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Departments of Medicine (J.C.S., L.M.E., M.F.S., J.S.D.), Urology (S.B., H.G.K.), Oncology (M.D.M.), and Cardiology (J.R.C.), University Hospital of Wales, Heath Park, Cardiff, United Kingdom CF14 4XW; and Medical Research Council Clinical Trials Unit (M.P.), London, United Kingdom NW1 2DA
Address all correspondence and requests for reprints to: Dr. Jamie C. Smith, Department of Endocrinology, 7th Floor Link Corridor, University Hospital of Wales, Heath Park, Cardiff, United Kingdom CF14 4XW. E-mail: smithjc1{at}cardiff.ac.uk
Abstract
Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 ± 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 ± 6% (mean ± SD) at baseline to 29 ± 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 ± 7 to 129 ± 10 msec (P = 0.003). Fat mass increased from 20.2 ± 9.4 to 21.9 ± 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 ± 6.8 to 61.5 ± 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6–49.1) to 15.1 (range, 7.3–83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0–85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 ± 7% at 3 months to 29 ± 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043).
These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.
CARDIOVASCULAR DISEASE is the major cause of death among men and women worldwide. The observation that premenopausal women have a significantly reduced incidence of cardiovascular disease suggests that sex hormones play a pivotal role in determining cardiovascular risk. The role of estrogens in atherogenesis has been extensively studied (1, 2, 3), but the nature of the relationship between androgens and vascular disease is poorly understood (4). Traditionally, androgens have been considered to be proatherogenic in males, and this view is supported by evidence from studies demonstrating improvements in both lipoprotein profiles (5, 6) and vascular endothelial function in males receiving androgen suppression therapy (7). However, evidence of an inverse correlation between testosterone levels and several cardiovascular risk factors (8, 9, 10) has recently emerged. This supports the opposing view that physiological levels of androgens may, in fact, protect the vasculature. Furthermore, studies in men have demonstrated that low testosterone concentrations are associated with lower high density lipoprotein cholesterol and higher triglyceride concentrations, hyperinsulinemia, and increased abdominal adiposity (11, 12, 13, 14, 15), features typical of the metabolic syndrome of insulin resistance (16).
In addition to its role in the metabolism of adipose tissue stores, testosterone may be involved directly in the regulation of vascular tone. Testosterone has been shown to dilate coronary, aortic, and brachial vasculature by both endothelial-dependent and independent mechanisms (17, 18, 19, 20). These observations suggest that testosterone may be an important regulator of vascular compliance in large and medium-sized arteries. Reduced vascular compliance resulting from impaired endothelial release of mediators such as nitric oxide contributes to arterial stiffening (21, 22). In addition to being a marker for degenerative physical changes, increased vascular stiffness has important hemodynamic consequences, and evidence is mounting that vascular stiffness is an independent marker of cardiovascular risk (23, 24).
Spontaneous male hypogonadism is a relatively rare disorder, but iatrogenic hypogonadism is more commonly encountered in the treatment of prostate cancer with hormone manipulation therapy. The use of LH-releasing hormone (LHRH) analogs has emerged as an effective form of androgen deprivation therapy for this androgen-sensitive tumor (25). Patients are rendered hypogonadal for the duration of therapy through the reduction of testicular androgen levels. It is possible that the significant alteration in sex hormone levels for those undergoing treatment has important, but as yet undetermined, physical, metabolic, and vascular effects. We have therefore investigated the vascular effects of LHRH analogs in males with prostate cancer by assessing central arterial pressure waveforms. In addition, we have investigated the effects of treatment on lipoprotein profiles, insulin sensitivity, and body composition.
Subjects and Methods
Subjects
Twenty-two patients (mean age, 67 ± 8 yr) with newly
diagnosed prostate cancer, who were due to commence androgen
deprivation therapy, were recruited from the combined urology/oncology
clinic at the University Hospital of Wales and studied during a 6-month
period. Informed written consent was obtained for each patient, and
approval for the study was obtained from the local ethics committee.
The patients were started on androgen deprivation therapy for their
condition according to standard clinical criteria. Twenty-one patients
received treatment consisting of a 2-wk pretreatment period with oral
cyproterone acetate (300 mg daily), followed by long-acting LHRH analog
therapy (leuprorelin acetate, 3.75 mg), administered by monthly im
injection. One patient underwent bilateral orchidectomy. All patients
received this therapy for 3 months. After this initial period, patients
were divided into subgroups A and B. In group A (14 patients), LHRH
analog therapy was discontinued. In group B (8 patients), patients
continued to receive androgen deprivation therapy for the remainder of
the study period. The characteristics of individual patients at entry
in the study are shown in Table 1
. Four
patients had preexisting hypertension and were receiving
antihypertensive medication consisting of an angiotensin-converting
enzyme inhibitor (patient 16), angiotensin-converting enzyme
inhibitor/diuretic combination (patient 20), ß-blocker (patient 19),
and calcium channel blocker (patient 3). Two patients (patients 3 and
10) were current cigarette smokers. One patient (patient 21) had
dietary controlled type 2 diabetes. Measurements of large artery
stiffness, metabolic parameters (lipid profiles, glucose, and insulin),
sex hormone concentrations (testosterone and estradiol), and body
composition were performed at baseline (pretreatment) and at 1, 3, and
6 months during the study period. To avoid confounding influences on
the variables under investigation, patients with advanced prostate
cancer were excluded from the study. Patients with clinical evidence of
cardiac or cerebrovascular disease were also excluded.
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Arterial stiffness and central aortic pressure were measured noninvasively by the technique of pulse-wave analysis using the SphygmoCor apparatus (version 6.01, PWV Medical, Sydney, Australia) as developed by O’Rourke (26). All measurements were taken from the radial artery at the wrist using a micromanometer (SPC-301, Millar Instruments, Houston, TX), applying the principle of applanation tonometry to flatten the artery by gentle pressure. Data were collected directly into a desktop computer and processed by the system software to allow accurate on-line recording of the radial artery waveform. The corresponding aortic pressure waveform can then be generated from an averaged radial artery waveform (derived from 20 sequentially recorded radial artery waveforms) using a validated transfer factor (26, 27, 28). Computerized analysis of the central waveform allows determination of the augmentation, the augmentation index, central aortic pressure, and the timing of wave reflection. The augmentation index is defined as the difference between the first and second peaks of the central arterial waveform, expressed as a percentage of the pulse pressure (26). The timing of the reflected wave, determined by calculating the time between the foot of the pressure wave and the inflection point, provided an estimation of aortic pulse-wave velocity (29, 30). Radial blood pressure was calibrated against brachial blood pressure, which was measured using conventional mercury sphygmomanometry [Korotkoff phases 1 (systole) and 5 (diastole)]. All subjects were studied in the fasting state. Two sequential measurements were made for each subject, and from these the mean augmentation, augmentation index, timing of the reflected wave, and central aortic pressure were calculated. All measurements were performed by a single operator. Reproducibility of the augmentation index using the SphygmoCor apparatus was determined using methodology described previously (31). The mean difference ± SD between repeated measurements of the augmentation index was 0.84 ± 4.0%.
Biochemical and body compositional measurements
Insulin was measured by RIA (Medgenix, Appligene-Oncor-Lifescreen, Watford, UK). The between-assay precision at an insulin concentration of 18.2 mU/liter was 14.2%, and that at 126 mU/liter was 18.4%. Testosterone was measured by a competitive immunochemiluminometric assay (Bayer Corp., Newbury, UK). The between-batch imprecision at a testosterone concentration of 16.4 nmol/liter was 8.6%, and that at 31.5 nmol/liter was 6.6%. Serum estradiol was measured by an in-house, high sensitivity RIA. Interassay variation was below 10% for estradiol concentrations above 30 pmol/liter and was between 20–25% at 10 pmol/liter. Serum lipids and plasma glucose were measured using standard techniques. Body composition analysis, performed using bioelectrical impedance (Tanita, Tokyo, Japan), provided measurements of fat mass and lean body mass.
Statistical analysis
All statistical analyses were performed using SPSS for Windows (version 9.0, SPSS, Inc., Chicago, IL). Data are expressed as the mean ± SD for normally distributed values and the median (range) for data with a nonnormal distribution. Statistical comparisons between groups were performed using ANOVA, paired t tests, and Wilcoxon tests (nonnormally distributed variables). Correlation between variables was evaluated using Spearman’s and Pearson’s correlation coefficients. P < 0.05 was considered significant.
Results
The effects of induced hypogonadism on physical and biochemical
parameters in all patients during the first 3 months are shown in Table 2. Although there was no change in total
body weight after treatment, significant changes in body composition
were observed. Fat mass increased from 20.2 ± 9.4 kg at baseline
to 21.9 ± 9.6 kg at 3 months (P = 0.008). Lean
body mass decreased from 63.2 ± 6.8 kg at baseline to 62.3
± 5.4 kg at 1 month (P = 0.003) and to 61.5 ±
6.0 kg by 3 months (P = 0.016). Testosterone
concentration decreased from 14.5 ± 4.1 nmol/liter at baseline to
1.2 ± 1.0 nmol/liter by 3 months (P < 0.0001).
In addition, estradiol decreased from 105 ± 19 pmol/liter at
baseline to 35 ± 31 pmol/liter by 3 months (P <
0.0001). There were no changes in lipid profiles or glucose during
treatment. However, median serum insulin rose from 11.8 (range,
5.6–49.1) mU/liter to 15.1 (7.3–83.2) mU/liter at 1 month
(P = 0.021) and to 19.3 (0–85.0)mU/liter by 3 months
(P = 0.020). A positive correlation was noted between
the change in fat mass and the change in insulin concentration over the
3-month period (r = 0.56; P = 0.013; Fig. 1).
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. Although there was no
evidence of changes in heart rate or peripheral blood pressure,
significant changes in central hemodynamic indexes were observed during
the initial 3-month treatment period. Augmentation increased from
13 ± 6 to 15 ± 8 mm Hg (P = 0.039), and the
augmentation index increased from 24 ± 6% to 29 ± 9%
(P = 0.003). The timing of wave reflection was
significantly reduced from 137 ± 7 ms at baseline to 129 ±
10 ms at 3 months (P = 0.003), indicating an increase
in aortic pulse-wave velocity. An example of the changes observed in
the central pressure waveform after induced hypogonadism is shown in
Fig. 2.
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). In group B, the augmentation index
remained elevated at 6 months compared with pretreatment (33 ±
12% vs. 23 ± 12%, P = 0.043). In
contrast, results from group A showed that the augmentation index
decreased from 31 ± 7% at 3 months to 29 ± 5% at 6
months. This 6 month value did not differ significantly from the
pretreatment value of 24 ± 7%.
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The role of androgens in cardiovascular disease remains controversial due to conflicting data indicating that physiological concentrations of androgens might be protective (8, 10) or detrimental (5, 6, 7) to cardiovascular risk in men. We have considered men with prostate cancer receiving androgen deprivation therapy to provide a model to study the vascular and metabolic effects of male hypogonadism. Our results indicate that males with prostate cancer, rendered hypogonadal by LHRH analog therapy, experience an increased augmentation of central arterial pressure, as shown by rises in the augmentation index. Treatment-induced changes in the timing of wave reflection were also observed, in that the reflected pressure wave returned to the ascending aorta sooner, indicating a higher pulse wave velocity. Taken together, these changes, which were evident after 3 months of androgen-suppressive therapy, suggest increased systemic arterial stiffness. The observation of improving arterial compliance after the cessation of treatment in a subgroup of patients strengthens these observations and suggests a reversible phenomenon.
Healthy arteries are compliant structures capable of buffering the pressure changes that occur during the cardiac cycle. Energy is absorbed during systole and released during diastole, resulting in smooth peripheral blood flow and the maintenance of diastolic coronary perfusion. Antegrade arterial pressure waves are reflected back from the periphery, arriving in the central arteries after the central systolic pressure peak (32). With arterial stiffening, profound changes occur in the arterial pressure waveform. Pulse-wave velocity increases, resulting in the reflected wave arriving earlier, thus adding to the central pressure wave to produce an augmented central systolic pressure (33). Central pressure is the major determinant of left ventricular afterload and the subsequent development of left ventricular hypertrophy (33, 34), a strong independent risk factor for cardiovascular disease (35, 36). It is therefore becoming apparent that increased large artery stiffness is an important contributor to the development of cardiovascular disease. The demonstration of vascular stiffening after treatment in our subjects supports the hypothesis that male hypogonadism is associated with an alteration in central arterial hemodynamics that could increase cardiovascular risk. Although a direct effect of LHRH analogs on the vasculature cannot be wholly discounted, it is more likely that a fall in sex hormone concentrations is responsible. Androgen-suppressive therapy induces a state of marked testosterone deficiency. The serum testosterone concentration in all subjects was suppressed to castrate levels within 4 wk of the commencement of treatment. Androgen receptors have been demonstrated within aortic, peripheral vascular, and ventricular mammalian cells (37) and more recently in normal male and female left ventricles (38). In addition, testosterone has direct influences on blood vessel hemodynamics, although the exact mechanisms remain undetermined. In vitro, testosterone induces relaxation of rabbit coronary arteries and aorta through an endothelial-independent mechanism (18). However, testosterone produced dilatation of canine coronaries via a nitric oxide-dependent pathway in vivo (17), and in males with coronary artery disease, high dose testosterone enhanced flow-mediated dilatation of the brachial artery (20), suggesting an endothelium-dependent mechanism. Similarly, in men with established coronary disease, testosterone, administered by intracoronary infusion and at physiological concentrations, dilated coronary arteries and increased blood flow (19). These observations suggest a direct role for testosterone in modulating blood flow and vessel resistance in medium-sized and large arteries. In the present study treatment- induced hypotestosteronemia may therefore have resulted in impaired vasodilatory function of conduit arteries, thus reducing aortic compliance.
We observed significant changes in metabolic and body compositional parameters in our patients after the induction of hypogonadism. Although there were no changes in total body weight, alterations in body composition characterized by a reduction in lean body mass and an increase in fat mass occurred with treatment. In addition, insulin concentrations rose despite unchanged plasma glucose, suggesting reduced insulin sensitivity. These results are in agreement with other studies that have demonstrated a relationship between testosterone and abnormalities of carbohydrate and lipid metabolism (10, 11, 12, 13, 14). In healthy male populations testosterone concentrations are negatively correlated with the degree of central abdominal obesity (12), and in hypogonadal males there is a tendency for increased visceral adiposity and reduced muscle mass that are reversible after androgen replacement (39). The underlying mechanisms responsible for these observations are not well defined. AR are known to be present on visceral adipocytes, and it is likely that testosterone is directly involved in the mobilization of free fatty acids (40). Testosterone deficiency results in reduced lipolysis in visceral adipose tissue (12) and therefore the accumulation of abdominal fat stores. Our finding that increases in fat mass were positively correlated with rising insulin concentrations supports the concept that central abdominal adiposity is closely associated with disturbances in insulin and glucose metabolism in hypogonadal males. This relationship is an established phenomenon in the development of type 2 diabetes (41) and is a strong predictor of cardiovascular risk. The metabolic derangement that developed in our subjects after treatment may have contributed directly to vascular stiffening. Insulin itself, in physiological concentrations, acts as a vascular hormone and is known to be an important regulator of vascular compliance in large arteries (42, 43). In healthy nonobese individuals, physiological concentrations of insulin reduce wave reflection and hence augmentation, leading to a state of diminished vascular stiffness (42). However, in obese insulin-resistant individuals the ability of insulin to reduce aortic wave reflection is severely blunted (42). This phenomenon may therefore have been partly responsible for the arterial stiffening occurring in our hypogonadal patients.
Despite the fact that estrogens are produced in significant quantities
in males, there has been relatively little study of their biological
role in men and specifically their effects on the vasculature. In
addition to inducing testosterone deficiency, both orchidectomy and
LHRH analogs result in a lowering of estrogen (44), which,
in males, is derived predominantly from androgenic precursors of
testicular origin (45). Indeed, in the present study we
observed a substantial fall in serum estradiol concentrations within a
3-month period. The role of estrogen as a vascular hormone in women has
been studied extensively. The beneficial effects of estrogen are
probably mediated partly through favorable quantitative and qualitative
changes in the lipid profile (46). However, estrogen
also has direct effects on vascular endothelium, acting as an
endothelium-dependent vasodilator by enhancing nitric oxide
bioavailability (47, 48). Similarly, estrogen may play a
role in the maintenance of vascular function in males. There is
evidence for a direct effect of estrogen on vascular cells
(49), and ER protein has been identified in vascular
smooth muscle cells in man (50). In a male model of
estrogen deficiency, marked impairment of endothelium-dependent
vasodilatation of the brachial artery has been demonstrated
(51), and in the male ER
knockout mouse, there is
evidence of impaired aortic nitric oxide release (52).
Estrogen deficiency resulting in vascular dysfunction may be important
in the context of males with prostate cancer who are subject to a
combined state of androgen and estrogen deficiency. In the past,
estrogen therapy formed the mainstay of hormonal treatment in prostate
cancer (53). This therapy was strongly associated with the
occurrence of vascular thromboembolic complications resulting from the
high doses used (54) and has since been overshadowed by
the advent of LHRH analogs. However, it is possible that lower doses of
estrogen, in more physiological concentrations, offer cardiovascular
protection. Indeed, recent evidence suggests that low dose estradiol
administration to healthy young males is associated with enhanced
endothelium-dependent vasodilatation (55). Furthermore, a
low dose estrogen regimen used in Finnish men with prostate cancer
resulted in a significant lowering of cardiovascular mortality
(56).
Prostate cancer is one of the leading causes of death in men, but despite this, a substantial proportion of patients with prostate cancer die of other unrelated causes (57). Comorbid conditions are common in this group, but a particularly strong association has been noted between the presence of cardiovascular disease and the eventual cause of death (57). This raises the possibility that prostate cancer itself or the treatment used in some way aggravates the natural course of vascular disease. This study, by demonstrating that hormone manipulation therapy adversely affects vascular function, provides a mechanism that could explain this association. This is an important consideration given that a large number of males in an age group susceptible to atherogenic disease receive this form of therapy.
Acknowledgments
Footnotes
Abbreviation: LHRH, LH-releasing hormone.
Received December 1, 2000.
Accepted May 4, 2001.
References
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P. Szulc, F. Duboeuf, F. Marchand, and P. D Delmas Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study Am. J. Clinical Nutrition, August 1, 2004; 80(2): 496 - 503. [Abstract] [Full Text] [PDF]
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M. R. Smith, M. Goode, A. L. Zietman, F. J. McGovern, H. Lee, and J. S. Finkelstein Bicalutamide Monotherapy Versus Leuprolide Monotherapy for Prostate Cancer: Effects on Bone Mineral Density and Body Composition J. Clin. Oncol., July 1, 2004; 22(13): 2546 - 2553. [Abstract] [Full Text] [PDF]
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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]
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 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]
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 C. Parker and D. Dearnaley Re: All-Cause Mortality in Randomized Trials of Cancer Screening J Natl Cancer Inst, June 5, 2002; 94(11): 861 - 862. [Full Text] [PDF]
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