Testosterone Research

A total of 39 RCTs and 10 observational studies were included. Meta-analysis was done using data from 30 RCTs. Compared with placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (odds ratio [OR] 0.87; 95% CI, 0.39-1.93; 16 RCTs), stroke (OR 2.17; 95% CI, 0.63-7.54; 9 RCTs), or mortality (OR 0.88; 95% CI, 0.55-1.41; 20 RCTs).

We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke, or mortality in randomized controlled trials.

Alexander, G. C., Iyer, G., Lucas, E., Lin, D., & Singh, S. (2017). Cardiovascular risks of exogenous testosterone use among men: A systematic review and meta-analysis. The American Journal of Medicine, 130(3), 293-305.

Key Points

Question: What are the cardiovascular risks of testosterone replacement therapy (TRT) in men with androgen deficiency?
Findings: When use in androgen-deficient men with documented low morning testosterone levels, TRT was not associated with an increased risk of cardiovascular outcomes. During long-term follow-up the risk of cardiovascular outcomes was lower in testosterone-treated men.
Meaning: These findings support the use of TRT in androgen-deficient men.

Cheetham, T. C., An, J., Jacobsen, S. J., Niu, F., Sidney, S., Quesenberry, C. P., & VanDenEeden, S. K. (2017). Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Internal Medicine, 177(4), 491-499.

In older men with testosterone deficiency, receipt of androgen therapy was associated with a reduced risk of rehospitalization (91 of 929 androgen users [9.8%] vs 708 of 5443 non-androgen users [13.0%]; OR, 0.73; 95% CI, 0.58-0.92) in the 30 days after hospital discharge. In a logistic regression analysis adjusting for multiple demographic, clinical, and health service variables, the OR was similar (OR, 0.75; 95% CI, 0.59-0.95). The adjusted OR for unplanned 30-day hospital readmissions was 0.62 (95% CI, 0.47-0.83). Each of these findings persisted across a range of propensity score analyses including adjustment, stratification, and inverse probability treatment weighting and several sensitivity analyses.

Androgen therapy may reduce the risk of rehospitalization in older men with testosterone deficiency. Given the high rates of early hospital readmission among older adults, further exploration of this intervention holds broad clinical and public health relevance.

Baillargeon, J., Deer, R. R., Kuo, Y. F., Zhang, D., Goodwin, J. S., & Volpi, E. (2016). Androgen therapy and rehospitalization in older men with testosterone deficiency. Mayo Clinic Proceedings, 91(5), 587-595.

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.

Morgentaler, A., Miner, M. M., Caliber, M., Guay, A. T., Khera, M., & Traish, A. M. (2015). Testosterone therapy and cardiovascular risk: Advances and controversies. Mayo Clinic Proceedings, 90(2), 224-251.

This study was conducted to examine the association between testosterone therapy and new myocardial infarction (MI) and stroke events in a series of patients treated at Low T Centers across the United States, consisting of mainly young (mean age = 46), otherwise, healthy men. Electronic medical records were queried between the years 2009 and 2014 to identify patients diagnosed with hypogonadism, MI, and stroke, as indicated by ICD-9 codes. The incidence of MI and stroke events was compared to community-based registries. 39,936 patients recruited from 40 Low T Centers across the United States were treated and 19,968 met eligibility criteria for receiving testosterone treatment. The incidence rate ratio (IRR) for MI in testosterone- (T-) treated versus nontreated patients was 0.14 (C.I. = 0.08 to 0.18, p < 0.0001) whereas the IRR for stroke for T-treated versus nontreated patients was 0.11 (C.I. = 0.02 to 0.13, p < 0.0001). There was no evidence of worsening preexisting MI or stroke in patients treated with testosterone.The experience in Low T Centers shows that, in a testosterone patient registry, testosterone is generally safe for younger men who do not have significant risk factors. Of patients that developed MI with testosterone, there was no association with testosterone or hematocrit levels.

Tan, R. S., Cook, K. R., & Reilly, W. G. (2015). Myocardial infarction and stroke risk in young healthy men treated with injectable testosterone. International Journal of Endocrinology, 2015, 970750.

Testosterone is a key hormone in the pathology of metabolic diseases such as obesity. Low testosterone levels are associated with increased fat mass (particularly central adiposity) and reduced lean mass in males. A bidirectional relationship between testosterone and obesity underpins this association indicated by the hypogonadal–obesity cycle and evidence weight loss can lead to increased testosterone levels. Androgenic effects on enzymatic pathways of fatty acid metabolism, glucose control and energy utilization are apparent and often tissue specific with differential effects noted in different regional fat depots, muscle and liver to potentially explain the mechanisms of testosterone action. Testosterone replacement therapy demonstrates beneficial effects on measures of obesity that are partially explained by both direct metabolic actions on adipose and muscle and also potentially by increasing motivation, vigour and energy allowing obese individuals to engage in more active lifestyles. The degree of these beneficial effects may be dependent on the treatment modality with longer term administration often achieving greater improvements. Testosterone replacement may therefore potentially be an effective adjunctive treatment for weight management in obese men with concomitant hypogonadism.

Kelly, D. M., & Jones, T. H. (2015). Testosterone and obesity. Obesity Reviews, 16(7), 581-606.

The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease.

Corona, G., Maseroli, E., Rastrelli, G., Isidori, A. M., Sforza, A., Mannucci, E., & Maggi, M. (2014). Cardiovascular risk associated with testosterone-boosting medications: A systematic review and meta-analysis. Expert Opinion on Drug Safety, 13(10), 1327-1351.

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.

Kelly, D. M., & Jones, T. H. (2014). Testosterone and cardiovascular risk in men. Frontiers in Hormone Research, 43, 1-20.

In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment.

Shores, M. M., Smith, N. L., Forsberg, C. W., Anawalt, B. D., & Matsumoto, A. M. (2012). Testosterone treatment and mortality in men with low testosterone levels. The Journal of Clinical Endocrinology & Metabolism, 97(6), 2050-2058.

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

Malkin, C. J., Pugh, P. J., West, J. N., van Beek, E. J. R., Jones, T. H., & Channer, K. S. (2006). Testosterone therapy in men with moderate severity heart failure: A double-blind randomized placebo controlled trial. European Heart Journal, 27(1), 57-64.

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, K.-T., Dowsett, M., Folkerd, E., Bingham, S., Wareham, N., Luben, R., . . . Day, N. (2007). 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, 116(23), 2694-2701.

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

Laughlin, G. A., Barrett-Connor, E., & Bergstrom, J. (2008). Low serum testosterone and mortality in older men. The Journal of Clinical Endocrinology and Metabolism, 93(1), 68-75.

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, G. P., Bandinelli, S., Ling, S. M., Metter, E. J.,… Ferrucci, L. (2007). Relationship between low levels of anabolic hormones and 6-year mortality in older men: The aging in the Chianti Area (InCHIANTI) study. Archives of Internal Medicine, 167(20), 2249-2254.

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

Shores, M. M., Matsumoto, A. M., Sloan, K. L., & Kivlahan, D. R. (2006). Low serum testosterone and mortality in male veterans. JAMA Internal Medicine, 166(15), 1660-1665.

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, K. M., Steeds, R. P., Jones, T. H., Diver, M. J., & Channer, K. S. (2000). Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina. Circulation, 102(16), 1906-1911.

Testosterone increased time to ischaemia and haemoglobin while reducing body mass index, and triglycerides in male subjects. The protective effect of testosterone on myocardial ischaemia is maintained throughout treatment without decrement. Previously noted potentially beneficial effects of testosterone on body composition were confirmed and there were no adverse effects.

Mathur, A., Malkin, C., Saeed, B., Muthusamy, R., Jones, T. H., & Channer, K. (2009). Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. European Journal of Endocrinology, 161(3), 443–449.

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, C. J., Pugh, P. J., Morris, P. D., Kerry, K. E., Jones, R. D., Jones, T. H., & Channer, K. S. (2004). Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart, 90(8), 871-876.

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, A. V., Denham, J. W., Crook, J., Chen, M.-H., Goldhaber, S. Z., Lamb, D. S., … Kantoff, P. W. (2007). Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. Journal of Clinical Oncology, 25(17), 2420-2425.

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

Webb, C. M., Adamson, D. L., de Zeigler, D., & Collins, P. (1999). Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. American Journal of Cardiology, 83(3), 437-439.

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

Webb, C. M., McNeill, J. G., Hayward, C. S., Zeigler, D. d., & Collins, P. (1999). Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation, 100(16), 1690-1696.

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, S. Z., & Weng, X. Z. (1993). Therapeutic effects of an androgenic preparation on myocardial ischemia and cardiac function in 62 elderly male coronary heart disease patients. Chinese Medical Journal, 106(6), 415-418.

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., Iijima, K., Eto, M., & Ouchi, Y. (2010). Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis, 210(1), 232-236.

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, K. S., & Jones, T. H. (2006). Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. European Journal of Endocrinology, 154(6), 899-906.

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, M. A., Boneva, Z., & Christov, V. G. (2003). Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. The Aging Male 6(1), 1-7.

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., Hirschberg, A. L., Byström, B., Schoultz, B. V., & Rådestad, A. F. (2009). Testosterone addition to estrogen therapy – Effects on inflammatory markers for cardiovascular disease. Gynecological Endocrinology, 25(12), 823-827

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, X.-Y., Mao, J.-F., Lu, S.-Y., Zhang, Q., & Shi, Y.-F. (2009). Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients. Chinese Medical Journal, 122(23), 2846-2850.

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, A. M., Abdou, R., & Kypreos, K. E. (2009). Androgen deficiency and atherosclerosis: The lipid link. Vascular Pharmacology, 51(5), 303-313.

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

Cherrier, M. M., Matsumoto, A. M., Amory, J. K., Asthana, S., Bremner, W., Peskind, E. R., . . . Craft, S. (2005). Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology, 64(12), 2063-2068.

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

Lu, P. H., Masterman, D. A., Mulnard, R., Cotman, C., Miller, B., Yaffe, K., . . . Cummings, J. L. (2006). Effects of testosterone on cognition and mood in male patients with mild alzheimer disease and healthy elderly men. JAMA Neurology, 63(2), 177-185

“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, J. K., Watts, N. B., Easley, K. A., Sutton, P. R., Anawalt, B. D., Matsumoto, A. M., . . . Tenover, J. L. (2004). Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. The Journal of Clinical Endocrinology & Metabolism, 89(2), 503-510.

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, P. J. (2004). Testosterone treatment for men with chronic heart failure. Heart, 90(4), 446-447.

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

Malkin, C. J., Pugh, P. J., West, J. N., van Beek, E. J. R., Jones, T. H., & Channer, K. S. (2006). Testosterone therapy in men with moderate severity heart failure: A double-blind randomized placebo controlled trial. European Heart Journal, 27(1), 57-64.

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. (2001). Androgen replacement therapy in the aging male—a critical evaluation. The Journal of Clinical Endocrinology & Metabolism, 86(6), 2380-2390.

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, S. A., Connolly, M. J., O’Connell, M. D. L., Adams, J. E., Oldham, J. A., & Wu, F. C. W. (2010). 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. The Journal of Clinical Endocrinology & Metabolism, 95(2), 639-650.

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, F. R., Castaneda-Sceppa, C., Binder, E. F., Schroeder, E. T., Wang, Y., Bhasin, S.,… Azen, S. P. (2009). Testosterone and growth hormone improve body composition and muscle performance in older men. Journal of Clinical Endocrinology & Metabolism, 94(6), 1991-2001.

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

Andrade Júnior, E. S. d., Clapauch, R., & Buksman, S. (2009). Short term testosterone replacement therapy improves libido and body composition. Arquivos Brasileiros de Endocrinologia & Metabologia, 53, 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. s., Vandenput, L., Labrie, F., Karlsson, M. K., Ljunggren, O. s., Mellström, D., & Ohlsson, C. (2009). Low serum testosterone and estradiol predict mortality in elderly men. The Journal of Clinical Endocrinology & Metabolism, 94(7), 2482-2488.

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

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

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, E. L. & Averbeck, M. A. (2009). Prostate carcinoma and testosterone: risks and controversies. Arg Bras Endocrinology and Metabolism, 53(8), 956-962.

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. (2009).Testosterone deficiency in elderly men. Pol Merkur Lekarski, 27(162), 571-523.

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.

Herbenick, D., Reece, M., Schick, V., Sanders, S. A., Dodge, B., & Fortenberry, J. D. (2010). Sexual behaviors, relationships, and perceived health status among adult women in the United States: Results from a national probability sample. The Journal of Sexual Medicine, 7, 277-290.

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. (2009). Androgen replacement therapy improves health-related quality of life in late onset hypogonadism patients. Hinyokika Kiyo, 55(12), 741-744.

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. (2010). A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women. The Journal of Sexual Medicine, 7(3), 1284-1290.

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.

Glaser, R., Dimitrakakis, A., & Messenger., G. (2011). Improvement In Scalp Hair Growth In Androgen-Deficient Women Treated With Testosterone: A Questionnaire Study. British Journal Dermatology.