2 groups. This finding is consistent with previous studies on GnRH analogs (Smith et al, 2001; Dockery et al, 2003) but is the first study of longer than 12 weeks duration, and the first to examine effects of bicalutamide on arterial stiffness, this drug having very different effects on the physiological sex hormone profile from that of goserelin. The bicalutamide group's measurements reverted back toward baseline by 6 months, whereas the measurements continued to increase in both the radial and femoral artery region in the group receiving goserelin; however, comparisons between the 2 drug groups was not significant at either the 12- or 24-week time points. ± The observational cohort of age- and disease-matched men on no active treatment showed a lack of notable change in arterial stiffness parameters over a similar time period. They were not randomized and were at a different disease stage; nevertheless, they provide useful observational data in a study in which a placebo-controlled arm could not ethically be used.
Aortic pulse wave velocity has substantial evidence as an independent predictor of cardiovascular risk in several high-risk groups, including hypertensives and healthy older subjects (Laurent et al, 2001; Sutton-Tyrrell et al, 2005), and is therefore recognized as one of the more important measures of arterial stiffness to date. Evidence also exists of increased radial artery PWV being predictive of cardiovascular events (Grey et al, 2003). Recent guidance from the analysis of several large-scale studies of PWV measurements suggests that a 1 standard deviation increment in C-F PWV is equivalent to 1.5 to 2 times the risk of an increase in systolic blood pressure of 10 mm Hg. Although limited in many respects, particularly in that gender differences in PWV are not accounted for, it demonstrates the importance of PWV as a further modifiable cardiovascular risk factor (Khoshdel et al, 2007).
Androgen receptors are widespread in endothelial and smooth muscle cells and mediate at least some of the modifying properties of testosterone on the vascular system (Hanke et al, 2001). Direct vasodilatory effects of testosterone on calcium channels, potassium channels, or both of vascular smooth muscle are also recognized (Deenadayalu et al, 2001; Jones et al, 2002). Testosterone might therefore maintain a beneficial effect on the vasculature that is lost on effective castration. Goserelin has also been shown to lead to hyperinsulinemia (Smith et al 2001; Dockery et al, 2003), although we did not observe this effect on this occasion, perhaps because many of the men started vasoactive medications during our study, which could have masked serum insulin changes. Lipid levels were not altered significantly in this study either; however, from the literature, no consistent effect of androgen suppression on lipid levels is discovered; therefore, lipid and insulin pathways do not appear to be factors in the arterial stiffness changes we observed (Wu et al, 2003).
Anemia might increase pulse wave velocity (Nichols and O'Rourke, 1990), but hematocrit fell to a similar degree in both drugs; therefore, anemia could not explain the divergent results we observed after 12 weeks. We previously reported an increase in NT-proBNP levels in this group of patients, which interestingly paralleled their increase in arterial stiffness at 12 weeks. BNP is known to be related to arterial stiffness (Yambe et al, 2006), yet the goserelin group had the most significant increase in arterial stiffness by 24 weeks, and they did not show BNP changes over the same time period, so this is unlikely to be a factor (Dockery et al, 2008).
The different effect of the 2 drugs on the sex hormone profile might account for the seemingly divergent effect on arterial stiffness seen after 12 weeks. The important difference is that circulating testosterone is still present with bicalutamide (being an androgen receptor blocker), potentially allowing any direct vasodilatory effect on the vessel wall to continue. However, the fact that both drugs caused an increase in arterial stiffness after 12 weeks means that this pathway is less important initially, with the loss of testosterone action on the classical receptor being the factor that both drugs have in common. Equally important could be the rise in estradiol that occurs with bicalutamide because of peripheral aromatization of testosterone, whereas goserelin causes a fall in estradiol because of testosterone depletion. Again, this pathway cannot account for the initial parallel increase in stiffness in both drug groups, although it might contribute to the later divergence. Gonadotrophin levels and adrenal androgen effects were also different between the 2 drugs, although no data presently exist on cardiovascular effects of these; however, collectively, the altered hormone milieu could potentially be a contributor to the different vascular effects observed.
A number of limitations to the study, apart from the lack of a placebo arm, are mentioned. The subjects were not a homogeneous group, in that many had cardiovascular disease, although this is to be expected in such an age group, and many started vasoactive medications during the study period; this would have affected arterial stiffness readings, but excluding these subjects on repeat analysis gave similar results. We did not take in-depth details of regular exercise at each visit; subjects could have altered their lifestyle, although the overall effect of exercise on arterial stiffness is unclear (Miyachi et al, 2004). All the men in this study suffered from prostate cancer, so these findings cannot be extrapolated to the general population. However, it is important to establish any potential adverse cardiovascular effects of anti-androgens because the optimal treatment of prostate cancer remains unclear (Iversen et al, 2004; Wirth et al, 2004). Prostate cancer is predominantly a disease of older men who are by virtue of their age and sex alone already at greater cardiovascular risk, so even a short-term adverse effect on arterial stiffness might not be entirely benign in such subjects.
Both androgen receptor blockade and androgen suppression cause an initial adverse effect on arterial pulse wave velocity. This effect is sustained with androgen suppression but appears to revert with the receptor blocker, perhaps because of their divergent effects on the sex hormone profile.
Footnotes
Educational grant from Astra-Zeneca. They had no role in any aspect of the study plan, conduct, analysis, interpretation of data, or writing of manuscripts.
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