Testosterone Replacement: Essential in Pain Management
Testosterone replacement has been around since the 1970s. However, there has been a sharp increase in the number of prescriptions for testosterone in the past decade. Between 2000 and 2011, for example, the United States saw a 4-fold increase in testosterone use among men, many of whom had normal levels of testosterone.1
To review, testosterone helps support body composition, bone and muscle strength, and quality of life.2-6 In older men, testosterone replacement has been shown to increase lean body mass and improve strength,2,3 whereas testosterone deficiency has been associated with an increase mortality risk.6
Recent studies, however, have suggested that there is a link between testosterone replacement and an increased risk for heart disease and stroke.7,8 This has led the FDA to announce that they are going to investigate the safety of FDA-approved testosterone products.9 This has raised some concern among pain practitioners who want to know whether testosterone replacement is safe.
Despite these reports, testosterone replacement remains an essential element of chronic pain management in both males and females. Why? Chronic pain patients often have low serum testosterone levels. This is caused by both the condition and the treatments. Pain itself can cause hyperarousal of the hypothalamic-pituitary-adrenal axis, depleting patients of hormones such as cortisol and testosterone.10-15 In addition, chronic opioid therapy causes hypogonadism. For both these conditions, testosterone replacement is a needed remedy. The only cases in which this would be contraindicated are patients with active cancer of the prostate, ovaries, and/or breast. This article will review the role of testosterone replacement in pain patients in light of recent controversies.
The Cardiovascular Controversy
The first publication that prompted the FDA to reassess the cardiovascular safety of testosterone therapy was an observational study of older men in the US Veteran Affairs health system by Vigen et al.7 The veterans included in this study had low serum testosterone (<300 ng/dL), were over 60 years of age, and were undergoing coronary angiography to assess for the presence of coronary artery disease. According to the authors, those who were placed on testosterone therapy had a 30% increased risk of stroke, heart attack, and death compared to those not prescribed testosterone therapy.
However, there were some limitations to the Vigen et al study and there have been many published criticisms, including letters from leading endocrinologists and urologists.16-21 Table 1 lists some of the major criticisms of the study, which was an observational study rather than the more rigorous randomized control study. Many of the critics of the study reject its veracity and continue to support testosterone replacement in males who are middle age and older and have low testosterone levels.
The second study reported an increased risk of heart attack in older men, as well as in younger men with pre-existing heart disease, who filled a prescription for testosterone therapy.8 The study reported a 2-fold increase in the risk for heart attack among men aged 65 years and older in the first 90 days following the first prescription. Among younger men <65 years old with a pre-existing history of heart disease, the study reported a 2- to 3-fold increased risk for heart attack in the first 90 days following a first prescription. Younger men without a history of heart disease who filled a prescription for testosterone, however, did not have an increased risk for heart attack.
Since over a million men take testosterone replacement,1 these studies caused predictable reactions. In addition to the FDA announcement, there was immediate and widespread media coverage in the lay press. Indeed, even before the print was dry, lawyers were advertising for plaintiffs to sue the makers of testosterone products.
In summary, these studies contradict the literature on the safety of testosterone replacement that spans more than 20 years.2-6,22-28 Pain practitioners must now, in light of these studies, factor in the possibility of an adverse cardiovascular event (myocardial infarction or stroke) when prescribing testosterone replacement. Pain patients with known cardiovascular disease, especially, need to be informed of a possible increased risk and must weigh the risks of hormone therapy versus its benefits.
The Prostate Specific Antigen Controversy
Prostate-specific antigen, or PSA, is a protein produced by cells of the prostate gland. According to the National Cancer Institute (NCI), the PSA test originally was approved by the FDA in 1986 to monitor the progression of prostate cancer in men who already had been diagnosed with the disease. In 1994, the FDA expanded the use of the PSA test, in conjunction with a digital rectal exam, to test asymptomatic men for prostate cancer. Most recently, however, a number of leading organizations have questioned the need for aggressive screening and have issued new guidelines for PSA testing in men that further define appropriate candidates for screening (Table 2). Routine testing no longer is recommended by the American Academy of Family Physicians. The American Society of Clinical Oncology recommends against PSA testing in males unless they have obstructive urinary symptoms, such as hesitancy, frequency, and nocturia. Also, the American Urological Association recommends that PSA testing should be considered primarily for men between the ages of 55 to 69.
So why is PSA testing an issue in pain patients with low testosterone levels? Testosterone replacement therapy may increase prostate size and elevate PSA levels in men with low testosterone levels, raising their risk of developing prostate cancer. As noted, in normal aging, testosterone levels drop and prostate cancer rates increase. However, there is no evidence that testosterone replacement therapy increases the risk for prostate cancer in hypogonadal men.29
The debate over PSA testing has been fueled by the number of false-positive results that occur, leading to unnecessary and expensive tests, surgery, and radiation that have been harmful in many cases. Two recent publications have added to the argument against PSA testing. The first is the book The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster by Richard Albin and Ronald Piana. In it, the authors argue that some health care providers have conspired to oversell the PSA test and the procedures that follow. The second was an article from the politically powerful American Association of Retired Persons (AARP). In the article, entitled “10 Tests to Avoid,” they recommend that PSA testing not be done (AARP Bulletin, March 2014).
(Currently, Medicare provides coverage for an annual PSA test for all Medicare-eligible men age 50 and older, according to the NCI. Many private insurers cover PSA screening as well.)