Cortisol, Testosterone, and Coronary Heart Disease: Prospective Evidence From the Caerphilly Study

Background—There is a popular belief that chronic stress causes heart disease through psychoneuroendocrine mechanisms. We have examined whether an elevated circulating cortisol-to-testosterone ratio increases the risk of ischemic heart disease. Methods and Results—We undertook a prospective cohort study of 2512 men aged 45 to 59 years between 1979 and 1983 from Caerphilly, South Wales, with a mean follow-up of 16.5 years. Subjects underwent a clinical examination, and morning fasting blood samples were taken for analysis of cortisol levels, testosterone levels, and other cardiovascular risk factors. The ratio of cortisol to testosterone showed weak associations with potential confounding factors but strong positive associations with components of the insulin resistance syndrome (P<0.001). A positive linear trend was seen across quintiles of cortisol:testosterone ratio for incident ischemic heart disease (age-adjusted OR per z score change in ratio 1.22, 95% CI 1.07 to 1.38, P=0.003). This was markedly attenuated after adjustment for components of the insulin resistance syndrome (age-adjusted OR per z score change in ratio 1.10, 95% CI 0.96 to 1.25, P=0.18). There was no association between the cortisol:testosterone ratio and other causes of death (age-adjusted hazard ratio 0.99, 95% CI 0.88 to 1.11, P=0.81). Conclusions—This is the first population-based prospective study that has found a specific association between cortisol:testosterone ratio and incident ischemic heart disease, apparently mediated through the insulin resistance syndrome. Whether this reflects the effects of chronic stress, behavioral factors, or genetic influences remains to be determined.

[1]  P Royston,et al.  The use of fractional polynomials to model continuous risk variables in epidemiology. , 1999, International journal of epidemiology.

[2]  J. Gallacher,et al.  Blood pressure reactions to the cold pressor test and the prediction of future blood pressure status: data from the Caerphilly study. , 1996, Journal of human hypertension.

[3]  P. Björntorp.  Neuroendocrine perturbations as a cause of insulin resistance , 1999, Diabetes/metabolism research and reviews.

[4]  P C Elwood,et al.  Fibrinogen, Viscosity, and White Blood Cell Count Are Major Risk Factors for Ischemic Heart Disease: The Caerphilly and Speedwell Collaborative Heart Disease Studies , 1991, Circulation.

[5]  B. Chipps,et al.  Reduction of serum testosterone levels during chronic glucocorticoid therapy. , 1986, Annals of internal medicine.

[6]  Robert M. Sapolsky,et al.  Why Zebras Don't Get Ulcers , 1994 .

[7]  K. Channer,et al.  Testosterone for secondary prevention in men with ischaemic heart disease? , 2003, QJM : monthly journal of the Association of Physicians.

[8]  S. M. Brown.  An Introduction to Behavioral Endocrinology , 1978, The Yale Journal of Biology and Medicine.

[9]  E. Filaire,et al.  Preliminary results on mood state, salivary testosterone:cortisol ratio and team performance in a professional soccer team , 2001, European Journal of Applied Physiology.

[10]  Shuiping Zhao,et al.  The association of low plasma testosterone level with coronary artery disease in Chinese men. , 1998, International journal of cardiology.

[11]  Dietrich von Holst,et al.  The concept of stress and its relevance for animal behavior , 1998 .

[12]  N. Kalin,et al.  Effects of Chronic Medical Illness and Dementia on the Dexamethasone Suppression Test , 1983, Journal of the American Geriatrics Society.

[13]  D. Carroll,et al.  Are the effects of psychosocial exposures attributable to confounding? Evidence from a prospective observational study on psychological stress and mortality , 2001, Journal of epidemiology and community health.

[14]  J P Henry,et al.  Biological basis of the stress response. , 1993, Integrative physiological and behavioral science : the official journal of the Pavlovian Society.

[15]  M. Golub.  The adrenal and the metabolic syndrome , 2001, Current hypertension reports.

[16]  R. Fitzgerald,et al.  Testosterone Concentrations in Men on Chronic Glucocorticosteroid Therapy , 1997, Journal of the Royal College of Physicians of London.

[17]  Weng Xz,et al.  Therapeutic effects of an androgenic preparation on myocardial ischemia and cardiac function in 62 elderly male coronary heart disease patients. , 1993 .

[18]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[19]  H SELYE,et al.  Stress and disease , 1955, Transactions of the American Laryngological, Rhinological and Otological Society, Inc.

[20]  B. Walker,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society Elevated Plasma Cortisol Concentrations: A Link between Low Birth Weight and the Insulin Resistance Syndrome?* , 2022 .

[21]  J. Gallacher,et al.  Blood pressure reactions to the cold pressor test and the prediction of ischaemic heart disease: data from the Caerphilly Study. , 1998, Journal of epidemiology and community health.

[22]  F. Braceland.  THE STRESS OF LIFE , 1976 .

[23]  E. González-Bono,et al.  Psychophysiological responses to the Stroop Task after a maximal cycle ergometry in elite sportsmen and physically active subjects. , 2001, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[24]  V. A. Kral,et al.  Diurnal variation of the serum cortisol level of geriatric subjects. , 1971, Journal of gerontology.

[25]  E. Keverne,et al.  Are subordinates always stressed? a comparative analysis of rank differences in cortisol levels among primates , 2003, Hormones and Behavior.

[26]  K. Channer,et al.  Testosterone: a natural tonic for the failing heart? , 2000, QJM : monthly journal of the Association of Physicians.

[27]  J. Yarnell,et al.  Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[28]  Wolfgang Babisch,et al.  Traffic noise, work noise and cardiovascular risk factors : the Caerphilly and Speedwell collaborative heart disease studies , 1990 .

[29]  B. McEwen.  Protective and damaging effects of stress mediators. , 1998, The New England journal of medicine.

[30]  G. Lac,et al.  Changes in cortisol and testosterone levels and T/C ratio during an endurance competition and recovery. , 2000, The Journal of sports medicine and physical fitness.

[31]  D. Carroll,et al.  Pressor reactions to psychological stress and prediction of future blood pressure: data from the Whitehall II study , 1995, BMJ.

[32]  James M. Dabbs,et al.  Salivary testosterone measurements: Reliability across hours, days, and weeks , 1990, Physiology & Behavior.

[33]  W. Ettinger,et al.  High Density Lipoprotein Cholesterol is Associated with Serum Cortisol in Older People , 1995, Journal of the American Geriatrics Society.

[34]  H. Schwertner,et al.  Relationship between Cortisol and Cholesterol in Men with Coronary Artery Disease and Type A Behavior , 1984, Arteriosclerosis.

[35]  D. Nashel.  Is atherosclerosis a complication of long-term corticosteroid treatment? , 1986, The American journal of medicine.

[36]  G. Smith,et al.  Is control at work the key to socioeconomic gradients in mortality? , 1997, The Lancet.

[37]  A. Ahmed,et al.  Corticosteroids: a review with emphasis on complications of prolonged systemic therapy. , 1989, Annals of allergy.

[38]  D. Carroll,et al.  Psychological stress and cardiovascular disease: empirical demonstration of bias in a prospective observational study of Scottish men , 2002, BMJ : British Medical Journal.

[39]  H. Syddall,et al.  Cortisol and the metabolic syndrome in South Asians , 2003, Clinical Endocrinology.

[40]  M Feinleib,et al.  The relationship of psychosocial factors to coronary heart disease in the Framingham study. I. Methods and risk factors. , 1978, American journal of epidemiology.

[41]  B. McEwen,et al.  Subordination stress: Behavioral, brain, and neuroendocrine correlates , 1993, Behavioural Brain Research.

[42]  Robert Karasek,et al.  Physiology of Stress and Regeneration in Job Related Cardiovascular Illness , 1982 .

[43]  Evangelia Charmandari,et al.  Endocrinology of the stress response. , 2005, Annual review of physiology.

[44]  P. Sterling,et al.  Biological basis of stress-related mortality. , 1981, Social science & medicine. Part E, Medical psychology.

[45]  S. Lightman,et al.  The Effect of Oestradiol and Progesterone on Hypoglycaemic Stress‐Induced Suppression of Pulsatile Luteinizing Hormone Release and on Corticotropin‐Releasing Hormone mRNA Expression in the Rat , 2003, Journal of neuroendocrinology.

[46]  H. Hauner,et al.  Body fat distribution and its association with metabolic and hormonal risk factors in women with angiographically assessed coronary artery disease. Evidence for the presence of a metabolic syndrome. , 1994, Atherosclerosis.

[47]  P. Elwood,et al.  Sex hormones, insulin, lipids, and prevalent ischemic heart disease. , 1987, American journal of epidemiology.

[48]  M. Marmot,et al.  Chronic Stress Accelerates Atherosclerosis in the Apolipoprotein E Deficient Mouse , 2003, Stress.

[49]  R. Sapolsky,et al.  Stress-induced suppression of testicular function in the wild baboon: role of glucocorticoids. , 1985, Endocrinology.

[50]  G. Lac,et al.  Saliva Cortisol, Testosterone and T/C Ratio Variations During a Wrestling Competition and During the Post-Competitive Recovery Period , 1999, International journal of sports medicine.

[51]  B. McEwen,et al.  Stress and the individual. Mechanisms leading to disease. , 1993, Archives of internal medicine.

[52]  I. Jones,et al.  Behavioral and endocrinological correlates of social status in the male sugar glider (Petaurus breviceps Marsupialia: Petauridae) , 1994, Physiology & Behavior.

[53]  I. Janszky,et al.  Cortisol and vital exhaustion in relation to significant coronary artery stenosis in middle-aged women with acute coronary syndrome , 2002, Psychoneuroendocrinology.

[54]  R. Nelson.  An introduction to behavioral endocrinology, 3rd ed. , 2005 .

[55]  S. Lurie,et al.  STRESS OF LIFE , 1998 .

[56]  D. Riad-fahmy,et al.  A simple, direct radioimmunoassay for plasma cortisol, featuring a 125I radioligand and a solid-phase separation technique. , 1979, Clinical chemistry.

[57]  J. Abramson,et al.  Cornell Medical Index as a health measure in epidemiological studies. A test of the validity of a health questionnaire. , 1965, British journal of preventive & social medicine.

[58]  R. Sapolsky,et al.  Endocrinology alfresco: psychoendocrine studies of wild baboons. , 1993, Recent progress in hormone research.

[59]  D. Riad-fahmy,et al.  A Simple Robust Assay for Testosterone in Male Plasma Using an 125I-Radioligand and a Solid-Phase Separation Technique , 1979, Annals of clinical biochemistry.

[60]  E. Brunner,et al.  Socioeconomic determinants of health: Stress and the biology of inequality , 1997 .

[61]  C. Christiansen,et al.  The relationship of natural androgens to coronary heart disease in males: a review. , 1996, Atherosclerosis.

[62]  P. Hugenholtz,et al.  Post-heparin lipases, lipids and related hormones in men undergoing coronary arteriography to assess atherosclerosis. , 1983, Atherosclerosis.

[63]  P. Royston.  Multiple Imputation of Missing Values , 2004 .

[64]  B. Singer,et al.  Price of adaptation--allostatic load and its health consequences. MacArthur studies of successful aging. , 1997, Archives of internal medicine.

[65]  G. Gillies,et al.  Stress, stress hormones and the immune system , 1997 .

[66]  A. Vingerhoets,et al.  Stress research: its present status and issues for future developments. , 1988, Social science & medicine.

[67]  T. Seeman,et al.  Aging and hypothalamic-pituitary-adrenal response to challenge in humans. , 1994, Endocrine reviews.

[68]  T M Hayes,et al.  Associations of alcohol consumption with plasma high density lipoprotein cholesterol and its major subfractions: the Caerphilly and Speedwell Collaborative Heart Disease Studies. , 1988, Journal of epidemiology and community health.

[69]  E. Sprague,et al.  The association of elevated plasma cortisol and early atherosclerosis as demonstrated by coronary angiography. , 1977, Atherosclerosis.

[70]  S. Wu,et al.  Therapeutic effects of an androgenic preparation on myocardial ischemia and cardiac function in 62 elderly male coronary heart disease patients. , 1993, Chinese medical journal.