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Safety of Testosterone Replacement Therapy

Adverse effects

Testosterone therapy is characterized by a wide margin of safety. Occasional adverse events for which there is evidence of association with testosterone administration include erythrocytosis (abnormally high numbers of red blood cells); acne and oily skin, particularly at the beginning of treatment and generally transient; reduced sperm production and fertility.1 Rarely, transient gynecomastia can occur at the beginning of treatment; in isolated cases frequent or sustained erections can occur. In these cases the dose must be reduced or the preparation withdrawn in order to prevent damage resulting from a sustained erection. Use of testosterone in high doses or over prolonged periods can result in clinically insignificant changes in lipid profiles. In predisposed men (e.g. marked obesity, chronic obstructive lung disease) induction or worsening of obstructive sleep apnea may rarely occur.1 The sleep apnea disappears when the testosterone therapy is discontinued.

Contraindications and Precautions

  • Testosterone replacement therapy should only be administered if hypogonadism has been established and other etiology that may be responsible for the signs and symptoms has been excluded.1-7 For example, pituitary tumor; hypopituitarism; diabetes insipidus; Alzheimer’s disease, vascular dementia; hypothyroidism; partial deficiency of adrenocorticotropic hormone; acute infection, inflammatory disease.
  • Although there are no clear indications that androgens actually generate prostatic carcinoma, they can enhance the growth of any existing prostatic carcinoma. Therefore carcinoma of the prostate has to be excluded before starting therapy with testosterone preparations.1-7
  • Androgens must not be given to patients with the very rare male breast cancer. As androgens are aromatized to estrogens, androgen therapy can stimulate proliferation of an estrogen-receptor-positive breast carcinoma.1-7 Gynecomastia, which can occur as a result of hypogonadism, is not a contraindication and usually subsides on androgen therapy.
  • As testosterone replacement therapy can be associated with an increase in hematocrit it should be avoided in patients with erythrocytosis.1-7
  • Because testosterone replacement therapy impairs production of sperm, it should be used with caution in men with fertility concerns.1,6
  • Testosterone replacement therapy is not recommended for use in children. In adolescents, although testosterone therapy may be indicated (e.g. in delayed puberty or other forms of primary or secondary hypogonadism), not all currently available testosterone preparations are approved for use in adolescents. Regulations relevant to your country of practice should be consulted.
  • Other conditions that can potentially be made worse by testosterone therapy include severe lower urinary tract symptoms associated with benign prostatic hypertrophy, severe congestive heart failure, and liver or renal disease.1-7
  • Abuse or overuse of testosterone treatment can be dangerous. For example, using higher than replacement doses to increase muscle bulk can cause acne, decreased testicular size, impotence, liver disease, heart attack, and stroke.Physicians should be aware of the signs and symptoms of anabolic abuse.

Guidelines on monitoring patients during testosterone replacement treatment

The international medical societies European Association of Urology (EAU), International Society for the Study of the Aging Male (ISSAM), International Society of Andrology (ISA), American Society of Andrology (ASA), and European Academy of Andrology (EAA) have issued recommendations on the definition, investigation, treatment and follow-up of men with late-onset hypogonadism.1,7 They recommend:

  • Evaluate the patient 3 months after commencing treatment then annually to assess response of signs and symptoms of hypogonadism to treatment and to evaluate any adverse effects. Failure to benefit clinical manifestations should result in discontinuation of treatment. As testosterone normally results in improvements in mood and well-being, the development of negative behavioral patterns during treatment calls for dose modifications or discontinuation of therapy.
  • Monitor serum testosterone levels 2–3 months after commencing treatment to ensure levels in the mid-normal physiological range have been attained.
  • Check hematocrit at baseline, at 3 months, and then annually. Therapy should be stopped if hematocrit is >54%, indicating erythrocytosis. Patient should be evaluated for hypoxia and sleep apnea. When hematocrit decreases to a safe level therapy may be reintroduced at a decreased dose.
  • Measure bone mineral density of lumbar spine and/or femoral neck after 1–2 years of testosterone therapy in men with osteoporosis or low trauma fracture.
  • Perform digital rectal examination and determination of prostate-specific antigen (PSA) levels at baseline in men over the age of 45 years, then at 3 to 6 months after commencing testosterone treatment, at 12 months, and then yearly thereafter (or according to standard prostate cancer screening protocols).
  • Evaluate formulation-specific adverse events at each visit.

Useful additional advice for men with hypogonadism

Prevent osteoporosis

  • Lifestyle and dietary changes to prevent osteoporosis are advised, including regular exercise and adequate amounts of calcium and vitamin D in the diet.

Learn about erectile dysfunction or infertility

  • Knowing what to expect and how to cope if erectile dysfunction or infertility are present can reduce psychological and relationship problems.

Reduce stress

  • Advice on minimizing the anxiety and stress that can accompany hypogonadism can benefit patients. Details on the availability of psychological or family counselling and support groups can help the patient and his family to understand and deal with the diagnosis.

Allow time for the benefits of testosterone replacement therapy to appear

  • Improvements in signs and symptoms of low testosterone, such as libido, sexual, physical and mental functioning and mood, may take several months to fully appear.
  • Useful patient support and information websites are included in the Useful information resources for healthcare professionals and their patients section.

  1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006; 91(6): 1995-2010.
  2. Qoubaitary A, Swerdloff RS, Wang C. Advances in male hormone substitution therapy. Expert Opin Pharmacother 2005; 6(9): 1493-506.
  3. Seftel A. Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents. Int J Impot Res 2007; 19(1): 2-24.
  4. Sharma V, Perros P. The management of hypogonadism in aging male patients. Postgrad Med 2009; 121(1): 113-21.
  5. Tung DS, Cunningham GR. Androgen deficiency in men. The Endocrinologist 2007; 17(2): 101-115.
  6. Zitzmann M, Nieschlag E. Testosterone substitution: current modalities and perspectives. J Reproduktionsmed Endokrinol 2006; 3(2): 109-116.
  7. Wang, C., E. Nieschlag, R. Swerdloff, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol 2008, 159(5): 507-514‚Äč.