Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men
November 2015
Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. Basaria S, Harman SM, Travison TG, et al. JAMA. 2015;314(6):570-581.
Currently there are only a few high quality studies investigating the effects of testosterone therapy for a duration of 3 years1-4, and medical societies have long been urging for more long-term studies evaluating the safety and efficacy of testosterone therapy.5-7
On August 11th2015 a notable 3-year long RCT was published in JAMA (Journal of the American Medical Association), which attracted a lot of attention.8 While interpreted by many as showing that testosterone therapy does not confer any benefits on atherosclerosis, sexual function and quality of life, a closer look at the data actually does show two important findings.
KEY POINTS
- The results of the 3-year long JAMA study were reported in the abstract as mainly neutral, concluding that testosterone therapy did not affect markers of atherosclerosis (intima-media thickness and coronary artery calcium score), nor improve overall sexual function or health-related quality of life.
- As expected, hematocrit and PSA levels increased more in the testosterone group, but values stayed largely within the normal range. This within-normal-range increase is a physiological response to testosterone therapy.
- Two important positive outcomes, which were not mentioned in the study abstract, were:
- The number of subjects reporting adverse events or serious adverse events did not differ between testosterone and placebo groups. This confirms that testosterone therapy is safe, even in men over 60 years of age.
- In men not taking statins, one marker of atherosclerosis (coronary artery calcium) was significantly lower in the testosterone group than in the placebo group.
- An important problem of the study, also not mentioned in the abstract, was that testosterone levels declined over time, despite dose-adjustments aiming to achieve testosterone levels between 500 and 900 ng/dL. This suggests low adherence and sub-optimal testosterone therapy.
What is known
Evidence for and against testosterone therapy is conflicting. Previous studies have shown an increase (in men with pre-existing morbidities)9 or no increase in adverse events10, and either increased11,12or reduced13-15risk of stroke and heart attacks. Three other studies even show increased longevity (reduced mortality risk) with testosterone therapy.14,16,17
Heart disease is caused by atherosclerosis.18 Two common techniques for measuring subclinical atherosclerosis – which reflects lifetime risk factor exposure19– is carotid intima-media thickness (CIMT) and coronary artery calcium (CAC).
CIMT has been validated as a measure of the atherosclerotic burden20 and of the risk for cardiovascular events.21 CAC reflects atherosclerotic plaque burden, because calcium deposits are related to the lipid and apoptotic remnants of the plaque.22
Many studies show that low testosterone levels are associated with increased atherosclerotic burden (measured by CIMT)23-33, and clinical trials of testosterone therapy have shown significant reductions in CIMT.34,35
What this study adds
The new study in JAMA aimed to determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels.8
156 participants were randomized to receive 7.5 g of 1% testosterone gel and 152 were randomized to receive placebo gel daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL (see commentary below).
Results showed that testosterone therapy did not affect markers of atherosclerosis (intima-media thickness and coronary artery calcium score), nor improve overall sexual function or health-related quality of life.
Testosterone therapy elevated hematocrit and PSA levels increased more in the testosterone group, but values stayed largely within the normal range. The number of participants reporting adverse events or serious adverse events did not differ between groups.
Two important positive outcomes, which were not mentioned in the study abstract, were:
- The number of subjects reporting adverse events or serious adverse events did not differ between testosterone and placebo groups. This confirms that safety is not a major issue in testosterone therapy.
- In men not taking statins, one marker of atherosclerosis (coronary artery calcium) was significantly lower in the testosterone group than in the placebo group.
Commentary
The finding that hematocrit and PSA elevations largely stayed within normal range, and that the number of participants reporting adverse events or serious adverse events did not differ between groups, is positive news, especially considering that this is one of the few long-term studies in men of advanced age (mean age 67 years).
There are several issues with this study. An important methodological problem - also not mentioned in the abstract - was that testosterone levels declined over time despite dose-adjustments aiming to achieve testosterone levels between 500 and 900 ng/dL. This suggests low adherence and sub-optimal testosterone therapy. Data for achieved testosterone were only reported graphically (figure 1), as opposed to numerically, making it harder to see actual absolute changes in testosterone levels.
Figure 1: Total and free testosterone levels at baseline and during testosterone therapy. Figure reprinted with permission from: Basaria S, Harman SM, Travison TG, et al. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA. 2015;314(6):570-581
Nevertheless, looking at the graphs in the original paper, the following approximate testosterone levels were achieved (see red lines in figure 1):
6 months: total testosterone: 640 ng/dL free testosterone: 120 pg/mL
18 months: total testosterone: 600 ng/dL free testosterone: 110 pg/mL
36 months: total testosterone: 460 ng/dL free testosterone: 85 pg/mL
This clearly shows that the study failed to achieve testosterone levels between 500 and 900 ng/dL for the total duration of the study, especially after the 18 month mark, after which levels in both total and free testosterone drastically plummeted. This was not reported in the study abstract. It is notable that this reduction in testosterone levels occurred despite the prescribed use of a relatively high dose of testosterone gel – 7.5 g per day – as opposed to the recommended starting dose of 5 g per day. Thus, strictly speaking, this was off-label use.
Because of the failure to maintain testosterone levels in the targeted therapeutic range, the conclusion that testosterone therapy (which maintains effective therapeutic testosterone levels throughout the treatment duration) does not reduce atherosclerosis progression, is be premature.
Another important issue is that two thirds of the subjects in the testosterone group were taking statins. It is well-documented that statins36-38- which are widely prescribed for dyslipidemia – significantly reduce endogenous testosterone levels. Hence, it is possible that statins could partly counteract benefits of testosterone therapy, which in this case would be the rate of progression (or regression) of subclinical atherosclerosis.
The placebo group experienced a marked reduction in cholesterol levels (both total and LDL cholesterol). As medication dosages were not reported, this raises the question if the placebo group increased their statin dose. If so, this would explain both the cholesterol reductions, the drop in testosterone levels – especially free testosterone (see figure 1) - and the lack of effect on subclinical atherosclerosis.
Regarding safety, it should be pointed out that the hematocrit and PSA elevations in the testosterone group stayed within the normal range, and are to be expected with testosterone therapy. More importantly, the number of subjects reporting adverse events or serious adverse events did not differ between testosterone and placebo groups. These are solid data supporting the concept that testosterone therapy does not increase atherosclerosis / cardiovascular risk – and may actually reduce it in men who are not taking statins - and confirms that long-term testosterone therapy is probably safe.
Regarding sexual function, it has to be underscored that the study subjects were selected solely based on testosterone levels, without requirement for symptoms. Moreover, the cut-off for testosterone was 400 ng/dL (13.9 nmol/L), and most of the testosterone-treated patients (54.2%) had testosterone levels above 300 ng/dL (10.4 nmol/L). According to a study by Buvat et al., testosterone improves sexual function only in men with levels below a threshold of 300 ng/dL.39 Zitzmann et al. identified 8 nmol/L (231 ng/dl) as a threshold for erectile dysfunction.40
Thus, as baseline testosterone levels were above 300 ng/dL in most testosterone treated men and sexual function already was good - as indicated by the greater baseline scores for sexual desire and orgasmic function - it is unrealistic to expect sexual function or quality of life to improve markedly. Especially considering that the treatment failed to maintain effective therapeutic testosterone levels thoughts the 3 year treatment. Nonetheless, the curves for sexual symptoms are all better numerically in the testosterone group than in the placebo group, although differences were not significant. As illustrated in figure 2, all sexual function parameters trended in the same directions as the changes in testosterone levels.
Figure 2: Sexual function at baseline and during testosterone therapy.
Finally, it is critical to remember that each androgen dependent effect has its own testosterone threshold.41 Lack of improvement in sexual function and quality of life – two outcomes that require only relatively low testosterone levels40– does not mean that other effects (such as subclinical atherosclerosis, body fat loss and muscle gain) would not improve from testosterone therapy that achieves a higher and sustained therapeutic elevation in testosterone levels. In fact, previous studies that did achieve effective therapeutic testosterone levels for a sufficient duration have shown reductions in subclinical atherosclerosis34,35, and previous 3-year long testosterone therapy studies did report significant body fat loss and increases in lean body mass (muscle) gain.2,42
Recommendations
References
- Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J. Clin. Endocrinol. Metab. 2004;89(2):503-510. Return to content
- Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J. Clin. Endocrinol. Metab. 2005;90(3):1502-1510. Return to content
- Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J. Clin. Endocrinol. Metab. 1999;84(6):1966-1972. Return to content
- Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J. Clin. Endocrinol. Metab. 1999;84(8):2647−2653. Return to content
- Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2010;95(6):2536-2559. Return to content
- Dohle GR, Arver S, Bettocchi C, al. e. EAU Guidelines on Male Hypogonadism. European Association of Urology 2012. Return to content
- Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J. Androl. 2009;30(1):1-9. Return to content
- Basaria S, Harman SM, Travison TG, et al. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA. 2015;314(6):570-581. Return to content
- Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 2010;363(2):109-122. Return to content
- Srinivas-Shankar U, Roberts SA, Connolly MJ, 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;95(2):639-650. Return to content
- Vigen R, ODonnell 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
- Baillargeon J, Urban RJ, Kuo YF, et al. Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Ann. Pharmacother. 2014;48(9):1138-1144. Return to content
- Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur. Heart J. 2015. Return to content
- Tan RS, Cook KR, Reilly WG. Myocardial Infarction and Stroke Risk in Young Healthy Men Treated with Injectable Testosterone. International journal of endocrinology. 2015;2015:970750. 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
- Toth PP. Subclinical atherosclerosis: what it is, what it means and what we can do about it. Int. J. Clin. Pract. 2008;62(8):1246-1254. Return to content
- Erbel R, Budoff M. Improvement of cardiovascular risk prediction using coronary imaging: subclinical atherosclerosis: the memory of lifetime risk factor exposure. Eur. Heart J. 2012;33(10):1201-1213. Return to content
- Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2002;106(16):2055-2060. 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
- Schmermund A, Mohlenkamp S, Erbel R. Coronary artery calcium and its relationship to coronary artery disease. Cardiol. Clin. 2003;21(4):521-534. Return to content
- De Pergola G, Pannacciulli N, Ciccone M, Tartagni M, Rizzon P, Giorgino R. Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int. J. Obes. Relat. Metab. Disord. 2003;27(7):803-807. 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
- Fu L, Gao QP, Shen JX. Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian journal of andrology. 2008;10(2):214-218. Return to content
- Fukui M, Kitagawa Y, Nakamura N, et al. Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. J. Androl. 2003;26(6):1869-1873. 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
- 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
- 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
- MTsujimura 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. 2014;17(2):63-65. Return to content
- Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. Eur. J. Epidemiol. 2003;157(1):25-31. Return to content
- Francomano D, Bruzziches R, Barbaro G, Lenzi A, Aversa A. Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. J. Endocrinol. Invest. 2014;37(4):401-411. 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
- Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Medicine. 2013;11:57. Return to content
- Corona G, Boddi V, Balercia G, et al. The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction. The journal of sexual medicine. 2010;7(4 Pt 1):1547−1556. Return to content
- Cohen PG. Statins and male hypogonadism. The journal of sexual medicine. 2011;8(6):1826. Return to content
- Buvat J, Montorsi F, Maggi M, et al. Hypogonadal men nonresponders to the PDE5 inhibitor tadalafil benefit from normalization of testosterone levels with a 1% hydroalcoholic testosterone gel in the treatment of erectile dysfunction (TADTEST study). The journal of sexual medicine. 2011;8(1):284-293. Return to content
- Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J. Clin. Endocrinol. Metab. 2006;91(11):4335- 4343. Return to content
- Sattler F, Bhasin S, He J, et al. Testosterone threshold levels and lean tissue mass targets needed to enhance skeletal muscle strength and function: the HORMA trial. J. Gerontol. A. Biol. Sci. Med. Sci. 2011;66(1):122-129. Return to content
- Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men J. Clin. Endocrinol. Metab. 2000;85(8):2839- 2853. Return to content
