Safety profile of testosterone therapy

Testosterone therapy has a well known safety profile.1-3 Side effects for which there is evidence of association with testosterone administration include:

 

  • 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.

 

If elevations in haematocrit 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

 

    (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.

    Clinical guidelines state the following contraindications against testosterone treatment:2,24

     

    • 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.

    References

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    • 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
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    • 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
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    • 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
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