Research news

Testosterone, mortality and longevity

May 2015

Testosterone and mortality. Muraleedharan V, Jones TH. Clin. Endocrinol. (Oxf). 2014;81(4):477−487.

Observational studies demonstrate that men with low or low-normal endogenous testosterone are at an increased risk of mortality compared to those with higher levels, and that cardiovascular disease accounts for the greater proportion of deaths in those with low testosterone.¹

This editorial summarises a review paper which addressed the following two questions:¹

Is testosterone deficiency directly involved in the pathogenesis of these conditions or is it merely a biomarker of ill health and the severity of underlying disease processes?
Does testosterone therapy retard disease progression and ultimately enhance the clinical prognosis and survival?

KEY POINTS¹

Testosterone deficiency is an independent risk factor for future development of obesity, the metabolic syndrome and type 2 diabetes, which are major risk factors for cardiovascular disease, which is the leading cause of death worldwide.
Testosterone deficiency is an indicator of general poor health and the severity of underlying disease processes.
Experimental data suggest that testosterone deficiency may be directly involved in the pathogenesis of atherogenesis and development of cardiovascular disease.
Men with testosterone deficiency have an up to 2-fold increased mortality risk primarily from cardiovascular disease.
Survival and longevity are the ultimate goals of interventions in medicine. Two notable studies show that testosterone therapy increases longevity in hypogonadal men 2-fold.

What this review adds

The review by Muraleedharan and Jones sought to synthesize available evidence in order to shed light on two important questions:

Is testosterone deficiency directly involved in the pathogenesis of these conditions or is it merely a biomarker of general poor health and the severity of underlying disease process?

It is well-documented that testosterone deficiency is a reflection of ill general health. Lower testosterone levels in men are associated with a poor quality of life, mood changes (including lack of motivation, difficulties with concentration and depression), fatigue, sexual dysfunction, reduced libido/sexual activity, loss of muscle mass and physical strength, frailty, impairment of the immune system, insulin resistance, obesity (both general and abdominal), metabolic syndrome, diabetes, atherosclerosis, vascular disease, cardiovascular events and mortality.¹⁹^,20

Mechanistic studies indicate that testosterone deficiency possibly may be directly involved in the pathogenesis of metabolic diseases, and possibly accelerate development and/or progression of atherosclerosis.^21-23 A few intervention studies support a possible causality of testosterone and atherogenesis.¹¹^,24^,25 Ultrasound measurement of CIMT, a surrogate measure of the presence of atherosclerosis, strongly predicts future clinical cardiovascular events.^26-28
One small study found that testosterone therapy for 12 months resulted in a greater reduction in CIMT in testosterone treated men than placebo²⁵. This was confirmed in a more recent larger study.¹¹ In the latter study, CIMT values were similar at baseline in the testosterone treatment and placebo groups, while after 12 months, a significant reduction of CIMT was detected in the testosterone treated men that was maintained after 24 months of treatment.¹¹ The treatment induced increase in testosterone levels was correlated with the magnitude of reduction in CIMT.¹¹ Most cross-sectional studies also show significant associations of testosterone deficiency and severity of CIMT^29-34, and in older men (over 70 years) low free testosterone levels predict progression of CIMT over 4 years of follow-up, independently of cardiovascular risk factors.³⁵

As mentioned above, a growing number of studies show that testosterone deficiency has an adverse effect on salient cardiovascular risk factors. This, coupled with the increase in CIMT seen in hypogonadal men and decrease in CIMT upon testosterone therapy, will likely add up to cause premature mortality.

Observational studies in populations of both healthy and diseased men demonstrate those with low or low-normal endogenous testosterone are at an increased risk of mortality compared to those with higher testosterone levels.¹ For example, multiple prospective studies have demonstrated a 24% to 96% (almost 2-fold) increased risk of mortality in apparently healthy middle-aged and older men who have low testosterone levels at baseline.^36-43 It is notable that cardiovascular disease accounts for most deaths in men with low testosterone levels.¹

All this suggests that testosterone deficiency may be directly involved in the pathogenesis of chronic diseases, as opposed to simply being a bystander.

Does testosterone therapy retard disease progression and ultimately enhance the clinical prognosis, survival and longevity?

Survival and longevity are the ultimate goals of interventions in medicine. As of this writing, two studies have been published that examined the effect of testosterone therapy in men with hypogonadism on survival and longevity.^44,⁴⁵

Shores et al. retrospectively analysed 1031 male veterans greater than 40 years old who had attended clinics and found to have low testosterone ≤8.7 nmol/L (250 ng/dL).⁴⁴ They compared survival rates in men who had received testosterone therapy with those who had not and found that testosterone therapy significantly reduced mortality over a mean follow-up period of 40.5 months.⁴⁴ The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men. After multivariable adjustment including age, body mass index (BMI), testosterone level, medical morbidity, diabetes and coronary heart disease, testosterone treatment was associated with a 39% decreased risk of death (HR = 0.61). In addition, this study showed no difference in the mortality rates from prostate cancer between testosterone-treated and testosterone-untreated groups.⁴⁴

Muraleedharan et al. examined retrospectively the effect of testosterone therapy on all-cause mortality in hypogonadal type 2 diabetic men, and found significant survival benefits.⁴⁵ The majority of patients 60/64 (93.75%) received testosterone gel, 3/64 (4.68%) buccal testosterone and one (1.56%) intramuscular testosterone undecanoate. Testosterone therapy for a mean duration of 41.6 months was associated with a reduced mortality of 8.4%, compared to 19.2% in the untreated group (n = 174). Testosterone replacement led to a realignment of survival prognosis with that expected in a testosterone replete man with type 2 diabetes. The multivariate-adjusted hazard ratio for decreased survival in the untreated group was 2.3, i.e. diabetic hypogonadal men who did not receive testosterone treatment had a 2.3-fold increased mortality risk. This study concluded that low testosterone levels predict an increase in all-cause mortality during long-term follow-up and that testosterone therapy may improve survival in hypogonadal men with type 2 diabetes.⁴⁵

These two remarkable studies in different populations show similar results of testosterone therapy on improving survival of hypogonadal men. While both of these studies where retrospective and thereby suffer the limitations of retrospective studies, the fact remains that a more than two-fold improvement in the chances of survival in both studies is very significant.

Summary

A growing body of evidence shows that testosterone deficiency has adverse effects on several salient cardiovascular risk factors, and is associated with an increased severity of atherosclerosis (measured by CIMT).

The observations that men with higher endogenous testosterone levels have reduced mortality and that low testosterone increases the risk of cardiovascular death, coupled with results showing a reduction in atherosclerosis with testosterone therapy, suggests that testosterone deficiency over time has an adverse effect on the atherosclerotic process.

These observations, together with the improvement of multiple established cardiovascular risk factors (including CIMT) by testosterone therapy, suggest that testosterone therapy may help prevent the development and/or progression of atherosclerosis and cardiovascular disease.

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References

Muraleedharan V, Jones TH. Testosterone and mortality. Clin. Endocrinol. (Oxf). 2014;81(4):477-487. Return to content
Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nature reviews. Endocrinology. 2013;9(8):479-493. Return to content
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2015 Update: A Report From the American Heart Association. Circulation. 2014. Return to content
Kelly DM, Jones TH. Testosterone and cardiovascular risk in men. Front. Horm. Res. 2014;43:1-20. Return to content
Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends in endocrinology and metabolism: TEM. 2010;21(8):496-503. Return to content
Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin. Endocrinol. (Oxf). 2010;73(5):602-612. Return to content
Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract. 2014;8(4):e339-349. Return to content
Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. International journal of endocrinology. 2014;2014:683515. Return to content
Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring). 2013;21(10):1975 1981. Return to content
Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. The journal of sexual medicine. 2013;10(2):579-588. Return to content
Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. The journal of sexual medicine. 2010;7(10):3495- 3503. Return to content
Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in aging men with metabolic syndrome. International journal of endocrinology. 2014;2014:527470. Return to content
Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829 1836. Return to content
Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS one. 2014;9(1):e85805. Return to content
Morgentaler A. Will I have a heart attack or stroke if I take testosterone therapy? The journal of sexual medicine. 2014;11(6):1601-1602. Return to content
Morgentaler A, Lunenfeld B. Testosterone and cardiovascular risk: world's experts take unprecedented action to correct misinformation. The aging male : the official journal of the International Society for the Study of the Aging Male. 2014;17(2):63-65. Return to content
Morgentaler A, Traish A, Kacker R. Deaths and cardiovascular events in men receiving testosterone. JAMA. 2014;311(9):961-962. Return to content
Morgentaler A. Letter to JAMA Asking for Retraction of Misleading Article on Testosterone Therapy. Availible at http://www.androgenstudygroup.org/index.php/initiatives/letter-to-jama-asking-for-retraction-of-misleading-article-on-testosterone-therapy , accessed July 2, 2014. 2014. Return to content
Yeap BB, Araujo AB, Wittert GA. Do low testosterone levels contribute to ill-health during male aging? Crit. Rev. Clin. Lab. Sci. 2012;49(5-6):168-182. Return to content
Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids. 2014;88C:106-116. Return to content
Herring MJ, Oskui PM, Hale SL, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the basic science literature. Journal of the American Heart Association. 2013;2(4):e000271. Return to content
Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. J. Endocrinol. 2013;217(3):R47-71. Return to content
Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J. Endocrinol. 2013;217(3):R25-45. Return to content
Zitzmann Michael VE, Wenk Melanie, Saad Farid, and Nieschlag Eberhard. Testosterone administration decreases carotid artery intima media thickness as a marker of impaired vascular integrity in middle-aged overweight men. Journal of Men's Health. 2009;6(3):243-243. Return to content
Mathur A, Malkin C, Saeed B, Muthusamy R, Jones TH, Channer K. Long-term benefits of testosterone therapy on angina threshold and atheroma in men. Eur. J. Endocrinol. 2009;161(3):443 449. Return to content
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115(4):459-467. Return to content
Doneen AL, Bale BF. Carotid intima-media thickness testing as an asymptomatic cardiovascular disease identifier and method for making therapeutic decisions. Postgrad. Med. 2013;125(2):108-123. Return to content
Bauer M, Caviezel S, Teynor A, Erbel R, Mahabadi AA, Schmidt-Trucksass A. Carotid intima-media thickness as a biomarker of subclinical atherosclerosis. Swiss Med Wkly. 2012;142:w13705. Return to content
Dorr M, Wallaschofski H, Friedrich N. Association of low total testosterone levels and prevalent carotid plaques: result of the study of health in Pomerania. Eur. J. Epidemiol. 2009;24(7):389 391. Return to content
Makinen J, Jarvisalo MJ, Pollanen P, et al. Increased carotid atherosclerosis in andropausal middle-aged men. J. Am. Coll. Cardiol. 2005;45(10):1603-1608. Return to content
Soisson V, Brailly-Tabard S, Empana JP, et al. Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis. 2012;223(1):244-249. Return to content
Svartberg J, von Muhlen D, Mathiesen E, Joakimsen O, Bonaa KH, Stensland-Bugge E. Low testosterone levels are associated with carotid atherosclerosis in men. J. Intern. Med. 2006;259(6):576-582. Return to content
Tsujimura A, Yamamoto R, Okuda H, et al. Low serum free testosterone level is associated with carotid intima-media thickness in middle-aged Japanese men. Endocr. J. 2012;59(9):809-815. Return to content
van den Beld AW, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grobbee DE. Endogenous hormones and carotid atherosclerosis in elderly men. Am. J. Epidemiol. 2003;157(1):25-31. Return to content
Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SW, van der Schouw YT. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation. 2004;109(17):2074-2079. Return to content
Haring R, Volzke H, Steveling A, et al. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur. Heart J. 2010;31(12):1494-1501. Return to content
Hyde Z, Norman PE, Flicker L, et al. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J. Clin. Endocrinol. Metab. 2012;97(1):179-189. Return to content
Khaw KT, Dowsett M, Folkerd E, et al. 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(23):2694- 2701. Return to content
Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J. Clin. Endocrinol. Metab. 2008;93(1):68-75. Return to content
Menke A, Guallar E, Rohrmann S, et al. Sex steroid hormone concentrations and risk of death in US men. Am. J. Epidemiol. 2010;171(5):583-592. Return to content
Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch. Intern. Med. 2006;166(15):1660-1665. Return to content
Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J. Clin. Endocrinol. Metab. 2009;94(7):2482- 2488. Return to content
Vikan T, Schirmer H, Njolstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur. J. Endocrinol. 2009;161(3):435-442. Return to content
Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J. Clin. Endocrinol. Metab. 2012;97(6):2050-2058. Return to content
Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur. J. Endocrinol. 2013;169(6):725-733. Return to content