Symptoms to Diagnosis

An obese 48-year-old man with progressive fatigue and decreased libido

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The physician counsels the patient regarding the implications, potential adverse outcomes, and available treatments for his obesity, including lifestyle modification and bariatric surgery. The patient declines surgery and wishes to adopt a weight-reducing diet and exercise program, for which he is referred to a dietitian.

In addition, in view of the patient’s clinically and biochemically proven hypogonadism, his physician offers testosterone replacement therapy. He orders a serum prostate-specific antigen (PSA) level, which is 1.3 ng/dL (reference range < 4 ng/dL). The patient is prescribed 5 g of 1% testosterone gel daily.


4. Which is the most common adverse effect of testosterone replacement therapy?

  • Cardiovascular events
  • Erythrocytosis
  • Prostate cancer
  • Infertility
  • Obstructive sleep apnea
Table 5. Benefits of testosterone therapy
Testosterone is indicated for men with an established diagnosis of hypogonadism. The benefits of testosterone replacement are summarized in Table 5.5,6

Clinicians should be very cautious in initiating testosterone replacement therapy in any patient with an unstable medical condition.

There are several formulations of testosterone replacement therapy, including intramuscular injections, transdermal gels or patches, buccal tablets, an intranasal gel, and oral tablets. Of note, there are 2 different forms of oral testosterone preparations: testosterone undecanoate and 17-alpha alkylated testosterone. The former is unavailable in the United States and the latter is not recommended for use due to its proven hepatic toxicity.41

Testosterone and erythrocytosis

Meta-analyses have concluded that the most frequent adverse event of testosterone replacement therapy is a significant rise in hematocrit.42 This rise was found to be dose-dependent and was more marked in older men.43 Although all preparations can cause erythrocytosis, parenteral forms have been observed to raise it the most, particularly short-term injectables.44,45

The mechanism behind this increase is attributed to increased erythropoietin levels and improved usage of iron for red blood cell synthesis.46 In fact, testosterone replacement therapy has been shown to improve hemoglobin levels in patients with anemia.47 On the other hand, increasing hematocrit levels may lead to thrombotic and vasoocclusive events.44

Figure 1. Hematocrit monitoring for patients on testosterone replacement therapy.

Figure 1. Hematocrit monitoring for patients on testosterone replacement therapy.

It is strongly recommended that baseline hematocrit levels be measured before initiating testosterone replacement therapy.5,6 The hematocrit level should also be monitored 3 to 6 months into treatment and yearly thereafter while on testosterone.5Figure 1 summarizes the appropriate steps to undertake regarding hematocrit levels, according to the American Urological Association.6

Testosterone and prostate cancer

The relationship between testosterone treatment and prostate cancer has long been studied. Historically, testosterone replacement therapy was believed to increase the risk of prostate cancer; however, recent studies and meta-analyses have shown that this is not the case.42,48 Nevertheless, clinical guidelines still recommend prostate monitoring for men on testosterone replacement therapy.5,6

Table 6. Prostate monitoring for patients on testosterone replacement therapy, according to age
Furthermore, the clinician should make sure the patient does not have prostate cancer before initiating testosterone replacement therapy. Since there is a significant incidence of prostate cancer in men with serum PSA of 2.5–4.0 ng/mL, a patient with hypogonadism and a serum PSA in that range or higher should have appropriate evaluation before initiating testosterone replacement therapy.49 The Endocrine Society recommendations for prostate monitoring are summarized in Table 6.5

Testosterone and cardiovascular risk

The evidence regarding this issue has been contradictory and inconsistent. Meta-analyses have demonstrated that low testosterone is associated with higher risk of major adverse cardiovascular events.50 These studies argue for the use of testosterone replacement therapy in hypogonadal men to decrease the risk. However, other studies and meta-analyses have found that testosterone replacement therapy is associated with increased cardiovascular risk and have concluded that major adverse cardiac events are in fact a risk of testosterone replacement therapy.51

Current recommendations advocate against the use of testosterone replacement therapy in men with uncontrolled heart failure or with cardiovascular events in the past 3 to 6 months.5,6 Cardiovascular risk factors should be addressed and corrected, and patients should be educated on cardiovascular symptoms and the need to report them if they occur.

Testosterone and infertility

As described earlier, testosterone replacement therapy increases negative feedback on the pituitary and decreases LH and FSH production, leading to less spermatogenesis. Other treatment options should be sought for hypogonadal men wishing to preserve fertility.

Other adverse effects

Other adverse effects of testosterone replacement therapy include acne, oily skin, obstructive sleep apnea, gynecomastia, and balding.

Given all the adverse events that can be associated with testosterone replacement therapy, the risks and benefits of treating hypogonadism in each patient should be taken into consideration, and an individualized approach is required.

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