The Relationship Between Low Testosterone and Cardiovascular Disease

Transcription

1 Testosterone and Cardiovascular Risk in Men Daniel M. Kelly a T. Hugh Jones a, b a Department of Human Metabolism, Medical School, The University of Sheffield, Sheffield, and b Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, UK Abstract Testosterone deficiency is highly prevalent in men with cardiovascular disease (CVD) and is associated with an increased mortality. Low testosterone also has an adverse effect on several cardiovascular risk factors, which include insulin resistance, diabetes, dyslipidaemia, central adiposity and endothelial dysfunction. Male gender is a well-recognised risk factor for premature CVD and mortality. The question of whether or not testosterone deficiency is a contributory factor to atherogenesis or merely a biomarker of ill health arises. Animal studies and experiments on isolated cells indicate that many of the mechanisms intimate to the atherosclerotic process are beneficially modulated by testosterone. Epidemiological studies have shown that men with endogenous testosterone levels in the mid-upper normal range have reduced cardiovascular events and mortality compared to those with low or lower range, and with high range testosterone. Testosterone replacement in men diagnosed with hypogonadism where mid-normal range levels are achieved have shown a beneficial effect on several cardiovascular risk factors, cardiac ischaemia, functional exercise capacity and improved mortality. Yet studies where patients were either undertreated or given high-dose testosterone have been associated with an increased risk of cardiovascular-related events. Clinical monitoring and titration of testosterone dose is therefore of paramount importance S. Karger AG, Basel Epidemiology Although cardiovascular disease (CVD) affects both sexes, more than twice as many men are affected compared to women, establishing male gender as an important risk factor. This relationship persists at all ages and is not explained by differences in the frequency of standard risk factors between men and women, such as smoking, hypertension, diabetes and hypercholesterolemia. For many years, this higher cardiovascular risk in men incited the premise that testosterone is bad for the heart and was supported by case reports of sudden cardiovascular death amongst male athletes abusing anabolic steroids. Currently, however, a large amount of evidence suggests that low

2 levels of testosterone, rather than testosterone per se, are associated with cardiovascular morbidity and mortality, and testosterone deficiency has emerged as an independent cardiovascular risk factor [1]. Testosterone and Coronary Heart Disease A large number of cross-sectional epidemiological studies have been performed assessing testosterone status in men with coronary heart disease (CHD). Over the years, these studies have used different definitions of CHD and also measured various fractions of testosterone. In the majority of cases, testosterone was low in those with CHD, but a significant number did not find any correlation (table 1). Those studies which measured the biologically active components of testosterone (free or bioavailable free + albumin bound) rather than the total testosterone (includes sex hormone binding globulin-bound testosterone which is considered to be inactive) were more likely to report a correlation between low testosterone and presence of CHD. The importance of measuring a biologically active testosterone fraction was confirmed in a coronary angiographic study. This study compared men with >70% stenosis (i.e. flow limiting) of at least one artery with men who had normal angiograms. Men with CHD had significantly lower free and bioavailable testosterone whereas total testosterone approached but did not reach significance. Cardiovascular Events and Mortality The MrOs (Osteoporotic Fractures in Men) study from Sweden is a large communitybased study originally set up to examine the effects of several parameters on fractures. When cardiovascular events were analysed they found that men in the higher quartile of testosterone had less events when compared to those in the lower three quartiles [2]. This study is particularly important as it measured testosterone by mass spectroscopy, which removes several questions in relation to differences and problems with immunoassays and is considered to be more accurate. A recent large (n = 3,650 men >65 years old) French study has identified a J-shaped association between both total and bioavailable testosterone and CVD events, with men in the lowest and highest total testosterone quintiles having an increased risk. In support of this finding, the HIM (Health in Men) study from Western Australia found that men with testosterone levels in the mid range had lower all-cause mortality; however, those with high normal testosterone and independently high dihydrotestosterone (DHT) had reduced CHD deaths [3]. A Japanese study of 171 middle-aged men (30 69 years) with any coronary risk factor without evidence of prior CVD followed for 77 months found those in the lower tertile of testosterone were associated with an increased risk of cardiovascular events. Furthermore, testosterone levels in an acute setting predict clinical outcomes 2 Kelly Jones

3 Table 1. Cross-sectional studies investigating serum testosterone in men with CHD Author, year Patients, n Definition of CHD Androgens measured Androgen levels in CHD cohort Zumoff et al., MI, CAD TT Luria et al., MI TT Labropoulos et al., MI TT Phillips et al., CHD TT Heller et al., CHD TT Medoza et al., MI TT Barth et al., CAD TT Hromadova et al., Coronary findings TT Breier et al., CAD TT Small et al., IHD TT Franzen and Fex, MI TT Aksut et al., MI/angina TT Sewdarsen et al., MI TT/FT / Chute et al., CAD TT/FT / Hamalainen et al., CHD TT/FT / Lichtenstein et al., ,512 IHD TT Swartz and Young, MI TT Sewdarsen et al., MI TT Baumann et al., Atherosclerosis TT Slowinska-Srzednicka et al., MI TT Sewdarsen et al., MI TT/FT / Gray et al., ,709 CAD TT/FT / Cengiz et al., MI, angina TT Hauner et al., CAD TT Rice et al., MI TT/FT / Phillips et al., CAD TT/FT / Hautanen et al., CAD TT Mitchell et al., MI TT/FT / Marques-Vidal et al., MI TT Feldman et al., ,709 Heart disease TT/FT / Zhoa and Li, CAD TT Kabakci et al., CAD TT/FT / Schuler-Luttmann et al., CAD TT/FT / English et al., CAD TT/FT/BT / / Pugh et al., MI TT/BT / BT = Bioavailable testosterone; FT = free testosterone; IHD = ischemic heart disease; MI = myocardial infarction; TT = total testosterone; = no change; = decrease. Full references stated in the table are available in reference [4] and cannot be fully printed in the manuscript due to restriction to number of manuscripts that can be sited. after coronary events as men admitted with acute myocardial infarction demonstrated higher mortality after 30 days when their testosterone was low (table 2) [4]. Several community- and hospital outpatient-based studies have also reported that men with low circulating testosterone are at greater risk of all-cause mortality than those with higher levels. Specifically some studies have shown that those at Testosterone and Cardiovascular Risk 3

4 Table 2. Effect of baseline testosterone on CVD mortality Author, year (study name) Patients, n Population studied Follow-up period CVD mortality HR/OR for TT unless indicated (95% CI) Smith et al., ,512 Population based 16.5 years HR 0.94 ( ) (NS) IHD Khaw et al., 2007 (EPIC-Norfolk) 2,314 Population based 7 years OR quintile 2, 3, 4 vs. 1 CVD 0.89 ( ) 0.60 ( ) 0.53 ( ) CHD 0.71 ( ) 0.59 ( ) 0.52 ( ) Araujo et al., 2007 (MMAS) 1,686 Population based 15.3 years RR FT: 0.80 ( ) p = 0.02 for trend Laughlin et al., 2008 (Rancho Bernardo Study) 794 Population based 11.8 years HR 1.38 ( ) Carrero et al., Haemodialysis 41 months HR 3.19 ( ) Vikan et al., 2009 (Tromsö) 1,568 Population based 11.2 years HR FT: 1.24 ( ) Haring et al., 2010 (SHIP) 1,954 Population based 7.2 years HR 2.56 ( ) Menke et al., 2010 (NHANES III) 1,114 Population based 18 years HR: baseline year 9 FT: 1.53 ( ) TT: NS Year 9 18: NS Corona et al., ,687 Erectile dysfunction 4.3 years HR 7.1 ( ) Malkin et al., CHD (positive angiogram) Haring et al., ,822 Men with CKD, albuminuria, kidney dysfunction Kyriazis et al., Haemodialysis 37 months (median) Lerchbaum et al., ,069 Coronary angiography referrals 6.9 years HR BT: 2.2 ( ) TT: 2.5 ( ) 9.9 years HR 2.01 ( ) HR 2.92 ( ) 7.7 years HR 1.77 ( ) Hyde et al. [3], 2012 (HIM) 4,249 Population based 5.1 years HR 1.71 ( ) EPIC-Norfolk = European Prospective Investigation into Cancer in Norfolk; MMAS = Massachusetts Male Aging Study; SHIP = Study of Health in Pomerania; CKD = chronic kidney disease; TT = total testosterone; BT = bioavailable testosterone; FT = free testosterone; HR = hazard ratio; OR = odds ratio; CI = confidence interval; NS = not significant. Most of the references for the studies in this table are available in reference [5]. 4 Kelly Jones

5 increased mortality are in the lower quartile of testosterone. Some studies were sufficiently powered to identify that the major cause of death was related to CVD. Other causes in a minority of reports found a significantly increased risk of respiratory and/or cancer deaths. A meta-analysis of these studies has confirmed that low testosterone is a biomarker for a future increased risk of all-cause and cardiovascular mortality and that a decrease of 2.18 nmol/l in testosterone was associated with a 35% increased risk of all-cause mortality and a 25% increased risk of cardiovascular mortality [5]. Androgen deprivation therapy (ADT) for prostate cancer is a unique situation where the direct effects of lowering testosterone can be observed. ADT in some studies increases the risk of CHD, incident diabetes and cardiovascular death. A scientific advisory by the American Heart Association, American Urology Association and the American Cancer Society has recommended that especially for men with known CHD all secondary prevention measures should be fully optimised [6]. Cardiovascular Risk Factors The metabolic syndrome (MetS) is a condition characterised by a clustering of commonly associated cardiovascular risk factors strongly related to the future development of CHD, myocardial infarction, stroke and sudden cardiac death. It is defined as the presence of at least three risk factors from central obesity, impaired fasting glucose or glucose tolerance or known type 2 diabetes mellitus (T2DM), hypertension, hypertriglyceridaemia and low high-density lipoprotein (HDL) cholesterol. Insulin resistance is the central biochemical defect common between MetS and T2DM, and promotes the development of many of the risk factors that make up MetS, as well as inducing vascular endothelial dysfunction and a pro-inflammatory milieu. In turn, central obesity contributes to insulin resistance and is also considered an inflammatory condition. Therefore, a negative cycle of metabolic, vascular and inflammatory dysregulation evolves with these risk factors individually and collectively perpetuating the development of atherosclerosis and CVD. The association of testosterone with these cardiovascular risk factors is discussed below. Obesity Obesity is associated with lower levels of total, bioavailable and free testosterone levels in several epidemiological studies using traditional measures such as body mass index (BMI) and waist circumference to assess central obesity. It is important to recognise that central obesity comprises both subcutaneous abdominal fat as well as visceral fat. Low testosterone is associated with increased accumulation of both these fat depots. Indeed, increased percentage body fat is a common clinical feature of hypogonadism, Testosterone and Cardiovascular Risk 5