Safety profile of testosterone therapy
- Increased haematocrit
- PSA increased
- Acne and oily skin (particularly at the beginning of treatment and generally transient)
- Reduced sperm production and fertility
The use of Nebido is contraindicated in men with:
- Androgen-dependent carcinoma of the prostate or of the male mammary gland
- Past or present liver tumours
- Hypersensitivity to the active substance or to any of the excipients.
The use of Nebido in women is contraindicated.
(The following is an excerpt from the European Association of Urology guidelines on hypogonadism).2
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 systematic reviews 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.4,5 According to a 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.6 No randomised placebo-controlled trials are available yet to document its longterm safety profile in these patients.
Nebido is contraindicated in men with androgen-dependent carcinoma of the prostate or of the male mammary gland.
The fear of increased risk of heart attack and stroke was mainly caused by two high profile studies.7,8 The European licensing authority found that the signal for an increased cardiovascular risk associated with the use of testosterone was weak and inconclusive.9 Since the publication of these studies in 2013 / 2014, many new studies have refuted the alleged cardiovascular risks10-23, and support the position statement of the European licensing authority that testosterone therapy is not associated with increased risk of heart attack and stroke. To the contrary, many of the newer studies actually show reduced risk of cardiovascular events as well as reduced mortality.10-23
In patients suffering from severe cardiac, or ischaemic heart disease, treatment with testosterone may cause severe complications characterised by oedema with or without congestive cardiac failure. In such case, treatment must be stopped immediately.
- 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)
- Haematocrit > 54% (EAU guidelines) or >48% (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
- Androgen-dependent carcinoma of the prostate or of the male mammary gland
- Past or present liver tumours
- Hypersensitivity to the active substance or to any of the excipients
- The use of Nebido in women is contraindicated
It should be noted that in a 2015 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.24
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.25-30 Even in men with severe LUTS, no differences in IPSS were seen in men receiving testosterone replacement therapy vs. placebo.30 Notably, there was actually a small improvement in IPSS scores in the testosterone-treated group.30
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.31,32 Also, in healthy men without obstructive sleep apnoea, testosterone therapy does not cause any adverse sleep related effects.25 Please refer to the SmPC for a full list of contraindications and precautions. Sleep apnoea has been reported under treatment with testosterone-containing preparations and pre-existing sleep apnoea may be potentiated. Urinary disorders are listed as adverse reactions in the SmPC.
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 peak oxygen uptake (p<0.01) and leg strength (p<0.05) in the testosterone treated group from baseline.33 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.
Please refer to the SmPC for a full list of contraindications and precautions.
- 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. Return to content
- Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S, Punab M. 2017 EAU Guidelines on Male Hypogonadism. Return to content
- 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. Return to content
- 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. Return to content
- 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. Return to content
- 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. 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
- 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 September 2020). 2014. 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
- Eisenberg ML, Li S, Herder D, Lamb DJ, Lipshultz LI. Testosterone therapy and mortality risk. Int J Impot Res. 2015;27(2):46-48. Return to content
- 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. Return to content
- 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. Return to content
- 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. Return to content
- 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). Return to content
- Patel P, Arora B, Molnar J, Khosla S, Arora R. Effect of testosterone therapy on adverse cardiovascular events among men: a meta-analysis. J Am Coll Cardiol. 2015;65(March). 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
- 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 Return to content
- 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. Return to content
- 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. Return to content
- 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. Return to content
- 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. Return to content
- 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. Return to content
- 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 Aug;90(8):1104-15. doi: 10.1016/j.mayocp.2015.06.002. Epub 2015 Jul 20. PMID: 26205546. Return to content
- 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. Return to content
- 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. Return to content
- 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. 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
- 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
- Tan WS, Low WY, Ng CJ, et al. Efficacy and safety of long-acting intramuscular testosterone undecanoate in ageing men: a randomised controlled study. BJU Int. 2013;111(7): 1130-1140. Return to content
- 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. Return to content
- 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, placebocontrolled trial. J Sleep Res. 2013;22(3):331-336. Return to content
- 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. Return to content
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