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:

 

  • Elevation in hematocrit within the normal range.
  • 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

 

    (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.

    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 risks17-30, 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

    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)
    • Past or present liver tumours
    • The use of Nebido in women is contraindicated.

     

    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 therapy.32

     

    Six new RCTs all show that testosterone 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 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.

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