Treatments
Before considering TRT, physicians need to emphasize lifestyle modifications as first-line treatment for hypogonadism. The most important modifications include weight loss, tobacco cessation, and moderation in alcohol use.
Patients need to be advised of possible adverse events (AEs) of TRT, which may include gynecomastia, polycythemia, sleep apnea, decreased high-density lipoprotein cholesterol, benign prostatic hypertrophy, infertility, testicular atrophy, and abnormal liver function tests. More recently, several studies have shown an association between TRT and an increase in cardiovascular complications, such as stroke, heart attacks, and death.
Prior to considering TRT, a careful history and physical examination, including a clinical prostate examination, should be performed. Minimum additional tests should include hematocrit, fasting lipid profile (FLP), complete metabolic profile (CMP), and prostate-specific antigen (PSA). Initiation of TRT is not recommended for patients with metastatic prostate cancer; breast cancer; an unevaluated prostate nodule; a PSA > 4 ng/mL (or > 3 ng/mL in African Americans or men with a first-degree relative with prostate cancer); hematocrit > 50%; untreated severe obstructive sleep apnea; uncontrolled or poorly controlled congestive heart failure; or an International Prostate Symptoms Score (IPSS) > 19.9
A past history of prostate cancer had previously been a contraindication for the use of TRT. However, more recent studies have shown that TRT can be used in those who have no evidence of active or metastatic disease and who are under the close supervision of a physician.33-35
Widespread screening is not recommended, and population-based surveys can be unreliable. Fifteen percent of healthy young men, for example, will have a low serum testosterone level in a given 24-hour period.9 Thirty percent of men with an initial testosterone level in the mildly hypogonadal range will have a normal testosterone level when retested; moreover the threshold below which AEs occur remains unknown.9
The goal of TRT is to achieve a total testosterone level in the 400 ng/mL to 700 ng/mL range with improved clinical signs and symptoms.9 Laboratory tests should be conducted at 3 months, 6 months, and then annually. These tests include hematocrit, PSA, and a testosterone level.32 Testing for CMP and FLP should also be considered. If, during therapy, the hematocrit is > 54%, the patient should be assessed for hypoxia and sleep apnea, and treatment should resume at a lower dose only when the hematocrit returns to baseline.9 A digital examination of the prostate is recommended for men with a PSA of > 0.6 ng/mL. A urologic consultation should be obtained for an increase in the PSA of > 1.4 ng/mL over 12 months, a PSA velocity of > 0.4 ng/mL per year (using the PSA after 6 months as a reference), or for an IPPS of > 19.9
Emerging Cardiovascular Concerns
The Testosterone for Older Men study, a randomized, placebo- controlled clinical trial of testosterone therapy in men with a high prevalence of cardiovascular disease, showed significantly greater improvements in leg-press, chest-press, and stair-climbing exercises while carrying a load compared with that in the placebo group.36 However, the study was stopped early due to an increased risk of cardiovascular AEs in those who received testosterone gel.
Vigen and colleagues examined a cohort of veterans who underwent coronary angiography and had a low serum testosterone level.37 The use of TRT in this cohort was also associated with an increased risk of adverse cardiovascular outcomes. This study generated several letters and a recent article in response that vigorously questioned the validity of the methods used and the conclusions reached.38-44 Prior clinical studies of TRT had not detected cardiac AEs, but these trials were generally of short duration and not powered for clinical endpoints.37
A FDA Safety Announcement as well as a VA National Pharmacy Benefits Management bulletin were based on the results of these studies.45 The FDA did not conclude that TRT increased the risk of stroke, heart attack, or death, but health care providers were asked to consider whether the benefits of TRT are likely to exceed the potential risk of treatment.
Direct-to-Consumer Marketing
Some direct-to-consumer marketing promotes the use of aromatase inhibitors, such as anastrozole. This class of medications prevents the conversion of endogenous and exogenous testosterone to estrogen by the aromatase enzyme, which is found predominately in abdominal adipose tissue. There is no evidence that naturally occurring elevations in estrogen cause low testosterone or that treatment of elevated estrogen with an aromatase inhibitor during TRT has any significant clinical benefit in terms of male sexuality.46 Nevertheless, some CAM providers now hypothesize that the increase in cardiovascular AEs with TRT noted in the recent studies may have been due to the increase in estrogen that is associated with TRT.46