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Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials

Lin Xu, Guy Freeman, Benjamin J Cowling and C Mary Schooling*

BMC Medicine 2013, 11:108  doi:10.1186/1741-7015-11-108

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Differing Cardiovascular Risk Between Transdermal and Intramuscular Testosterone Administration?

Joshua Yarrow   (2013-05-29 14:12)  Malcom Randall VA Medical Center

Xu et al., [1] reported the largest meta-analysis to-date evaluating cardiovascular-related event risk in men receiving exogenous testosterone (T). In contrast to all previous meta-analyses on this topic [2-4], the authors report that exogenous T significantly increased risk of cardiovascular-related events and that risk appeared higher in trials not funded by the pharmaceutical industry vs. those receiving pharmaceutical funding. However, we believe the authors overlooked an important concept regarding mode of T administration (i.e., transdermal patch/gel vs. intramuscular). From the data presented by Xu et al., we observed that the Odds Ratios (ORs) were >1.0 for 14/23 randomized clinical trials (RCTs) administering either transdermal or intramuscular T [5-26]. Of these, the ORs were >1.0 for 10/12 RCTs administering transdermal T and for 4/11 RCTs administering intramuscular T. Importantly, the ORs were ≤1.0 for only 9 RCTs included in this meta-analysis (Figure 4 from Xu et al. [1]), of which 7/9 [including the 5 with the lowest ORs (ranging from 0.08 - 0.29)] administered intramuscular T. In contrast, the 3 RCTs with the highest ORs (ranging from 4.17 - 6.05) administered transdermal T.

Additionally, Xu et al., [1] appropriately included findings from RCTs that utilized T formulations that have not received FDA-approval in the United States, which raises an interesting question. Do cardiovascular-related events differ between T formulations that are approved for use by the FDA? Using the data provided by Xu et al., we surmise that 17 RCTs included in the meta-analysis administered T via FDA-approved formulations [5-19, 22-23], while 10 administered oral T formulations or T-undecanoate that are not FDA-approved (see Xu et al. [1] for complete list). Of those RCTs using FDA-approved formulations, 10/17 had ORs >1.0 and 7/17 had ORs ≤1.0 (Figure 4 from Xu et al. [1]). We further divided these RCTs transdermal vs. intramuscular T formulations and observed the following 1) a total of 12 RCTs administered transdermal T using FDA-approved formulations, of which 10/12 had ORs >1.0 (including the 3 studies with the highest ORs) [5-9, 12, 16-19, 22, 23] and 2) a total of 5 RCTs administered intramuscular T using FDA-approved formulations [10-11, 13-15] , of which 4/5 had ORs ≤1.0 (ranging from 0.12 - 0.29). Interestingly, of the aforementioned, the only RCT with an OR >1.0 that administered intramuscular reported only one cardiovascular-related event [13].

Given this data, there appears to be a distinction in the risk for T-induced cardiovascular-related events based on mode of T administration, with transdermal T formulations presenting more risk than intramuscular T. Interestingly, this differing relationship appears to persist for T formulations that are FDA-approved. For example, 82 cardiovascular-related events occurred in men receiving transdermal T (via FDA-approved formulations) vs. 46 receiving transdermal placebo. In contrast of only 2 cardiovascular-related events occurred in men receiving intramuscular T (via FDA-approved formulations) vs. 5 receiving intramuscular placebo. As such, we caution against over-generalization of the findings from the Xu et al. meta-analysis, until more rigorous analyses are conducted that directly examine whether T formulation/mode of administration influence cardiovascular-related event risk in older hypogonadal men.

1. Xu L, Freeman G, Cowling BJ, Schooling CM: Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013, 11:108.

2. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S: Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005, 60:1451-1457.

3. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, Sideras K, Uraga MV, Erwin PJ, Montori VM: Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007, 82:29-39.

4. Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM: Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010, 95:2560-2575.

5. Snyder PJ, Peachey H, Berlin JA, Rader D, Usher D, Loh L, Hannoush P, Dlewati A, Holmes JH, Santanna J, Strom BL: Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med 2001, 111:255-260.

6. Spitzer M, Basaria S, Travison TG, Davda MN, Paley A, Cohen B, Mazer NA, Knapp PE, Hanka S, Lakshman KM, Ulloor J, Zhang A, Orwoll K, Eder R, Collins L, Mohammed N, Rosen RC, DeRogatis L, Bhasin S: Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med 2012, 157:681-691.

7. Marin P, Holmang S, Gustafsson C, Jonsson L, Kvist H, Elander A, Eldh J, Sjostrom L, Holm G, Bjorntorp P: Androgen treatment of abdominally obese men. Obes Res 1993, 1:245-251.

8. Kaufman JM, Miller MG, Garwin JL, Fitzpatrick S, McWhirter C, Brennan JJ: Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med 2011, 8:2079-2089.

9. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S: Adverse events associated with testosterone administration. N Engl J Med 2010, 363:109-122.

10. Hall GM, Larbre JP, Spector TD, Perry LA, Da Silva JA: A randomized trial of testosterone therapy in males with rheumatoid arthritis. Br J Rheumatol 1996, 35:568-573.

11. Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C: Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997, 82:1661-1667.

12. 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, 102:1906-1911.

13. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL: Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004, 89:503-510.

14. Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S: Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 2004, 59:75-78.

15. Svartberg J, Aasebo U, Hjalmarsen A, Sundsfjord J, Jorde R: Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respir Med 2004, 98:906-913.

16. Brockenbrough AT, Dittrich MO, Page ST, Smith T, Stivelman JC, Bremner WJ: Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. Am J Kidney Dis 2006, 47:251-262.

17. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS: Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 2006, 27:57-64.

18. Merza Z, Blumsohn A, Mah PM, Meads DM, McKenna SP, Wylie K, Eastell R, Wu F, Ross RJ: Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Int J Androl 2006, 29:381-391.

19. Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla MC, Tindall DJ, Melton LJ 3rd, Smith GE, Khosla S, Jensen MD: DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006, 355:1647-1659.

20. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM: Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 2009, 54:919-927.

21. Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, Spera G: 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. J Sex Med 2010, 7:3495-3503.

22. Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, Wu FC: 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, 95:639-650.

23. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS: Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011, 34:828-837.

24. Ho CC, Tong SF, Low WY, Ng CJ, Khoo EM, Lee VK, Zainuddin ZM, Tan HM: A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the Aging Male Symptoms scale. BJU Int 2012, 110:260-265.

25. 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, 73:602-612.

26. Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR, Liu PY: Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial. Eur J Endocrinol 2012, 167:531-541.

Joshua F. Yarrow, PhD
Research Health Scientist
Malcom Randall VA Medical Center, Gainesville, FL

Stephen E. Borst, PhD
Associate Director of Research
Geriatrics Research, Education, and Clinical Center (GRECC)
Malcom Randall VA Medical Center, Gainesville, FL

Competing interests

The authors report no conflicts of interest.

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Provide a descriptive title for your comment here...Problems in the screening of articles for the meta-analysis

Andre Guay   (2013-05-21 10:12)  Department of Endocrinology, Center for Sexual Function, Lahey Clinic,Peabody,MA,USA email

Type youTestosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials

Lin Xu, Guy Freeman, Benjamin J Cowling, C MARY Schooling

Comment

Xu, et al, (1) in their recent meta-analysis suggested that very high levels of androgens may promote cardiovascular (CV) disease. However, this meta-analysis neither provided any correlation of CV events with actual testosterone (T) levels, nor there was any screening for levels of T in some selected studies included in this meta-analysis. This is probably why this meta-analysis did not include many more of the studies published in the literature. It is disturbing that the authors did not comment on a number of epidemiological and interventional studies with opposite conclusions from their own (2-7).

It is worthy to note that levels of T were not elevated with CV in some of the studies included in this meta-analysis. Further, some studies may have had low levels of T due to use of testosterone formulations that do not result in sustained physiological level of T for long period of time. In three of the studies included in this meta-analysis ( ref 5,61,48) the T esters used were inadequate to provide physiological levels. Simply these formulations produced a supra-physiological levels of T during the first 2-3 days, and a very low levels of T over the ensuing 10 -15 days. Two of the studies used oral T undecanoate or T enanthate, in which it is known that T levels are low and in one case are below those found in the placebo arm (8) due to erratic absorption and rapid clearance, and more doses per day are need. Several studies included in this meta-analysis used the T patch ( ref 58,59,60) which also suffers from serious limitations in T delivery and may not produce the physiological levels required and might be suspect as many men do not get adequate levels with this dosage.

Furthermore, inclusion of studies with very well recognized design flaws in this meta- analysis has definitely skewed the data and made it difficult to draw any accurate and warranted conclusions

Without correlating plasma T levels with CV events, we do not believe that the conclusions made in this study are supported by the data derived from the poorly thought out and equally ill-designed studies included in this meta-analysis. Indeed, supraphysiological levels of T and very low levels of T may be associated with increased CV risk. But to date, there are no data to suggest that physiological T levels contribute to CV risk. On the contrary, several other meta-analyses have been published (9-17) with the opposite conclusions from that drawn by Xu et al (1). It is disconcerting that the authors did not address in their discussion any of these studies and did not comment on why their conclusions were different from those in previous studies.

1. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013 Apr 18;11:108.
2. Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, Ljunggren O, Vandenput L, Mellström D, Tivesten A. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011 Oct 11;58(16):1674-81
3.Firtser S, Juonala M, Magnussen CG, Jula A, Loo BM, Marniemi J, Viikari JS, Toppari J, Perheentupa A, Hutri-Kähönen N, Raitakari OT. Relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24-45 years. The Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2012 May;222(1):257-62. doi: 10.1016/j.atherosclerosis.2012.02.020. Epub 2012 Feb 21.

4. Hildreth KL, Barry DW, Moreau KL, Vande Griend J, Meacham RB, Nakamura T, Wolfe P, Kohrt WM, Ruscin JM, Kittelson J, Cress ME, Ballard R, Schwartz RS. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab. 2013 May;98(5):1891-900. doi: 10.1210/jc.2012-3695. Epub 2013 Mar 26.
5. Effects of testosterone on muscle strength, physical function, body composition, and Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, Wu FC. 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):639-50.

6. Corona G, Rastrelli G, Vignozzi L, Mannucci E, Maggi M (2011) Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab 25:337:353.

7. Yeap BB, Hyde Z, Almeida OP, Norman PE, Chubb SA, Jamrozik K, Flicker L, Hankey GJ (2009) Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab 94:2353:2359.

8. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. 2008 Jan 2;299(1):39-52.
9. Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, Lenzi A, Forti G, Mannucci E, Maggi M.Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011 Jan;8(1):272-83. doi: 10.1111/j.1743-6109.2010.01991.x. Epub 2010 Aug 30.

10. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA.Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011 Oct;96(10):3007-19. doi: 10.1210/jc.2011-1137. Epub 2011 Aug 3.

11. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011 Jun;97(11):870-5. doi: 10.1136/hrt.2010.210757. Epub 2010 Dec 21.

12. Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT.Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol. 2011 Feb;40(1):189-207. doi: 10.1093/ije/dyq158. Epub 2010 Sep 24.

13. Wan ZH, Wen YB, Ding QF, Xu TY. [Effects of testosterone substitution on metabolic syndrome-related factors in hypogonadal males: a meta-analysis]. Zhonghua Nan Ke Xue. 2010 Jun;16(6):510-5.

14. Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010 Jun;95(6):2560-75. doi: 10.1210/jc.2009-2575.

15. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM.Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007 Jan;82(1):29-39.

16. Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A, Isidori A, Fabbri A, Lenzi A. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf). 2005 Oct;63(4):381-94.

17. Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal JA, Armstrong PW, Ezekowitz JA. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail. 2012 May 1;5(3):315-21. doi: 10.1161/CIRCHEARTFAILURE.111.965632.

André Guay MD, FACP, FACE, IF
Clinical Professor of Medicine (Endocrinology)
Tufts University School of Medicine, Boston, MA

Abdulmaged Traish PhD, MPH, MBA
Professor of Urology and Biochemistry
Boston University School of Medicine, Boston, MA
r comment here...

Competing interests

A competing interest exists when your professional judgment about a paper could possibly be influenced by considerations other than the paper's validity or importance. Detail possible competing interests here...

In the past year, I have been on the Advisory Board of Actient, recently bought out by Auxilium. My role was to make a teaching slide deck for physicians teaching about hypogonadism

I have not done research on any testosterone product

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