Lower Testosterone Levels Predict Incident Stroke and Transient Ischemic Attack in Older Men

ORIGINAL ARTICLE E n d o c r i n e C a r e Lower Testosterone Levels Predict Incident Stroke and Transient Ischemic Attack in Older Men Bu B. Yeap, Zoë Hyde, Osvaldo P. Almeida, Paul E. Norman, S. A. Paul Chubb, Konrad Jamrozik, Leon Flicker, and Graeme J. Hankey School of Medicine and Pharmacology (B.B.Y., S.A.P.C., L.F., G.J.H.), University of Western Australia, Crawley, WA 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y.), Fremantle Hospital, Fremantle, WA 6959, Australia; WA Centre for Health and Ageing (Z.H., O.P.A., L.F.), University of Western Australia, Crawley, WA 6009, Australia; School of Psychiatry and Clinical Neurosciences (O.P.A.), and School of Surgery (P.E.N.), University of Western Australia, Crawley, WA 6009, Australia; PathWest, Department of Biochemistry (S.A.P.C.), Fremantle Hospital, Fremantle, WA 6959, Australia; School of Population Health and Clinical Practice (K.J.), University of Adelaide, SA 5005, Australia Context: Lower circulating testosterone concentrations are associated with metabolic syndrome, type 2 diabetes, carotid intima-media thickness, and aortic and lower limb arterial disease in men. However, it is unclear whether lower testosterone levels predict major cardiovascular events. Objective: We examined whether lower serum testosterone was an independently significant risk factor for symptomatic cerebrovascular events in older men. Design: This was a prospective observational study with median follow-up of 3.5 yr. Setting: Community-dwelling, stroke-free older men were studied. Participants: A total of 3443 men at least 70 yr of age participated in the study. Main Outcome Measures: Baseline serum total testosterone, SHBG, and LH were assayed. Free testosterone was calculated using mass action equations. Incident stroke or transient ischemic attack (TIA) was recorded. Results: A first stroke or TIA occurred in 119 men (3.5%). Total and free testosterone concentrations in the lowest quartiles (⬍11.7 nmol/liter and ⬍222 pmol/liter) were associated with reduced event-free survival (P ⫽ 0.014 and P ⫽ 0.01, respectively). After adjustment including age, waist-hip ratio, waist circumference, smoking, hypertension, dyslipidemia, and medical comorbidity, lower total testosterone predicted increased incidence of stroke or TIA (hazard ratio ⫽ 1.99; 95% confidence interval, 1.33–2.99). Lower free testosterone was also associated (hazard ratio ⫽ 1.69; 95% confidence interval, 1.15–2.48), whereas SHBG and LH were not independently associated with incident stroke or TIA. Conclusions: In older men, lower total testosterone levels predict increased incidence of stroke or TIA after adjusting for conventional risk factors for cardiovascular disease. Men with low-normal testosterone levels had increased risk. Further studies are warranted to determine whether interventions that raise circulating testosterone levels might prevent cerebrovascular disease in men. (J Clin Endocrinol Metab 94: 2353–2359, 2009) ost circulating testosterone is bound to SHBG or albumin, with a small fraction of unbound or free testosterone. Among men, both total and free testosterone levels decline with increasing age, and the decline is steeper for free compared with M total testosterone (1, 2). This characteristic hormonal change of male aging is of interest because lower testosterone concentrations have been associated with increased incidence of metabolic syndrome and type 2 diabetes in middle-aged and older men ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/jc.2008-2416 Received November 5, 2008. Accepted April 1, 2009. First Published Online April 7, 2009 Abbreviations: CI, Confidence interval; HDL, high-density lipoprotein; HR, hazard ratio; TIA, transient ischemic attack. J Clin Endocrinol Metab, July 2009, 94(7):2353–2359 jcem.endojournals.org 2353 2354 Yeap et al. Low Testosterone and Stroke or TIA (3– 6). Additionally, lower testosterone levels are associated with carotid intima-media thickness, lower extremity peripheral arterial disease, and aortic atherosclerosis (7–10). However, despite the relationship between lower testosterone levels and conditions associated with either the increased risk or presence of atherosclerosis, it is unclear whether lower testosterone levels independently predict morbidity and mortality from cardiovascular disease. In studies of middle-aged and older men, low total or free testosterone concentrations were associated with higher overall mortality and with mortality from cardiovascular, cancer, and respiratory causes (11–13). However, other studies have reported negative or conflicting findings (14 –16). Furthermore, it is not clear whether lower testosterone levels are associated with nonfatal cardiovascular events (17). In cross-sectional and longitudinal observational studies, reverse causation needs to be considered because systemic illness can result in lower testosterone levels (18). Therefore it is possible that lower testosterone levels might be a marker for, rather than a cause of, subsequent poorer health outcomes in older men, which could account for its association with overall mortality rather than morbidity and mortality due to cardiovascular disease. Existing randomized trials of testosterone therapy in men have not been designed or powered to detect treatment-related differences in cardiovascular outcomes (19 –22). Thus, additional data addressing the key question of whether lower testosterone concentrations are an independently significant risk factor for vascular events in each of the cerebral, coronary, and peripheral arterial circulations would inform planning of intervention trials exploring cardiovascular outcomes. We sought to test the hypothesis that in community-dwelling older men, lower testosterone levels are independently associated with higher incidence of stroke and transient ischemic attack (TIA). Subjects and Methods Study population The origins and characteristics of the Health In Men Study (HIMS) have been described in depth elsewhere (23). Briefly, between October 2001 and August 2004, a total of 4263 community-dwelling men participated in the study by completing a health questionnaire and providing an early morning blood sample for analysis of biochemistry and hormone levels. Available sera were assayed to provide hormone data for 4165 men. After exclusion of men receiving hormonal therapy, men receiving any form of testosterone supplementation and those with prostate cancer, there were hormone results for 3638 men available for analysis (24). Of these men, a further 195 were excluded because they had a prior diagnosis of stroke or TIA, leaving 3443 men to be included in the longitudinal analysis. Height (in centimeters), weight (in kilograms), girth at hips and waist (in centimeters), and blood pressure were measured using standard procedures. Physical activity and alcohol use had been asce (...truncated)