Bu B. Yeap
a,bIntroduction
Pituitary secretion of luteinizing hormone (LH) stimu-lates testicular production of testosterone, the principal male sex hormone or androgen that circulates bound to sex hormone-binding globulin (SHBG) and albumin, with a small proportion unbound or ‘free’ [1]. Free and albumin-bound testosterone have been regarded as the bioavailable fraction more able to enter cells and bind the androgen receptor; however, this ‘free hormone hypo-thesis’ remains under debate [2,3]. Testosterone can be converted by the intracellular enzyme 5a-reductase into dihydrotestosterone, which is a more potent ligand for the androgen receptor. Alternatively, testosterone can be aromatized to oestradiol, which acts via the oestrogen receptor a and/or oestrogen receptor b to regulate skeletal maturation in men as well as women [4,5]. As men grow older, testosterone levels gradually fall [6–8]. The decline in circulating free testosterone is steeper than that of total testosterone, in part, due to the age-related rise in SHBG [9,10]. As a result, the prevalence of
androgen deficiency increases in older compared with middle-aged men [11,12]. Due to the ageing of popu-lations in various countries across the world, there is an intense interest to determine whether diminishing sex hormone levels represent causal factors for diseases in older men or whether they are simply biomarkers for existing ill-health. If a causal role exists for androgen deficiency with respect to cardiovascular disease (CVD), testosterone supplementation might reduce morbidity, increase longevity and preserve health in ageing men [1,13–16]. Alternatively, if no causal role exists, testos-terone therapy might not reduce cardiovascular events or mortality. This concept currently lacks support from randomized controlled trials of testosterone therapy in middle-aged or older men [17,18]. Although conventional testosterone supplementation elevates circulating testos-terone providing substrate for aromatization, the alterna-tive of aromatase inhibition reduces oestradiol levels to increase LH secretion and hence endogenous testoster-one production in men [19]. If increased estradiol levels were an adverse risk factor for CVD in men, the use of
a
School of Medicine and Pharmacology, University of Western Australia, Perth andb
Department of Endocrinology and Diabetes, Fremantle Hospital, Fremantle, Western Australia, Australia
Correspondence to Professor Bu Beng Yeap, MBBS, PhD, School of Medicine and Pharmacology, Level 2, T Block, Fremantle Hospital, Alma Street, Fremantle, WA 6160, Australia
Tel: +61 8 9431 3229; fax: +61 8 9431 2977; e-mail: byeap@cyllene.uwa.edu.au
Current Opinion in Endocrinology, Diabetes & Obesity2010, 17:269–276
Purpose of review
There is increasing interest in age-related changes in sex hormone levels as a potentially treatable cause of ill-health in men. Relationships between androgens and
cardiovascular disease will be discussed, with particular attention to more recently published research.
Recent findings
In middle-aged and older men, lower testosterone levels are associated with insulin resistance, metabolic syndrome and diabetes, interrelated conditions that predispose to cardiovascular disease. The relationship between androgens and preclinical
atherosclerosis requires confirmation. Nevertheless, lower testosterone levels predict cardiovascular events, such as stroke and transient ischaemic attack, in older men and are associated with higher cardiovascular and overall mortality. Testosterone is aromatized to oestradiol, and both higher and lower oestradiol levels have been associated with cardiovascular risk. Randomized trials have shown that testosterone supplementation in men with existing coronary artery disease can be protective against myocardial ischaemia. However, additional interventional studies are needed with endpoints of cardiovascular events.
Summary
Observational studies continue to relate reduced circulating testosterone to cardiovascular risk, atherosclerosis and mortality in men. The role of oestradiol as a marker for cardiovascular disease requires clarification. Larger randomized trials are needed to establish whether hormonal therapy would reduce the burden of cardiovascular disease in ageing men.
Keywords
cardiovascular disease, male ageing, mortality, testosterone Curr Opin Endocrinol Diabetes Obes 17:269–276
ß2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1752-296X
aromatase inhibitors could be further explored. Thus, understanding the relative contribution of testosterone and oestradiol to cardiovascular risk would inform the design of interventional studies of hormonal therapy in men exploring CVD-related endpoints.
Androgens, insulin resistance, diabetes and
cardiovascular risk
This section discusses the relationship between andro-gens and conditions associated with increased risk of CVD.
Androgens, insulin resistance and diabetes
Central adiposity predisposes to insulin resistance, meta-bolic syndrome and type 2 diabetes, interrelated con-ditions that are associated with an increased risk of CVD [20–23]. Men with metabolic syndrome or type 2 dia-betes have reduced testosterone levels [24–26]. Part of this relationship stems from the underlying association of obesity with both reduced testosterone levels and dia-betes [27,28]. Marked obesity is associated with reduced LH pulse amplitude and insulin resistance reduces tes-ticular responsiveness to LH, both mechanisms contri-buting to an impaired function of the pituitary–gonadal axis [29,30]. Conversely, testosterone therapy increases muscle mass and reduces accumulation of adipose tissue, thus modulating body composition in a metabolically favourable manner, although the magnitude of these changes tends to be limited [17,31,32]. In longitudinal studies [33,34], lower testosterone levels predict an increased incidence of both metabolic syndrome and type 2 diabetes. Thus, the relationship between circulat-ing testosterone and insulin sensitivity is bidirectional, nevertheless, representing a potential therapeutic approach for insulin-resistant men [35]. Of note, insulin resistance is closely related to lower SHBG levels, and reduced SHBG has been associated with adverse out-comes despite the expectation of higher circulating-free testosterone at constant total testosterone [36–38]. Therefore, the interaction of total and free testosterone and SHBG on insulin resistance as a marker of cardio-vascular risk is of interest, particularly as testosterone and SHBG levels diverge during male ageing [15].
Testosterone, sex hormone-binding globulin and insulin resistance in older men
In a recent cross-sectional analysis of 2470 nondiabetic older men, total and free testosterone and SHBG declined progressively with increasing insulin resistance estimated using a homeostatic model, HOMA2-IR [39]. After adjusting for age, BMI, waist circumference, high-density lipoprotein and triglyceride levels, total testos-terone was independently associated with insulin sensi-tivity whereas SHBG was not. This is noteworthy as reduced SHBG had been associated with metabolic
syn-drome in previous reports, including an earlier analysis involving the same cohort [24,40,41]. Thus, in older men, lower testosterone is associated with insulin resistance independently of measures of central obesity, while SHBG possesses limited utility as a marker [39]. The lack of an independent association between SHBG and insulin sensitivity suggests that the age-related rise in SHBG may not be protective against insulin resistance (and by inference, cardiovascular risk) in older men.
Testosterone, estradiol and diabetes
In middle-aged and older men, albumin-bound and free oestradiol levels decline with an increasing age [9,42], reflecting the age-related rise in SHBG. Total oestradiol levels have been reported to decrease [9] or remain stable with an increasing age [43,44]. Despite aromatization of testosterone to oestradiol contributing to its circulating levels, only moderate correlations have been reported between free testosterone with free estradiol (r¼0.20) and total testosterone with total oestradiol (r¼0.17 or 0.45) in men [9,45]. A source of discordance is that adipose tissue provides a major site for aromatization of testosterone; thus, unlike the inverse correlation of BMI with total and free testosterone, BMI and waist circumference are positively associated with total oestra-diol [43]. In keeping with these differences, the meta-analysis by Dinget al.[25] reported reduced testosterone and elevated oestradiol levels in men with diabetes compared with those without. A recent cross-sectional analysis involving 3156 men confirmed inverse associ-ations between impaired fasting glucose and diabetes with total testosterone and SHBG, and a positive corre-lation with oestradiol [46]. Therefore, contrasting associ-ations exist for these two sex hormones with body com-position and diabetes risk.
Androgens, atherosclerosis and
cardiovascular events
This section reviews observational studies that examine the association of androgens with several cardiovascular outcomes.
Androgens and atherosclerosis
Reduced testosterone levels have been associated with increased carotid intima–media thickness (CIMT) in men, a measure of preclinical atherosclerosis (Table 1) [47–51,52,53–57,58,59,60,61,62–67,68,69]. In a prospective study [50] of older men, progression of CIMT was inversely related to free rather than total testosterone level. By contrast, oestradiol levels were positively associated with progression of CIMT in middle-aged men [50,51]. However, the associations of sex hormones with CIMT have become less certain following the publication of results from the Tromso study [52]. This comprised a longitudinal analysis of
1101 men (1994–2001) and a cross-sectional analysis of 2290 men (in 2001). The longitudinal analysis involved men in whom hormone levels and CIMT were ascer-tained at both timepoints. An unexpected result in the
longitudinal analysis, which may reflect the selection of a subset from the original cohort, was that total and free testosterone levels rose between 1994 and 2001 whereas SHBG fell. Although CIMT increased, the proportion of Table 1 Observational studies examining the association between androgens and cardiovascular disease or mortality in middle-aged and older men
Study Size (nof men) Follow-up (years) Age (years) Results
van den Beldet al. [48] 403 X 73–94 Total testosterone inversely related to CIMT. Makinenet al. [49] 239 X 40–70 Androgen-deficient men had higher CIMT.
Mulleret al. [50] 195 4 70 Free testosterone inversely related to progression of CIMT. Total and free oestradiol related to progression of CIMT. Tivestenet al. [51] 313 3.2 58 Total and free oestradiol levels positively associated with
progression of CIMT.
Vikanet al. [52] 1101 7 59.09.3 Inverse association between total testosterone levels and carotid plaque area. No longitudinal association of sex hormone levels and change in plaque area or CIMT.
Dorret al. [53] 1177 X 62.29.4 Higher prevalence of carotid plaques in men with low total testosterone levels (below 10th percentile). No relationship between
testosterone and CIMT.
Haket al. [54] 504 6.5 55 Higher total and bioavailable testosterone (highest vs. lowest tertile) associated with reduced prevalence and less progression of abdominal aortic calcification.
Tivestenet al. [55] 3014 X 69–80 Free testosterone in lowest quartile and free oestradiol in highest quartile independently associated with ankle-brachial index<0.90. Smithet al. [56] 2512 16.5 45–59 482 deaths, 192 fatal and 128 nonfatal IHD events. Higher
cortisol:testosterone ratio associated with IHD deaths and IHD events.
Arnlovet al. [57] 2084 10 5612 386 had first cardiovascular event (including heart failure). Higher total oestradiol at baseline associated with lower incidence of CVD events. Testosterone not associated.
Vikanet al. [58] 1568 13 59.610.2 395 deaths (130 from CVD) and 144 men had first MI. Free testosterone in the lowest quartile (<158 pmol/l) predicted higher overall mortality (HR 1.24), total testosterone not associated. Risk for first-ever MI similar across total or free testosterone levels.
Akishitaet al. [59] 171 6.4 4813 20 CVD events. Men in lowest tertile of total testosterone (<14.2 nmol/l) had higher CVD event risk (HR 4.61).
Abbottet al. [60] 2197 7 71–93 124 had first stroke. Baseline oestradiol in top quintile (125 pmol/l) associated with higher risk, but total testosterone was not associated. Yeapet al. [61] 3443 3.5 70 First stroke or TIA occurred in 119 men. Total and free testosterone
in the lowest quartiles (<11.7 nmol/l and<222 pmol/l, respectively) predicted increased incidence of stroke or TIA (HR 1.99
and 1.69, respectively).
Shoreset al. [62] 858 4.31.8 40 208 deaths. Men with two or more low testosterone levels (total testosterone<8.7 nmol/l or free testosterone<0.03 nmol/l) had higher mortality (HR 1.88).
Khawet al. [63] 825 and 1489 10 40–79 825 deaths, 1489 controls. Total testosterone inversely related to mortality from all causes, CVD and cancer. A 6 nmol/l (1 SD) increase in total testosterone level was associated with an odds ratio for mortality of 0.81.
Laughlinet al. [64] 794 11.8 50–91 538 deaths. Total testosterone in the lowest quartile (<8.4 nmol/l) predicted increased mortality from all causes (HR 1.44) and from CVD and respiratory causes.
Lehtonenet al. [65] 187 10 71–72 68 deaths. Testosterone inversely associated with mortality. Araujoet al. [66] 1686 15.34.0 40–70 395 deaths. Higher free testosterone associated with higher IHD
mortality. Relative risk of death from IHD per 1 SD lower free testosterone was 0.80.
Maggioet al. [67] 410 6 65 126 deaths. Combination of bioavailable testosterone, insulin-like growth factor-I and dehydroepiandrosterone sulphate in lowest quartiles associated with higher mortality.
Tivestenet al. [68] 3014 4.5 75 383 deaths. Testosterone and oestradiol levels in the lowest quartiles predicted mortality (HR 1.46 and 1.33, respectively). Risk of death nearly doubled (HR 1.96) in men with low levels of both testosterone and oestradiol.
Ponikowskaet al. [69] 153 4 659 Men with type 2 diabetes and stable coronary artery disease. Low total testosterone (10th percentile of healthy peers) predicted cardiovascular mortality (HR 2.39).
CIMT, carotid intima–media thickness; CVD, cardiovascular disease; HR, hazard ratio; IHD, ischaemic heart disease; MI, myocardial infarction; SD, standard deviation; TIA, transient ischaemic attack; X, cross-sectional analysis.
men using lipid-lowering therapies increased and cholesterol levels fell. In the longitudinal analysis, there was no difference in plaque growth or increase in CIMT in men according to the baseline levels of testosterone or SHBG [52]. In the cross-sectional analysis, total testosterone was inversely associated with plaque area but not with CIMT after adjustment for covariates. This study prompted a cross-sectional analysis of 1177 men from the Pomerania study that confirmed higher preva-lence of carotid plaques in men with low testosterone levels with no relationship between testosterone and CIMT [53]. The cross-sectional associations of reduced testosterone and carotid plaque are consistent with previous studies reporting lower risk of abdominal aortic calcification and peripheral arterial disease (ankle: brachial index <0.90) in middle-aged and older men with higher testosterone levels [54,55]. In the latter study [55], higher oestradiol levels were also associated with a lower extremity of peripheral arterial disease. Cross-sectional analyses are unable to clarify direction of causation; nevertheless, the Tromso and Pomerania studies do not support a causal role for testosterone deficiency in the progression of preclinical atherosclero-sis estimated via CIMT.
Androgens and cardiovascular events
In this section, longitudinal cohort studies that examine the effect of sex hormones on the combined endpoint of nonfatal and fatal cardiovascular events will be reviewed. Previously, in large prospective cohort studies [56,57], baseline testosterone levels had not been associated with incidence of cardiovascular events (Table 1). In the Caerphilly study [56] involving 2512 men aged 45–59 years with a mean follow-up of 16.5 years, there were 320 fatal and nonfatal ischaemic heart disease events. The ratio of cortisol to testosterone was associated with incident ischaemic heart disease, but this was atte-nuated after adjustment for covariates, while testosterone itself was not associated. In the Framingham study [57] of 2084 middle-aged men without CVD at baseline, 386 men experienced a first CVD event during 10 years of follow-up. Higher oestradiol levels were associated with lower risk of cardiovascular events in older men (median age >56 years), with a hazard ratio of 0.86 [95% confi-dence interval (CI) 0.78–0.96,P¼0.005] per 1 SD incre-ment in log oestradiol. Of note, testosterone level was not significantly associated with incident CVD [57]. Results from the Tromso study have recently been published [58]. In this analysis of 1568 men aged (meanSD) 59.610.2 years followed for up to 13 years, there were 130 deaths from CVD and 144 men experienced a first-ever myocardial infarction (MI). Total and free testos-terone and estradiol levels were not associated with occurrence of first-ever MI [58]. In a small Japanese study [59] of 171 men aged 4813 years with risk factors for coronary disease, 20 cardiovascular events occurred
during a median of 4.5 years follow-up. Men with total testosterone levels in the lowest tertile (<14.2 nmol/l) had a four-fold higher risk of experiencing a cardiovas-cular event after adjustment for cardiovascardiovas-cular risk factors and medications use, while oestradiol was not associated. Therefore, more definitive studies are needed to estab-lish the role of circulating testosterone and oestradiol as predictors of coronary disease-related morbidity in middle-aged and older men.
Androgens and cerebrovascular events
The above studies have focussed on ischaemic heart disease or coronary events [56], or have used a broader composite endpoint in which these comprise the major proportion of CVD-related events with a smaller contri-bution from cerebrovascular disease [57,59]. There are studies utilizing stroke alone or in combination with transient ischaemic attack (TIA) to examine sex hormone influences on cerebrovascular disease as a distinct mani-festation of cardiovascular risk (Table 1). In the Hono-lulu-Asia Aging Study [60] of 2197 men with Japanese ancestry aged 71–93 years followed up to 7 years, 124 strokes occurred. Men in the top quintile of serum oestradiol (125 pmol/l) experienced a higher risk of stroke compared with those whose oestradiol levels were lower (hazard ratio 2.2, 95% CI 1.5–3.4, P<0.001). Stroke risk did not vary significantly across lowest to highest quintiles of total testosterone [60]. However, a longitudinal analysis from the Health In Men Study [61] reported contrasting results. In this population-based West Australian cohort, there were 3443 com-munity-dwelling men aged at least 70 years with no history of stroke who were followed prospectively for a median of 3.5 years. A first stroke or TIA occurred in 119 men. After adjustment, including age, waist–hip ratio, waist circumference, smoking, hypertension, dyslipidae-mia and medical comorbidity, total testosterone in the lowest quartile (<11.7 nmol/l) predicted increased inci-dence of stroke or TIA (hazard ratio 1.99, 95% CI 1.33– 2.99,P¼0.001). Free testosterone in the lowest quartile (<222 pmol/l) was also associated with incident stroke or TIA (hazard ratio 1.69, 95% CI 1.15–2.48, P¼0.008), whereas SHBG and LH were not independently associ-ated with them [61]. Therefore, these findings support the hypothesis that reduced circulating androgens are independently associated with higher incidence of clinically significant CVD-related events during male ageing.
Androgens and mortality
In a study [62] of 858 male veterans aged at least 40 years identified from a clinical database and followed for a mean of 4.3 years, those with two or more low testoster-one levels (total testostertestoster-one <8.7 nmol/l or free testo-sterone <0.03 nmol/l) had a higher mortality (adjusted hazard ratio 1.88, 95% CI 1.34–2.63,P<0.001) (Table 1).
A nested case–control study [63] from the European
Prospective Investigation into Cancer in Norfolk
(EPIC-Norfolk) compared 825 men aged 40–79 years at baseline who subsequently died with 1489 men still alive matched for age and date of baseline visit. Higher baseline endogenous testosterone levels were inversely related to all-cause cardiovascular and cancer mortality. A 6 nmol/l (1 SD) increase in total testosterone level was associated with an odds ratio of 0.81 for mortality (95% CI 0.71–0.92,P<0.01). In the Rancho Bernardo study [64] of 794 men aged 50–91 years followed for an average of 11.8 years, there were 538 deaths. Men with total tes-tosterone in the lowest quartile (<8.4 nmol/l) had an adjusted hazard ratio of 1.44 for dying (95% CI 1.12– 1.84) relative to those in the highest. Low total testos-terone predicted overall mortality and mortality from cardiovascular and respiratory causes (hazard ratios 1.38 and 2.29, respectively) [64]. In a smaller cohort of 187 men aged 71–72 years followed for 10 years, testosterone at baseline was inversely associated with mortality [65]. However, there are inconsistent reports. An analysis from the Massachusetts Male Aging Study [66] of 1709 men aged 40–70 years with 395 deaths during 15.3 years of follow-up found that higher free testosterone levels were associated with an increased ischaemic heart disease mortality. The relative risk of death from ischaemic heart disease per 1 SD lower free testosterone was 0.80 (95% CI 0.64–0.99). The aging in the Chianti area (InCHIANTI) study [67] of 410 men aged at least 65 years reported 126 deaths during a 6-year follow-up. The combination of lower testosterone, insulin-like growth factor-I and dehy-droepiandrosterone sulphate levels predicted higher mortality, rather than testosterone alone. An important recent evidence comes from the population-based Swedish Osteoporotic Fractures in Men (MrOS) cohort of 3014 men aged 69–80 years [68]. During 4.5 years of follow-up, 383 deaths occurred. In the multivariate model, total testosterone and total oestradiol in the lowest quar-tiles (11.7 nmol/l and59 pmol/l, respectively) predicted mortality (hazard ratios 1.46 and 1.33, respectively, and 95% CI 1.11–1.92 and 1.02–1.73, respectively) [68].
Total testosterone and oestradiol were correlated
(r¼0.54), and the risk of death was highest in men with both testosterone and oestradiol in the lowest quartiles (hazard ratio 1.96, 95% CI 1.46–2.62). In a small study [69] restricted to 153 men aged 659 years with type 2 diabetes and stable coronary artery disease, low total testosterone (10th percentile of healthy peers) predicted cardiovascular mortality (hazard ratio 2.39, 95% CI 1.24– 4.61,P¼0.009). Therefore, several longitudinal studies in community-dwelling middle-aged and older men have found that lower testosterone levels predict increased mortality from causes including CVD. However, there are inconsistent reports from comparable cohorts. Recent findings from the MrOS cohort suggest that lower oestra-diol levels also predict higher mortality in older men.
Trials of testosterone therapy with
cardiovascular-related endpoints
This section reviews interventional studies of testoster-one with endpoints relevant to CVD.
Androgens and cardiovascular risk factors
Previously reported clinical trials of testosterone therapy have generally not been designed or powered to detect effects on actual cardiovascular events [1,13,14,17,18, 70,71]. In a meta-analysis of 29 randomized controlled trials involving 1083 men aged 50–78 years with mean serum testosterone of 10.9 nmol/l, 625 were randomized to testosterone, 427 to placebo and 31 were observed [17]. Testosterone treatment reduced total body fat (1.6 kg or 6.2%), increased fat-free mass (þ1.6 kg or þ2.7%) and reduced total cholesterol (TC) (0.23 mmol/l) but not low-density lipoprotein (LDL) cholesterol. Endogen-ous testosterone levels correlate with high-density lipo-protein (HDL) cholesterol [1,13,72]; however, testoster-one therapy reduced HDL levels (0.085 mmol/l) in men with higher baseline testosterone. Another meta-analysis included 30 trials involving 1642 men of whom 808 were treated with testosterone [18]. Testosterone reduced TC levels (0.41 mmol/l) in men with low–normal or normal testosterone levels; however, treatment-related changes in other lipid fractions were not statistically significant. There were marginal changes in lipid levels, blood pres-sure and glycaemic indices. In a study of 24 hypogonadal men aged more than 30 years with type 2 diabetes, intramuscular testosterone 200 mg every fortnight over 3 months reduced insulin resistance (HOMA index,
1.73), fasting glucose concentration (1.58 mmol/l) and glycated haemoglobin (Hb) (0.37%) [73]. Waist circumference was reduced (1.6 cm) and TC decreased (0.4 mmol/l). However, in a study [74] of 55 men aged 64–73 years, 2 years’ treatment with transdermal testos-terone patches (5 mg/day) did not alter glucose or C-peptide concentrations, or change measures of glucose disposal. In a recent study [75] of 32 men with newly diagnosed type 2 diabetes and metabolic syndrome who had total testosterone of less than 12 nmol/l, addition of testosterone gel (50 mg/day) to diet and exercise over 52 weeks resulted in further improvement in glucose and lipid profiles compared with diet and exercise alone. At the end of the study, more of the testosterone-treated men no longer met the criteria for metabolic syndrome (81.3 vs. 31.3%). These studies support a beneficial meta-bolic effect of testosterone supplementation, particularly in men with lower testosterone levels and type 2 diabetes.
Androgens and arterial reactivity
Endothelial dysfunction is another measure of cardio-vascular risk which is assessed using measures of arterial reactivity [76]. In a sample of 206 men aged 68.1
13.7 years from the Baltimore Longitudinal Study of Aging [77], low testosterone level was an independent predictor
of common carotid arterial stiffness index. This finding contrasted with an early study [78] involving nine hypogo-nadal men aged 354 years, in whom subcutaneous depot testosterone therapy increased testosterone and oestradiol levels, but reduced flow-mediated dilatation of the brachial artery, consistent with impairment of endothelial function. Previous studies [14,16] have reported beneficial actions of testosterone on vascular reactivity including flow-mediated dilatation.Thishasbeensupportedbymorerecentfindings. In men aged 579 years with coronary heart disease and low–normal total testosterone levels (12 nmol/l), oral testosterone undecanoate therapy was associated with a beneficial effect, reducing indices of radial and aortic arterial stiffness [79]. Furthermore, in a study [80] of 18 hypogonadal men aged 62.58.3 years compared with 12 age-matched and weight-matched eugonadal controls, testosterone therapy raised testosterone levels and improved arterial stiffness assessed by pulse wave velocity measured between the common carotid and radial arteries. Therefore, in older men, testosterone appears to exert beneficial effects on arterial function. Larger interventional studies using standardized assessments of arterial function would help to confirm these findings.
Androgens and myocardial ischaemia
From the safety perspective, reported clinical trials have not shown any adverse increase in cardiovascular events, with testosterone therapy aiming to restore circulating hormones to levels seen in younger or middle-aged men [1,13,14]. Several previous studies [13,14,16] have reported beneficial actions of exogenous testosterone on coronary blood flow and exercise-induced myocardial ischaemia. The study by Webbet al.[79] found that oral testosterone undecanoate increased myocardial perfusion through unobstructed coronary arteries, but not global myocardial perfusion. There have been two recent reports that add to the existing literature. In a randomized trial involving 13 men aged 64.87.0 years with angina and total testosterone of 9.92.2 nmol/l, treatment with depot intramuscular testosterone undecanoate over 12 months increased testosterone levels, exercise capacity and time to ST segment depression during treadmill testing [81]. In a randomized trial of 87 men aged 747 years with diabetes and coronary artery disease, oral testosterone undecanoate for 12 weeks reduced the number of anginal attacks by 34% (P<0.05) [82]. Therefore, evidence continues to accu-mulate in support of testosterone being protective against myocardial ischaemia, particularly in men with low–nor-mal testosterone levels and those with diabetes or existing CVD. These tend to be smaller studies using surrogate or intermediate endpoints such as ECG changes or angina frequency rather than major cardiovascular events.
Conclusion
Observational studies highlight the association of reduced circulating testosterone with insulin resistance, metabolic
syndrome and type 2 diabetes. Lower testosterone levels are associated with carotid and aortic atheroma and lower limb arterial disease in cross-sectional studies, with limited longitudinal data associating reduced androgens with pro-gression of CIMT and incidence of coronary events. In the Health In Men Study, serum total testosterone in the lowest quartile of values (<11.7 nmol/l) predicted incidence of stroke or TIA in older men, and lower testosterone levels have been associated with higher overall and cardiovascular mortality in other prospective studies. Higher oestradiol levels are associated with diabetes and CIMT, but men with higher oestradiol levels had a lower risk of cardiovascular events in one study but a higher risk of stroke in another. In the Swedish MrOS study, both testosterone and oestra-diol in the lowest quartile of values (11.7 nmol/l and
59 pmol/l, respectively) predicted mortality, and men with both lower testosterone and lower oestradiol levels were at the highest risk. Clinical trials of testosterone supplementation in men have not shown any excess of adverse cardiovascular events, and small-scale interven-tional studies have shown beneficial actions of testosterone on arterial reactivity, myocardial perfusion and angina frequency.
Larger randomized controlled trials of testosterone supplementation with endpoints of cardiovascular events are needed to determine whether hormonal therapy would reduce CVD-related morbidity or mortality in ageing men. Recruitment into such studies could be offered to men with low–normal testosterone levels and men with metabolic syndrome or diabetes. Both the safety and efficacy of hormonal interventions need to be evaluated, and such studies should not displace accepted treatment of known cardiovascular risk factors. Before aromatase inhibition could be considered as an alternative means of raising testosterone levels in men, the role of circulating oestradiol to modulate cardiovas-cular risk would need to be fully explored and potential negative effects on bone considered [83]. In the mean-time, ageing men can always be reminded that greater engagement in healthy lifestyle behaviours is associated with higher subsequent total testosterone levels [84].
Acknowledgement
B.B.Y. has received a Clinical Investigator Award from the Sylvia and Charles Viertel Charitable Foundation, New South Wales, Australia, research support from the National Health and Medical Research Council of Australia and the Fremantle Hospital Medical Research Foundation and a speaker’s honorarium from Bayer Healthcare.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 308–309).
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59
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75
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80
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81
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A randomized trial of oral testosterone undecanoate for 12 weeks in 87 men aged 747 years with coronary artery disease. Compared with placebo, testosterone reduced the number of angina attacks per week by 34%, silent ischaemic episodes by 26% and total ischaemic burden on ambulatory ECG monitoring by 21%.
83 Burnett-Bowie S-A, McKay EA, Lee H, Leder BZ. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab 2009; 94:4785 –4792. 84 Yeap BB, Almeida OP, Hyde Z,et al. Healthier lifestyle predicts higher
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