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Testosterone Studies

Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

by: Abraham Morgentaler, MD; Martin M. Miner, MD; Monica Caliber, MSc; Andre T. Guay, MD; Mohit Khera, MD; and Abdulmaged M. Traish, PhD

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Circulation, 2007

In men, endogenous testosterone levels are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.

Khaw KT, Dowsett M, Folkerd E, Bingham S, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men. European Prospective Investigation Into Cancer (EPIC) prospective population study. Circulation. 2007;116:2694-2701.

The Journal of Clinical Endocrinology & Metabolism, 2008

"Low testosterone predicted increased risk of cardiovascular deaths and respiratory disease deaths."

Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J of Clinical Endocrin & Metab. 2008;93:68-75.

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Archives of Internal Medicine, 2007

"Age-associated decline in anabolic hormone levels is a strong independent predictor of mortality in older men. Having multiple hormonal deficiencies rather than a deficiency in a single anabolic hormone is a robust biomarker of poor health status in older persons."

Maggio M, Lauretani F, Ceda GP, Bandinelli S, et al. Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti Area (InCHIANTI) study. Arch Intern Med.167(20):2249-2254.

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Archives of Internal Medicine, 2006

"Low testosterone levels were associated with increased mortality in male veterans."

Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166(15):1660-1665.

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Circulation, 2000

"Low-dose supplemental testosterone treatment in men with chronic stable angina reduces exercise-induced myocardial ischemia."

"Twenty two men with chronic stable angina treated with Testosterone replacement therapy, had greater angina-free exercise tolerance compared to controls."

English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation. 2000;102:1906.

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European Journal of Endocrinology, 2009

"Testosterone increased time to ischaemia, haemoglobin, reduced body mass index, and triglycerides in male subjects with no adverse side effects."

Mathur A, Malkin C, Saeed B, Muthusamy R, et al. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Europ J of Endocrin. 2009;161(3):443-449.

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Heart, 2004

"Testosterone replacement therapy in hypogonadal men delays time to ischemia, improves mood, and is associated with potentially beneficial reductions of total cholesterol and serum tumour necrosis factor."

Malkin CJ, Pugh PJ, Morris PD, Kerry KE, et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart. 2004 Aug;90(8):871-876.

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Journal of Clinical Oncology, 2007

"Men 65 years or older who had their testosterone levels intentionally lowered as part of their prostate cancer treatment had an earlier onset of fatal heart attacks."

D'Amico AV, Denham JQ, Crook J, Chen MH, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol. 2007 Jun; 25(17):2420-2425.

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American Journal of Cardiology, 1999

"Testosterone may have a beneficial effect on myocardial ischemia patients with coronary artery disease."

Webb CM, Adamson DL, de Zeigler D, Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol. 1999 Feb;83(3):437-439.

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Circulation, 1999

"Testosterone, at physiological concentrations, induces coronary artery dilatation and increases coronary blood flow in men with established coronary artery disease."

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.

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Chinese Medical Journal, 1993

"Angina pectoris was relieved (effective rate, 77.4%), and myocardial ischemia in ECG and Holter recordings were improved (effective rate, respectively 68.8% and 75%)."

Wu SZ, Weng XZ. Therapeutic effects of an androgenic preparation on myocardial ischemia and cardiac function in 62 elderly male coronary heart disease patients. Chin Med J. 1993 Jun;106(6):415-418.

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Atherosclerosis, 2009

"A low plasma testosterone level is associated with CV events in middle-aged Japanese men, independent of coronary risk factors and endothelial function. This is the first report to show the relationship between endogenous testosterone and CV events in Asian population."

Akishita M, Hashimoto M, Ohike Y, Ogawa S, et al. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis. 2009;210(1):232-236.

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European Journal of Endocrinology, 2006

"Testosterone replacement therapy reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes. Improvements in glycaemic control, insulin resistance, cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk."

Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006 Jun;154(6):899-906.

Aging Male, 2003

"Testosterone therapy was given to 48 middle-aged men with type 2 diabetes, (visceral) obesity, and symptoms of androgen deficiency.

Testosterone had a positive effect on (visceral) obesity, metabolic control, and symptoms of androgen deficiency (including erectile dysfunction). There were no adverse effects on blood pressure or hematological, biochemical and lipid parameters, and no adverse events."

Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male. 2003 Mar;6(1):1-7.

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Gynecological Endocrinology, 2009

"Data suggest that testosterone addition to estrogen treatment in postmenopausal women has a modest influence on inflammatory markers and there were no apparent adverse effects. On the contrary, the estrogen-induced increase in hsCRP was suppressed."

Kocoska-Maras L, Hirchberg AL, Bystrom B, Schoultz BV, Radestad AF. Testosterone addition to estrogen therapy – effects on inflammatory markers for cardiovascular disease. Gynecol Endocrinol. 2009 Dec;25(12):823-827.

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Chinese Medical Journal, 2009

"Low levels of testosterone in male adolescents might be a risk factor for insulin resistance. TRT can significantly improve patients' insulin sensitivity and suppress serum hsCRP, which in return suggests that TRT may prevent the hypogonadotropic hypogonadal patients from developing diabetes mellitus and cardiovascular diseases (CVD) in future."

Wu XY, Mao JF, Lu SY, Zhang Q, Shi YF. Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients. Chin Med J. 2009 Dec;122(23):2846-2850.

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Vascular Pharmacology, 2009

"Androgen deficiency contributes to increased TGs, TC, LDL-C and reduced HDL-C while androgen treatment results in a favorable lipid profile, suggesting that androgens may provide a protective effect against the development and/or progression of atherosclerosis."

Traish AM, Abdou R, Kypreos KE. Androgen deficiency and atherosclerosis. The lipid link. Vascul Pharmacol. 2009;51(5-6):303-313.

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Neurology, 2005

"Improvements in spatial memory, constructional abilities, and verbal memory were evident in the Testosterone group."

Cherrier MM, Matsumoto AM, Amory JK, Asthana S, et al. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology. 2005 Jun;64(12):2063-2068.

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Archives of Neurology, 2006

"Testosterone replacement therapy improved overall quality of life in patients with Alzheimer's Disease."

Lu PH, Masterman DA, Mulnard R, Cotman C, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006 Feb;63(2):177-185.

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Journal of Clinical Endocrinology and Metabolism, 2004

"Testosterone therapy in older men with low serum T increases vertebral and hip BMD over 36 months, both when administered alone and when combined with Finasteride. These findings have important implications for the prevention and treatment of osteoporosis in older men with low T levels."

Amory JK, Watts NB, Easley KA, Sutton PR, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab. 2004 Feb; 89(2):503-510.

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Heart, 2004

"Twenty male patients with congestive heart failure were given testosterone or a placebo by intramuscular injection every two weeks for 12 weeks. Subjects taking testosterone had a significant increase in the distance walked in the Shuttle Walk Test, whereas the placebo group had no significant improvements."

Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart. 2004 Apr;90(4):446-447.

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European Heart Journal, 2006

"Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure."

Malkin CJ, Pugh PJ, West JN, van Beek EJ, et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006 Jan;27(1):57-64.

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Journal of Clinical Endocrinology & Metabolism, 2001

"Androgen supplementation in aging males with subnormal T levels seems to have beneficial effects on muscle mass and strength, bone mineral density, plasma lipids and insulin sensitivity, mood, libido and sense of well-being."

Vermeulen A. Androgen replacement therapy in males: A critical review. J Clin Endo Metab. 86(6):2380-2393.

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Journal of Clinical Endocrinology & Metabolism, 2010

"Testosterone treatment in intermediate-frail and frail elderly men with low to borderline-low Testosterone for 6 months may prevent age-associated loss of lower limb muscle strength and improve body composition, quality of life, and physical function."

Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010 Feb;95(2):639-650.

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Journal of Clinical Endocrinology & Metabolism, 2009

Supplemental testosterone produced significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation.

Sattler FR, Castaneda-Sceppa C, Binder EF, Schroeder ET, et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab. 2009 Jun; 94(6):1991-2001.

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Arg Bras Endocrinology & Metabolism, 2009

"Six months of testosterone replacement improved sexuality and body composition, with prostatic and hematological safety."

Andrade ES, Clapauch R, Buksman S. Short term testosterone replacement therapy improves libido and body composition. Arg Bras Endocrinol Metab. 2009;53(8):996-1004.

Elderly men with low serum testosterone or estradiol have increased risk of mortality, and subjects with low values of both testosterone and estradiol have the highest risk of mortality.

Tivesten A, Vandenput L, Labrie F, Karlsson MK, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94(7):2482-2488.

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Urologe A, 2010

Administration of testosterone in hypogonadal men with metabolic syndrome appears to be a promising treatment option to improve metabolic control.

Schubert M, Jockenhovel F. Testosterone and the metabolic syndrome. Urologe A. 2010 Jan;49(1):47-50.

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Arg Bras Endocrinol Metab, 2009

The available evidence suggests that testosterone replacement therapy can be cautiously considered in selected hypogonadal men treated with curative intent for low risk prostate cancer and without evidence of active disease.

Rhoden EL, Averbeck MA. Prostate carcinoma and testosterone: risks and controversies. Arg Bras Endocrinol Metabol. 2009 Nov;53(8):956-962.

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Pol Merkur Lekarski, 2009

Testosterone supplementation restores metabolic parameters to the eugonadal state, increases muscle mass and strength, improves bone mineral density and psychological function (cognition and mood), libido and sexual functioning; and enhances quality of life.

Rabijewski M, Zglicynski W. Testosterone deficiency in elderly men. Pol Merkur Lekarski. 2009 Dec;27(162):571-523.

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Journal of Sexual Medicine, 2010

Approximately two-thirds of men with testosterone deficiency who begin testosterone therapy will experience symptomatic benefit and will complete at least 12 months of treatment. Benefit was noted in a majority by 3 months.

Rhoden EL, Morgentaler A. Symptomatic response rates to testosterone therapy and the likelihood of completing 12 months of therapy in clinical practice. J Sex Med. 2010 Jan;7(1):277-283.

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Hinyokika Kiyo, 2009

"Androgen replacement therapy for late-onset hypogonadism patients was effective not only in curing symptoms but also in improving Health-Related Quality of Life scores."

Taniguchi H, Kawa G, Kinoshita H, Matsuda T. Androgen replacement therapy improves health-related quality of life in late onset hypogonadism patients. Hinyokika Kiyo. 2009 Dec;55(12):741-744.

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Journal of Sexual Medicine, 2010

Seventy-five postmenopausal women symptomatic for urogenital atrophy and sexual dysfunction were randomly divided into two study groups and one control group. The women in study group 1 received local estrogen cream; study group 2 received local estrogen and testosterone cream; the control group received nonhormonal lubricant (KY gel) for 12 weeks. Local estrogen either alone or with androgen is highly effective in relieving symptoms of urogenital atrophy and in improving sexual function in symptomatic postmenopausal women.

Raghunandan C, Agrawal S, Dubey P, Choudhury M, Jain A. A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women. J Sex Med. 2010;7(3):1284-1290.

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British Journal of Dermatology, 2011

76 of 285 [female] patients (26.7%) reported hair thinning prior to treatment. 47 of these patients (63%) reported hair re-growth on testosterone therapy. Conclusion: Testosterone therapy was found to have a beneficial effect on scalp hair growth in female patients treated for symptoms of androgen deficiency.

R. Glaser, C. Dimitrakakis, A.G. Messenger. Improvement In Scalp Hair Growth In Androgen-Deficient Women Treated With Testosterone: A Questionnaire Study. Br J Dermatol. 2011 Oct 3.