Safety of testosterone therapy

Testosterone therapy has a wide margin of safety.1-3 Occasional side effects for which there is evidence of association with testosterone administration include:

  • Small elevation in hematocrit within the normal range.
  • Small elevation in PSA level within the normal range.
  • Acne and oily skin (particularly at the beginning of treatment and generally transient).
  • Reduced sperm production and fertility.
  • Frequent or sustained erections (this is uncommon).

If elevations in hematocrit or PSA exceed the upper limit of the normal range, dose reduction or temporary break from testosterone therapy is recommended, until levels return to normal range.1-3

Prostate cancer concerns

(The following is an excerpt from the European Association of Urology guidelines on hypogonadism).2

Short-term randomised controlled trials support the hypothesis that testosterone treatment does not result in changes in prostatic histology nor in a significant increase in intraprostatic testosterone and DHT.4,5 Observational studies indicate that testosterone therapy does not increase the risk of developing prostate cancer, and does not result in more aggressive prostate tumours.4,6-8

Testosterone treatment is clearly contraindicated in men with advanced prostate cancer. A topic under debate is the use of testosterone treatment in hypogonadal men with history of prostate cancer and no evidence of active disease. So far only studies with a limited number of patients and a relatively short period of follow-up are available and indicate no increased risk for prostate cancer recurrence.9,10 According to a recent retrospective study on hypogonadal men with previous history of prostate cancer receiving testosterone following cancer diagnosis, treatment was not associated with increased overall or cancer-specific mortality, but testosterone treatment was more likely to be prescribed in patients undergoing radical prostatectomy for well-differentiated tumours.11 No randomised placebo-controlled trials are available yet to document its long-term safety in these patients.

Symptomatic hypogonadal men who have been surgically treated for localised prostate cancer and who are currently without evidence of active disease (i.e. measurable PSA, abnormal rectal examination, evidence of bone/visceral metastasis) can be cautiously considered for testosterone treatment.12 In these men, treatment should be restricted to those patients with a low risk for recurrent prostate cancer (i.e. Gleason score < 8; pathological stage pT1-2; pre-operative PSA < 10 ng/ml). It is advised that therapy should not start before one year of follow-up after surgery and patients should be without PSA recurrence.12

Patients who underwent brachytherapy or external beam radiation (EBRT) for low risk prostate cancer can also be cautiously considered for testosterone treatment in case of symptomatic hypogonadism with a close monitoring of prostate cancer recurrence.11-13 However, no long-term safety data are available in these patients.

More information about testosterone and testosterone therapy can be found in our Research News section:

  • Is there a protective role of testosterone against high-grade prostate cancer?15 April 2017Is there a protective role of testosterone against high-grade prostate cancer? read more
  • Testosterone Therapy in Men with Prostate Cancer – new research16 November 2016Testosterone Therapy in Men with Prostate Cancer – new research read more
  • Dispelling the myth of testosterone treatment and prostate cancer15 October 2016Dispelling the myth of testosterone treatment and prostate cancer read more
  • Incidence of Prostate Cancer after Testosterone Therapy for up to 17 years1 April 2015Incidence of Prostate Cancer after Testosterone Therapy for up to 17 years read more
  • Image: Testosterone and Prostate Cancer - a paradigm shift27 June 2014Testosterone and Prostate Cancer - a paradigm shift read more

Heart disease concerns

The fear of increased risk of heart attack and stroke was mainly caused by two high profile but flawed studies.14,15 No such concerns were expressed by the European Medicine Agency.16 Since the publication of these studies in 2013 / 2014, many new studies have refuted the alleged cardiovascular risks 17-30, and support the position statement of the European Medicine Agency that testosterone therapy is not associated with increased risk of heart attack and stroke. To the contrary, many of the new studies actually show reduced risk of cardiovascular events as well as reduced mortality.17-30

  • Real-life data - men with testosterone deficiency and a history of cardiovascular disease benefit from long-term testosterone therapy15 July 2016Real-life data - men with testosterone deficiency and a history of cardiovascular disease benefit from long-term testosterone therapyread more
  • Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease: Real-Life Results15 February 2017Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease: Real-Life Resultsread more
  • Testosterone treatment is not associated with risk of adverse cardiovascular events – RHYME study15 December 2016Testosterone treatment is not associated with risk of adverse cardiovascular events – RHYME studyread more
  • Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetes15 March 2016Testosterone levels, testosterone therapy and all-cause mortality in men with type 2 diabetesread more
  • Testosterone Replacement Therapy and Mortality in Older Men15 December 2015Testosterone Replacement Therapy and Mortality in Older Menread more
  • Testosterone Therapy and Cardiovascular Risk 1 June 2015Testosterone Therapy and Cardiovascular Riskread more
  • Testosterone and Cardiovascular Risk in Men29 November 2014Testosterone and Cardiovascular Risk in Menread more
  • Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men15 November 2015Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Menread more
  • Effective testosterone treatment reduces incidence of atrial fibrillation15 August 2017Effective testosterone treatment reduces incidence of atrial fibrillationread more
  • Testosterone, Mortality and Longevity1 May 2015Testosterone, Mortality and Longevityread more

Contraindications and Precautions for testosterone therapy

Clinical guidelines state the following contraindications against testosterone treatment: 2,31

  • Advanced or metastatic prostate cancer
  • Unevaluated prostate nodule or induration
  • Unevaluated PSA >4 ng/ml (>3 ng/ml in individuals at high risk for prostate cancer, such as African-Americans or men with first-degree relatives who have prostate cancer)
  • Hematocrit > 54% (EAU guidelines) or >50% (ES guidelines)
  • Severe LUTS associated with benign prostatic hypertrophy as indicated by AUA/IPSS >19
  • Uncontrolled or poorly controlled congestive heart failure
  • Desire for fertility in the near term (consider using alternative treatment with hCG or clomiphene citrate)

It should be noted that a recent analysis of randomised, double-blind, placebo-controlled trials (RCTs) concluded that severe lower urinary tract symptoms, as well as untreated sleep apnoea, may not be absolute contraindications to testosterone replacement therapy.32

Six new RCTs all show that testosterone replacement therapy in patients with LUTS does not worsen LUTS symptoms – measured by the validated International Prostate Symptom Score (IPSS) questionnaire – compared to placebo.33-38 Even in men with severe LUTS, no differences in IPSS were seen in men receiving testosterone replacement therapy vs. placebo.38 Notably, there was actually a small improvement in IPSS scores in the testosterone-treated group.38

Regarding untreated severe obstructive sleep apnoea (which was a contraindication in older guidelines), new RCTs show no worsening in sleep-related parameters after testosterone therapy vs. placebo.39,40 Also, in healthy men without obstructive sleep apnoea, testosterone therapy does not cause any adverse sleep related effects.33

The guidelines also cite severe, uncontrolled, or poorly controlled congestive heart failure as a relative contraindication to testosterone therapy. A placebo controlled trial of 41 hypogonadal men with stable congestive heart failure treated with injectable testosterone along with a standardised exercise regimen found significant improvements in peak oxygen uptake and leg strength in the testosterone treated group.41 This study suggests that men with well-controlled congestive heart failure may be considered for testosterone therapy. However, the specific contraindication against testosterone therapy in men with uncontrolled congestive heart failure remains unexamined.

References

1 Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686.

2 Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S, Punab M. 2017 EAU Guidelines on Male Hypogonadism.

3 Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. Appendix available at: http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf (accessed Jan 10, 2016). CMAJ. 2015;187(18):1369-1377.

4 Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296(19):2351-2361.

5 Thirumalai A, Cooper LA, Rubinow KB, et al. Stable Intraprostatic Dihydrotestosterone in Healthy Medically Castrate Men Treated With Exogenous Testosterone. J Clin Endocrinol Metab. 2016;101(7):2937-2944.

6 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.

7 Cooper CS, Perry PJ, Sparks AE, MacIndoe JH, Yates WR, Williams RD. Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men. J Urol. 1998;159(2):441-443.

8 Baillargeon J, Kuo YF, Fang X, Shahinian VB. Long-term Exposure to Testosterone Therapy and the Risk of High Grade Prostate Cancer. J Urol. 2015;194(6):1612-1616.

9 Shabsigh R, Crawford ED, Nehra A, Slawin KM. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. Int J Impot Res. 2009;21(1):9-23.

10 Kaplan AL, Hu JC, Morgentaler A, Mulhall JP, Schulman CC, Montorsi F. Testosterone Therapy in Men With Prostate Cancer. Eur Urol. 2016;69(5):894-903.

11 Kaplan AL, Trinh QD, Sun M, et al. Testosterone replacement therapy following the diagnosis of prostate cancer: outcomes and utilization trends. The journal of sexual medicine. 2014;11(4):1063-1070.

12 Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004;172(3):920-922.

13 Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007;109(3):536-541.

14 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.

15 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.

16 European Medicines Agency. No consistent evidence of an increased risk of heart problems with testosterone medicines. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Testosterone_31/Position_provided_by_CMDh/WC500177617.pdf (accessed October 21, 2017). 2014.

17 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.

18 Eisenberg ML, Li S, Herder D, Lamb DJ, Lipshultz LI. Testosterone therapy and mortality risk. Int J Impot Res. 2015;27(2):46-48.

19 Janmohamed S, Cicconetti G, Koro CE, Clark RV, Tarka E. The Association Between Testosterone Use and Major Adverse Cardiovascular Events (MACE): An Exploratory Retrospective Cohort Analysis of Two Large, Contemporary, Coronary Heart Disease Clinical Trials. Endocrine Rev 2015; 36 (suppl.): OR34-34.

20 Li H, Benoit K, Wang W, Motsko S. Association Between the use of exogenous testosterone therapy and risk of venous thrombotic events among exogenous testosterone treated and untreated men with hypogonadism. J Urol 2016;195:1065-1072.

21 Haider A, Haider KS, Doros G,Saad F,Rosano GMC. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy, observational, real-life data from a registry study. Vascul Health Risk Management 2016;12:251-261.

22 Ali Z, Greer DM, Shearer R, Gardezi AS, Chandel A, Jahangir A. Effects of testosterone supplement therapy on cardiovascular outcomes in men with low testosterone. J Am Coll Cardiol. 2015;65(March).

23 Patel P, Arora B, Molnar J, Khosla S, Arora R. Effect of testosterone therapy on adverse cardiovasular events among men: a meta-analysis. J Am Coll Cardiol. 2015;65(March).

24 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.

25 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;36(40):2706-2715.

26 Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clin Proc. 2015;90(8):1038-1045.

27 Etminan M, Skeldon SC, Goldenberg SL, Carleton B, Brophy JM. Testosterone therapy and risk of myocardial infarction: a pharmacoepidemiologic study. Pharmacotherapy. 2015;35(1):72-78.

28 Ramasamy R, Scovell J, Mederos M, Ren R, Jain L, Lipshultz L. Association Between Testosterone Supplementation Therapy and Thrombotic Events in Elderly Men. Urology. 2015;86(2):283-285.

29 Anderson JL, May HT, Lappe DL, et al. Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. Am J Cardiol. 2016;117(5):794-799.

30 Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. J Cardiovasc Pharmacol Ther. 2017;22(5):414-433.

31 Haider A, Haider KS, Doros G,Saad F,Rosano GMC. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy, observational, real-life data from a registry study. Vascul Health Risk Management 2016;12:251-261.

32 Seftel AD, Kathrins M, Niederberger C. Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Mayo Clin Proc. 2015;90(8):1104-1115.

33 Hildreth KL, Barry DW, Moreau KL, et al. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab. 2013;98(5):1891-1900.

34 Del Fabbro E, Garcia JM, Dev R, et al. Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. Support Care Cancer. 2013;21(9):2599-2607.

35 Kenny AM, Kleppinger A, Annis K, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc. 2010;58(6):1134-1143.

36 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.

37 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.

38 Tan WS, Low WY, Ng CJ, et al. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU Int. 2013;111(7):1130-1140.

39 Hoyos CM, Killick R, Yee BJ, Grunstein RR, Liu PY. Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2012;77(4):599-607.

40 Killick R, Wang D, Hoyos CM, Yee BJ, Grunstein RR, Liu PY. The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebo-controlled trial. J Sleep Res. 2013;22(3):331-336.

41 Stout M, Tew GA, Doll H, et al. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J. 2012;164(6):893-901.


Last updated: 2018
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