What is the controversy surrounding testosterone replacement therapy?
Common causes of testosterone deficiency in men consist of classical hypogonadism and increasing age.1 In hypogonadism, testes fail to produce appropriate levels of testosterone and sperm cells. Congenital or acquired disorders affecting testes decrease testosterone levels in primary hypogonadism, while hypothalamic-pituitary disturbances are responsible for decreased testosterone levels in secondary hypogonadism. Increasing age may decrease testosterone levels at a rate of 1% to 2% per year. Other contributors to testosterone deficiency include obesity, medications (eg, alkylating agents, ketoconazole, glucocorticoids), chronic diseases (eg, type 2 diabetes, cancer), and environmental factors (eg, phthalates and dioxins).1,2 The exact prevalence of testosterone deficiency is unknown because studies and diagnostic criteria vary in their definitions and estimations.2 For example, the prevalence of hypogonadism increases with age and can be as low as 4% in men aged 18 to 29 years old and 46% in men aged 50 to 65 years old.3
Numerous testosterone replacement therapy (TRT) products, which replenish testosterone levels and may resolve clinical symptoms of testosterone deficiency, are available on the market.1 Patients can receive TRT products via intramuscular, transdermal, subdermal, buccal, and nasal routes. The non-oral routes avoid rapid metabolism by the liver and ensure appropriate circulating levels of testosterone. Historically, oral routes of testosterone such as methyltestosterone, which is no longer available in the United States, caused liver toxicity. In the United States, sales of TRT products quadrupled between 2000 and 2011, while the diagnosis of testosterone deficiency remained unchanged.4
FDA Drug Safety Communication
On March 3, 2015, the United States Food and Drug Administration (FDA) released a drug safety communication regarding the approved indications and increased risk for major adverse cardiovascular outcomes and strokes with TRT products.5 The FDA stated that TRT products are only approved for hypogonadism or testosterone deficiency associated with a medical condition. Testosterone replacement therapy products should be avoided in patients with testosterone deficiency without an associated medical condition or testosterone deficiency due to aging.
The drug safety communication led to several undesirable consequences for patients.6 Testosterone replacement therapy products became automatically “off-label” in patients who were receiving these products for testosterone deficiency due to aging for several years. The public raised the concerns that physicians were prescribing TRT agents without reason. Today, healthcare providers hesitate to prescribe TRT products to patients with testosterone deficiency not only due to limited approved indications but also due to concerns with cardiovascular outcomes. Altered health insurer policies continue to limit the coverage of TRT agents.
The evidence supporting the drug safety communication remains controversial and conflicting.6 During the FDA review, the data from 3 trials of varying designs (mostly retrospective and observational) and 1 meta-analysis suggested increased cardiovascular risk with TRT agents.7-10 The criticisms around these trials consist of using higher doses of TRT agents than approved, misreporting primary results, and not recognizing issues within study designs.6,11 Other meta-analyses showed similar risk for cardiovascular outcomes, including myocardial infarction and stroke, and mortality between TRT agents and placebo.12,13 Moreover, the European Medicine Agency decided against adding a warning on cardiovascular risks after independent evidence review.14 The Agency stated that the data remain inconsistent and have study design issues.
Critics argue that, in fact, low testosterone levels may lead to mortality and coronary artery disease.6,11 The Testosterone Trials, which enrolled 790 men who were 65 years and older with hypogonadism, showed that testosterone supplementation improved sexual function, desire, and activity and revealed similar risks for major cardiovascular events between TRT and placebo, but the study was not powered to evaluate safety.15 Some observational studies showed reduced mortality, myocardial infarction, and stroke rates with long-term testosterone treatments and/or with treatment normalizing testosterone levels.16,17
Numerous recent guidelines attempted to address the proper prescribing of TRT agents. The 2018 Endocrine Society guideline recommends testosterone therapy to induce and maintain secondary sex characteristics and manage symptoms of testosterone deficiency in hypogonadal men.18 Men who have had myocardial infarction or stroke within the past 6 months should not receive testosterone therapy. The guideline recommends against prescribing testosterone therapy to men older than 65 years old with testosterone deficiency without symptoms. Providers may discuss testosterone therapy and its risks versus benefits with men over 65 years old who are displaying symptoms of testosterone deficiency. The 2020 guideline from the European Academy of Andrology suggests transdermal testosterone as the preferred TRT preparation in men with functional hypogonadism, defined as low testosterone levels and corresponding symptoms occurring in the absence of structural issues or conditions suppressing hypothalamic-pituitary function in middle-aged to older men.19 The guideline recommends TRT agents for improving libido, erectile, and sexual function in men with hypogonadism. Men with a recent major cardiovascular event, including stroke, should avoid taking TRT agents. The guideline recommends against TRT agents as anti-aging therapy in men over 65 years old as well as against numerous other indications.
Monitoring for efficacy should accompany testosterone therapy.1 Providers should monitor for improvements in energy, sexual function, body mass composition, and other clinical outcomes such as prostate volume and erythropoiesis over the first 3 to 6 months and bone mineral density over 24 months after starting a TRT agent. If improvement fails to occur over a defined time period, providers should discontinue therapy.
The available guidelines provide recommendations for monitoring the safety of testosterone therapy. The guidelines from the Endocrine Society and the European Academy of Andrology recommend checking PSA, as a marker for prostate cancer, before and at 3 to 12 months after initiation of testosterone therapy.18,19 After the first year, providers can follow local guidelines to perform prostate cancer screenings.19
Monitoring testosterone levels may be necessary for some patients. According to the European Academy of Andrology, young men may benefit from monitoring of serum total testosterone levels during active treatment; the target levels should fall close to the mid-normal range.19 The mid-normal range for testosterone levels is 400 to 700 ng/dL (14.1 to 24.5 nmol/L).1 Literature also suggests monitoring testosterone levels in patients with pre-existing cardiovascular disease. The frequency of monitoring is every 3 to 6 months after initiating or altering therapy and every 6 to 12 months during maintenance. Testosterone levels vary with a type of a TRT preparation used and timing of collection; thus, any dose adjustment requires 2 testosterone levels to confirm the results.
The controversy of prescribing TRT agents stems from the FDA drug safety communication released in 2015 that limited the approved indications and discussed increased risks of major adverse cardiovascular outcomes with TRT agents. The evidence supporting this communication remains controversial and conflicting, and some critics argue that low testosterone levels may lead to increased mortality and cardiovascular disease. The drug safety communication led to hesitation for prescribing TRT agents, especially in men with low testosterone levels due to aging, as well as limited coverage of these agents by health insurance. Today, the practice of prescribing TRT agents varies among medical specialties.11 For example, endocrinologists follow strict criteria when prescribing these agents, while urologists are more liberal with their prescribing patterns. The questions on clear indication and best candidates for testosterone therapy remain unanswered. The guidelines provide some recommendations when to consider initiating TRT agents, but the definition and classification of hypogonadism lack clarity. The guidelines provide recommendations for monitoring the efficacy and safety of TRT agents after initiation. But, further guidance and better research are necessary to clearly define the indications and risks of TRT agents.
- Tsametis CP, Isidori AM. Testosterone replacement therapy: For whom, when and how? Metabolism. 2018;86:69-78. doi: 10.1016/j.metabol.2018.03.007
- Hackett GI. Testosterone replacement therapy and mortality in older men. Drug Saf. 2016;39(2):117-130. doi: 10.1007/s40264-015-0348-y
- Shortridge EF, Polzer P, Donga P, Wade RL. Symptom report and treatment experience of hypogonadal men with and without type 2 diabetes in a United States health plan. Int J Clin Pract. 2015;69(7):783-790. doi: 10.1111/ijcp.12636
- Layton JB, Li D, Meier CR, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab. 2014;99(3):835-842. doi: 10.1210/jc.2013-3570
- FDA drug safety communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. U.S. Food and Drug Administration. Updated February 26, 2018. Accessed June 20, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due
- Miner M, Morgentaler A, Khera M, Traish AM. The state of testosterone therapy since the FDA’s 2015 labelling changes: Indications and cardiovascular risk. Clin Endocrinol (Oxf). 2018;89(1):3-10. doi: 10.1111/cen.13589
- Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122. doi: 10.1056/NEJMoa1000485
- Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836. doi: 10.1001/jama.2013.280386
- Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805. doi: 10.1371/journal.pone.0085805
- Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013;11:108. doi: 10.1186/1741-7015-11-108
- Morgentaler A, Traish A. The history of testosterone and the evolution of its therapeutic potential. Sex Med Rev. 2020;8(2):286-296. doi: 10.1016/j.sxmr.2018.03.002
- Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014;13(10):1327-1351. doi: 10.1517/14740338.2014.950653
- Alexander GC, Iyer G, Lucas E, Lin D, Singh S. Cardiovascular risks of exogenous testosterone use among men: a systematic review and meta-analysis. Am J Med. 2017;130(3):293-305. doi: 10.1016/j.amjmed.2016.09.017
- Testosterone-containing medicines. European Medicines Agency. Updated August 1, 2015. Accessed June 20, 2020. https://www.ema.europa.eu/en/medicines/human/referrals/testosterone-containing-medicines
- Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624. doi: 10.1056/NEJMoa1506119
- Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706-2715. doi: 10.1093/eurheartj/ehv346
- Wallis CJ, Lo K, Lee Y, et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol. 2016;4(6):498-506. doi: 10.1016/s2213-8587(16)00112-1
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. doi: 10.1210/jc.2018-00229
- Corona G, Goulis DG, Huhtaniemi I, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology. 2020. doi: 10.1111/andr.12770
Janna Afanasjeva, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois At Chicago College of Pharmacy
The information presented is current as June 20, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.