Abstract
Background. Studies on the relationship between testosterone concentrations and blood pressure have yielded inconsistent results. Therefore, this study investigated the prospective association of total testosterone (TT) concentrations with risk of incident hypertension and blood pressure change in 1484 men aged 20–79 years.
Methods. Data from the population-based Study of Health in Pomerania, Germany, were used. Serum TT concentrations, measured by chemiluminescent enzyme immunoassays, were categorised into age-specific quartiles. Generalised Estimating Equation (GEE) models, adjusted for age, waist circumference, physical activity, smoking and alcohol consumption were specified.
Results. During a median follow-up time of 5.0 years, the prevalence of hypertension increased from 50.6% to 57.1%. TT concentrations were significantly lower in men with baseline and incident hypertension. Analyses revealed that men with baseline TT concentrations in the lowest quartile had an increased risk of incident hypertension (odds ratio (OR), 1.19 (95% CI, 1.10–1.28)) compared to men with higher TT concentrations. Furthermore, we found a significant inverse association of TT concentrations and blood pressure, showing that men with baseline TT concentrations in the lowest quartile showed the slightest change in systolic blood pressure (−6.01 mmHg), diastolic blood pressure (−2.11 mmHg) and pulse pressure (−3.98 mmHg). Sensitivity analyses in a subpopulation of men without antihypertensive medication confirmed these findings.
Conclusion. These results show that low male TT concentrations are predictive of hypertension, suggesting TT as a potential biomarker of increased cardiovascular risk.
Introduction
Elevated blood pressure and hypertension are major risk factors for cardiovascular diseases (CVD) [Citation1], including arteriosclerosis, stroke and myocardial infarction [Citation2,Citation3]. Furthermore, hypertension is a major contributor in half of all cardiovascular deaths [Citation4,Citation5], especially among men [Citation6]. A decline in male total testosterone (TT) concentrations with increasing age is well established [Citation7], and low TT concentrations have been associated with a less favourable cardiovascular risk profile, including obesity [Citation8], unfavourable lipid profiles [Citation9] and increased risk of incident metabolic syndrome (MetS) [Citation10].
Previous results from case–control and cross-sectional studies suggesting an inverse association between TT, hypertension and blood pressure have been comprehensively reviewed [Citation11]. In addition, TT concentrations have been found to be inversely associated with pulse pressure (PP) [Citation12,Citation13]. Results from interventional studies have demonstrated beneficial effects of testosterone supplementation on blood pressure [Citation14,Citation15]. Previous prospective studies showed conflicting results, partly confirming the suggested inverse relationship between TT, hypertension and blood pressure [Citation16–19], and partly reporting no association [Citation20,Citation21].
In the Caerphilly [Citation19] and Rancho Bernardo studies [Citation16], an inverse association between TT concentrations and blood pressure was found among middle-aged men. By contrast, a small study of former participants in the Multiple Risk Factor Intervention Trial (MRFIT) [Citation21] and a nested case–control study [Citation20] found no association between TT and blood pressure. These inconsistencies may relate to differences in study design, study sample, characteristics of the study population or methodologies used.
Therefore, the present study aimed to investigate the prospective association between TT concentrations, hypertension and blood pressure in a large population-based sample of 1484 men aged 20–79 with completed 5-year follow-up.
Methods
Study population
Data from the Study of Health in Pomerania (SHIP), a population-based cohort study in north-eastern Germany, were used. Details of the study design, recruitment and procedures have been published previously [Citation22]. In brief, a two-stage stratified cluster sample of adults aged 20–79 years was drawn from the total population of West Pomerania, comprising 213,057 inhabitants in 1996. The net sample (without migrated or deceased persons) comprised 6265 eligible subjects. Only individuals with German citizenship and main residency in the study area were included. All subjects received a maximum of three written invitations. In cases of non-response, letters were followed by several phone calls or by home visits if contact by phone was not possible. Finally, after written informed consent was obtained from each participant, 4308 participants were examined (response rate, 68.7%) in two examination centres (Greifswald and Stralsund) between 1997 and 2001. The study protocol is consistent with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the University of Greifswald. From 2117 male baseline participants, 1589 were re-examined after 5 years between 2002 and 2006. Complete blood pressure readings were available in 1583 men. We excluded 82 men with missing TT data. Furthermore, 17 men were excluded for taking sex steroids (anatomic–therapeutic–chemical (ATC) code G03, n = 3), testosterone 5α-reductase inhibitors (ATC code G04CB, n = 9) or sex steroid antagonists (ATC code L02B, n = 5) at either or both of the two examinations. The final study population comprised 1484 men.
Measures
Socio-demographic and behavioural characteristics, as well as information about antihypertensive drug use, were assessed by computer-assisted personal interviews. Men who participated in physical training for at least 1 h a week were classified as being physically active. Mean daily alcohol consumption was calculated using beverage-specific pure ethanol volume proportions [Citation23]. Smoking habits were assessed by dividing men into categories of current, former and never-smokers. Waist circumference (WC) was measured to the nearest 0.1 cm using an inelastic tape midway between the lower rib margin and the iliac crest in the horizontal plane, with the subject standing comfortably with weight distributed evenly on both feet. After a resting period of at least 5 min, systolic (SBP) and diastolic blood pressure (DBP) were measured three times on the right arm of seated subjects by use of an oscillometric digital blood pressure monitor (HEM-705CP, Omron Corporation, Tokyo, Japan). The interval between the readings was 3 min. The mean of the second and third measurements was calculated and used for the present analyses. Hypertension was defined as SBP or DBP of ≥140 mmHg or ≥90 mmHg, respectively, or use of antihypertensive medication (ATC codes C02, C03, C04, C07, C08, C09) [Citation24,Citation25]. PP was defined as the difference between mean systolic and diastolic pressures.
Non-fasting blood samples were taken from the cubital vein in the supine position and were prepared for immediate analysis or stored at −80°C for further analysis. TT concentrations were measured from frozen serum aliquots using competitive chemiluminescent enzyme immunoassays on an Immulite 2500 analyser (Siemens Healthcare Medical Diagnostics, Bad Nauheim, Germany) [Citation26]. All assays were performed according to the manufacturers' recommendations by skilled technical personnel. Baseline TT measurements were carried out from December 2005 to January 2006. An aliquot of two alternating levels of a third party commercial control material (Bio-Rad Lyphochek Immunoassay Plus Control, lot 40151 and lot 40152; Bio-Rad, Munich, Germany) was included in each series in single determination. The inter-assay coefficient of variation was 13.2% with a systematic deviation of + 2.3% at the 3.2 nmol/l level, and 8.9% with a systematic deviation of + 0.24% at the 22.5 nmol/l level. Follow-up TT measurements were carried out from April 2008 to May 2008. An aliquot of three levels of the manufacturer's control material (Immunoassay Control, ref. CON6, lot 021, Siemens Healthcare Medical Diagnostics, Bad Nauheim, Germany) was included within each series in single determination. The inter-assay coefficient of variation was 14.3% with a systematic deviation of −8.8% at the 4.1 nmol/l level, 10.5% with a systematic deviation of −4.4% at the 12.1 nmol/l level and 13.6 with a systematic deviation of −8.5% at the 29.4 nmol/l level.
Statistical analysis
Categorical data are given as percentages, continuous data are given as mean (SD). To assess the association of baseline TT concentrations and risk of incident hypertension and changes in blood pressure variables, the generalised estimating equation (GEE) methodology with an exchangeable correlation matrix and robust standard errors was used [Citation27]. Categorical (hypertension) and continuous (SBP, DBP and PP) outcomes and the predictor variable (TT) were modelled with appropriate binomial or Gaussian distribution and logit or identity link functions, respectively. To analyse the risk of incident hypertension, the sample was limited to men without prevalent hypertension at baseline. Covariates adjusted for in the analyses included age, WC, physical activity, smoking and alcohol consumption. TT concentrations were categorised into the age-specific (by decades) quartiles of its distribution. To adjust for possible bias introduced by drop out, inverse probability weighting was used. We also considered adjustment for differences in the length of follow-up time by including the log of the length of follow-up in each of the longitudinal regression models. To assess the potential impact of antihypertensive medication, we conducted sensitivity analyses in a subpopulation without any medication. In addition, we stratified the study sample by blood sampling time (<11 a.m. vs. ≥11 a.m.) to assess the effect of diurnal variation on the estimates. p values <0.05 were considered statistically significant. All analyses were performed with Stata 10.0 (Stata Corp., College Station, TX).
Results
The median follow-up time was 5.0 years (15,284 person-years). Mean baseline SBP and DBP were at high-normal levels (142.2 mmHg and 86.4 mmHg, respectively) in these 1484 men with mean age 50.7 years. Comparing the characteristics of the study cohort by prevalent baseline hypertension and incident follow-up hypertension, we found significantly lower TT concentrations in hypertensive men than in non-hypertensive men at both baseline and follow-up examinations (). While mean levels of SBP, DBP and PP were significantly higher in hypertensive men at baseline, follow-up SBP and DBP were similar or even lower for men with incident hypertension compared to those without (). This finding is consistent with the increased use of antihypertensive medication, which rose from 30.3% at baseline to 43.3% at follow-up. Furthermore, men with prevalent baseline hypertension were significantly older, physically less active and had a higher WC than men without prevalent baseline hypertension ().
Table I. Characteristics of cohort of 1484 men.
GEE analyses revealed that men with baseline TT concentrations in the lowest quartile had an increased risk of incident hypertension (OR, 1.19 (95% CI, 1.10–1.28)) compared to men with TT concentrations in the highest quartile. This finding was independent of age, WC, physical activity, smoking and alcohol consumption (). Furthermore, we found a significant inverse association between TT and SBP, DBP and PP change ().
Table II. Association of baseline total testosterone concentrations (in quartiles) with change in blood pressure variables from GEE analyses.
In age-adjusted models, men with low baseline TT concentrations showed the smallest decrease in blood pressure over the study period (−5.52, −2.10, −3.43 mmHg in SBP, DBP and PP, respectively, for the lowest quartile), compared to men with TT concentrations in the highest quartile. Men with higher baseline TT concentrations showed a stronger decrease in blood pressure (−6.33, −3.08, −3.25 mmHg decrease in SBP, DBP and PP, respectively, for the second quartile; −8.30, −3.80, −4.50 mmHg decrease in SBP, DBP and PP, respectively, for the third quartile). Additional adjustment for WC, physical activity, smoking and alcohol consumption increased the overall estimates only slightly (). The revealed inverse association is depicted by negatively sloped linear fit lines for mean concentrations of baseline and follow-up TT over blood pressure ().
Figure 1. Influence of total testosterone concentrations on systolic blood pressure, diastolic blood pressure and pulse pressure. Scatterplot for the mean of baseline and follow-up values with linear fit line (solid lines), 95% confidence interval (grey) and locally weighted scatterplot smoothing [lowess] (dashed lines). The p-values from bivariate ordinary least-square linear regression models were <0.001 for systolic blood pressure, diastolic blood pressure and pulse pressure.
![Figure 1. Influence of total testosterone concentrations on systolic blood pressure, diastolic blood pressure and pulse pressure. Scatterplot for the mean of baseline and follow-up values with linear fit line (solid lines), 95% confidence interval (grey) and locally weighted scatterplot smoothing [lowess] (dashed lines). The p-values from bivariate ordinary least-square linear regression models were <0.001 for systolic blood pressure, diastolic blood pressure and pulse pressure.](/cms/asset/228b9d0b-9ad1-4c58-8b78-d3f609fc640b/itam_a_529194_f0001_b.gif)
Subgroup analyses in 789 men without antihypertensive medication yielded slightly decreased estimates, with statistical significance maintained (). Sensitivity analyses with sample stratified by blood sampling time confirmed the revealed inverse association of TT concentrations with incident hypertension and blood pressure, although the estimates were slightly decreased in men with blood sampled before 11 a.m. and slightly increased in men with blood sampled after 11 a.m. ().
Discussion
In the present study, we detected an increased risk of incident hypertension in men with low TT concentrations, independent of major confounders including age, WC, physical activity, smoking and alcohol consumption. Furthermore, we found a prospective inverse association between TT concentrations and changes in SBP, DPB and PP.
Several previous cross-sectional studies investigated the association between low TT concentrations and hypertension. For example, the Tromso study [Citation28], conducted in 1548 men aged 25–84 years, and the Rancho Bernardo study [Citation29], conducted in 1132 men aged 30–79 years, reported lower TT concentrations in men with hypertension (although the latter study [Citation29] used higher threshold levels for the definition of hypertension). Since cross-sectional studies are limited in their ability to assess causality, no direction of the association can be inferred from these studies, distinguishing between the effects of TT concentrations on hypertension versus the effects of hypertension on TT.
Most prospective evidence on the relationship between TT concentrations and blood pressure is based on studies with disease endpoint data [Citation16,Citation19]. A prospective study of 794 men, aged 50–91 years and followed-up for 11.8 years, reported 8% lower TT concentrations in men with hypertension [Citation17]. By contrast, the population-based observational Boston Area Community Health (BACH) survey [Citation30], conducted in 1885 men aged 30–79 years, reported no association of TT and hypertension after adjustment for body mass index.
Previous results from prospective studies examining the association of TT concentrations and blood pressure have been similarly conflicting. In a 5-year follow-up, the Caerphilly study found a negative correlation between testosterone and blood pressure in 2512 middle-aged men [Citation19]. Also, a 12-year follow-up of the Rancho Bernardo study in 1009 men aged 40–79 years found a negative association between TT and blood pressure [Citation16]. By contrast, however, a 13-year follow-up conducted in middle-aged men who were former participants of the MRFIT study [Citation21] and the European Prospective Investigation Into Cancer In Norfolk (EPIC) study found no association between TT and blood pressure [Citation20].
We detected a prospective inverse association between TT concentrations, hypertension and blood pressure in a large population-based sample of 1484 men aged 20–79 years. During the 5-year follow-up, the prevalence of hypertension generally increased among the studied men, whereas overall mean levels of SBP, DBP and PP significantly decreased. This finding is consistent with previous studies [Citation31,Citation32] and reflects the general increase in antihypertensive treatment in our study, from 30.3% at baseline to 43.3% at follow-up. Furthermore, subjects from the SHIP study region were shown to have one of the highest prevalences of hypertension seen among populations within Germany [Citation33]. As some previous studies [Citation34,Citation35] have suggested that antihypertensive medication may lower sex steroid concentrations, we performed sensitivity analyses in a subsample of men without antihypertensive medication. Under these conditions, we still detected an inverse association of TT concentration with blood pressure, although the estimates were less pronounced. The sensitivity analyses we conducted also showed that the risk of incident hypertension appeared to be related to the inclusion of antihypertensive medication in the definition of incident hypertension. This finding emphasises the need to properly consider antihypertensive medication in the definition of hypertension.
The specific mechanisms underlying the association between TT and blood pressure are still a subject of debate [Citation36,Citation37]. Several studies [Citation38,Citation39] have demonstrated the vasodilating effects of testosterone or 5α-dihydrotestosterone on vascular and non-vascular smooth muscle. These effects are probably mediated via inhibition of l-type calcium channels [Citation40,Citation41]. Furthermore, sex steroid receptors have been identified in various cell types, including endothelial and vascular smooth muscle cells [Citation38]. In addition, replacement trails [Citation14,Citation15] reported beneficial effects of TT on blood pressure during treatment. Whether testosterone affects blood pressure directly through its effects on the vascular endothelium, or indirectly through its association with CVD risk factors [Citation42], is currently not well understood [Citation43].
This study has several strengths. These strengths include a representative population-based sample of men from a defined geographic area, assessment of potentially influential medication in the investigated association and the longitudinal study design. But some potential limitations should also be considered. In a large scale population-based study like SHIP, participants were examined at different time points during the day, and blood sampling was done whenever the participants attended. Therefore, TT concentrations are based on a single serum sample, drawn between 8 a.m. and 4 p.m. As TT concentrations show a diurnal variation with a decline in the afternoon [Citation44], we performed sensitivity analyses using stratification of the study sample by blood sampling time (before and after 11 a.m.). Although statistical significance was maintained in these analyses, we did find differences between both groups, which may point to an intra-individual variance in single point TT measurements. However, there are previous investigations that also employ a single point TT measurement [Citation17,Citation20], and these measurements have usually been considered to reflect fairly reliably the annual mean androgen level in healthy middle-aged and elderly men [Citation45]. Further limitations of our study may arise from the lack of data about free testosterone, sex hormone-binding globulin, estrogen or albumin for calculation of bioavailable testosterone.
Perspectives
Our study provides new insights into the impact of male TT concentrations on hypertension and blood pressure and therefore on men's health. As the exact mechanisms by which TT concentrations are associated with hypertension and blood pressure are currently unknown [Citation46], we consider TT as a risk marker, rather than a risk factor. Risk markers are not assumed to play a direct causal role, but may be useful to predict risk. Further conclusions concerning causality and pathogenesis may be inferred from long-term, double-blind, randomised and placebo-controlled trials of testosterone replacement in men with well-documented testosterone insufficiency.
Supplementary Material
Download MP3 Audio (3.3 MB)Acknowledgements
The work is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research, the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects which are sharing data from the population-based Study of Health in Pomerania (SHIP; http://www.community-medicine. de ). The testosterone reagents used were sponsored by Siemens Healthcare Diagnostics, Eschborn, formerly DPC Biermann GmbH, Bad Nauheim, Germany. Novo Nordisk provided partial grant support for the determination of plasma samples and data analysis.
References
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206–1252.
- Nielsen WB, Vestbo J, Jensen GB. Isolated systolic hypertension as a major risk factor for stroke and myocardial infarction and an unexploited source of cardiovascular prevention: a prospective population-based study. J Hum Hypertens 1995;9:175–180.
- Pringle E, Phillips C, Thijs L, Davidson C, Staessen JA, de Leeuw PW, Jaaskivi M, Nachev C, Parati G, O'Brien ET, et al. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population. J Hypertens 2003;21:2251–2257.
- Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk factors and global and regional burden of disease. Lancet 2002;360:1347–1360.
- Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360: 1903–1913.
- Wiinberg N, Hoegholm A, Christensen HR, Bang LE, Mikkelsen KL, Nielsen PE, Svendsen TL, Kampmann JP, Madsen NH, Bentzon MW. 24-h ambulatory blood pressure in 352 normal Danish subjects, related to age and gender. Am J Hypertens 1995;8:978–986.
- Haring R, Ittermann T, Volzke H, Krebs A, Zygmunt M, Felix SB, Grabe HJ, Nauck M, Wallaschofski H. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. Aging Male, 2010 May 26. [Epub ahead of print] see: PMID: 20504090.
- Friedrich N, Rosskopf D, Brabant G, Volzke H, Nauck M, Wallaschofski H. Associations of anthropometric parameters with serum TSH, prolactin, IGF-I, and testosterone levels: results of the study of health in Pomerania (SHIP). Exp Clin Endocrinol Diabetes 2010;118:266–273.
- Haring R, Baumeister SE, Völzke H, Dorr M, Felix SB, Kroemer HK, Nauck M, Wallaschofski H. Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia. Eur J Cardiovasc Prev Rehabil. 2010 Jun 17. [Epub ahead of print] see: PMID: 20562628.
- Haring R, Volzke H, Felix SB, Schipf S, Dorr M, Rosskopf D, Nauck M, Schofl C, Wallaschofski H. Prediction of metabolic syndrome by low serum testosterone levels in men: results from the study of health in Pomerania. Diabetes 2009;58:2027–2031.
- Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev 2003;24:313–340.
- Corona G, Mannucci E, Lotti F, Fisher AD, Bandini E, Balercia G, Forti G, Maggi M. Pulse pressure, an index of arterial stiffness, is associated with androgen deficiency and impaired penile blood flow in men with ED. J Sex Med 2009;6:285–293.
- Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, Blackman MR, Metter EJ. Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab 2006;290:E234–E242.
- Anderson FH, Francis RM, Faulkner K. Androgen supplementation in eugonadal men with osteoporosis-effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone 1996;18:171–177.
- Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J Clin Endocrinol Metab 2007;92:3844–3853.
- Barrett-Connor E, Khaw KT. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation 1988;78:539–545.
- Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68–75.
- Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 2007;92:549–555.
- Yarnell JW, Beswick AD, Sweetnam PM, Riad-Fahmy D. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arterioscler Thromb 1993;13:517–520.
- Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007;116:2694–2701.
- Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol 1997;146:609–617.
- Volzke H, Alte D, Schmidt CO, Radke D, Lorbeer R, Friedrich N, Aumann N, Lau K, Piontek M, Born G, et al. Cohort profile: the study of health in Pomerania. Int J Epidemiol, in press. [Epub ahead of print].
- Alte D, Luedemann J, Rose HJ, John U. Laboratory markers carbohydrate-deficient transferrin, gamma-glutamyltransferase, and mean corpuscular volume are not useful as screening tools for high-risk drinking in the general population: results from the Study of Health in Pomerania (SHIP). Alcohol Clin Exp Res 2004;28:931–940.
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, et al.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572.
- Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, et al.Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–1187.
- Friedrich N, Volzke H, Rosskopf D, Steveling A, Krebs A, Nauck M, Wallaschofski H. Reference ranges for serum dehydroepiandrosterone sulfate and testosterone in adult men. J Androl 2008;29:610–617.
- Liang K, Zeger S. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22.
- Svartberg J, von Muhlen D, Schirmer H, Barrett-Connor E, Sundfjord J, Jorde R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study. Eur J Endocrinol 2004;150:65–71.
- Khaw KT, Barrett-Connor E. Blood pressure and endogenous testosterone in men: an inverse relationship. J Hypertens 1988;6:329–332.
- Kupelian V, Hayes FJ, Link CL, Rosen R, McKinlay JB. Inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups. J Clin Endocrinol Metab 2008;93:3403–3410.
- Dai WS, Gutai JP, Kuller LH, Laporte RE, Falvo-Gerard L, Caggiula A. Relation between plasma high-density lipoprotein cholesterol and sex hormone concentrations in men. Am J Cardiol 1984;53:1259–1263.
- Volzke H, Ittermann T, Schmidt CO, Dorr M, John U, Wallaschofski H, Stricker BH, Felix SB, Rettig R. Subclinical hyperthyroidism and blood pressure in a population-based prospective cohort study. Eur J Endocrinol 2009;161:615–621.
- Meisinger C, Heier M, Volzke H, Lowel H, Mitusch R, Hense HW, Ludemann J. Regional disparities of hypertension prevalence and management within Germany. J Hypertens 2006;24:293–299.
- Lindholm J, Winkel P, Brodthagen U, Gyntelberg F. Coronary risk factors and plasma sex hormones. Am J Med 1982;73:648–651.
- Turner HE, Wass JA. Gonadal function in men with chronic illness. Clin Endocrinol (Oxf) 1997;47:379–403.
- Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res 2002;53:688–708.
- Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency. III. Cardiovascular disease. J Androl 2009;30:477–494.
- Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone. Am J Physiol Regul Integr Comp Physiol 2004;286: R233–R249.
- Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 1999;100:1690–1696.
- Hall J, Jones RD, Jones TH, Channer KS, Peers C. Selective inhibition of l-type Ca2+ channels in A7r5 cells by physiological levels of testosterone. Endocrinology 2006;147:2675–2680.
- Scragg JL, Jones RD, Channer KS, Jones TH, Peers C. Testosterone is a potent inhibitor of l-type Ca(2+) channels. Biochem Biophys Res Commun 2004;318:503–506.
- Muller M, van der Schouw YT, Thijssen JH, Grobbee DE. Endogenous sex hormones and cardiovascular disease in men. J Clin Endocrinol Metab 2003;88:5076–5086.
- Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 2003;24:183–217.
- Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol (Oxf) 2003;58:710–717.
- Vermeulen A, Verdonck G. Representativeness of a single point plasma testosterone level for the long term hormonal milieu in men. J Clin Endocrinol Metab 1992;74:939–942.
- Basaria S, Dobs AS. Testosterone making an entry into the cardiometabolic world. Circulation 2007;116:2658–2661.