Counseling Male Patients on Testosterone Replacement Therapy With Efficacy and Safety in Mind

Andrea G. Douglas, PharmD Candidate 2016; Joylaina Speaks, PharmD Candidate 2016; Jennifer Elliott, PharmD; Deirdre B. Fanning, PharmD


US Pharmacist. 2015;40(8):25-30. 

In This Article

Adult Male Hypogonadism

It is important to understand hypogonadism before reviewing the cardiovascular trials leading to these FDA updates. Male hypogonadism is a clinical syndrome of congenital or acquired origin manifesting as decreased testosterone levels with or without decreased spermatogenesis. It will present with signs and symptoms of androgen deficiency. Primary hypogonadism, a disease of testicular function, typically presents as low testosterone concentration with or without impaired spermatogenesis and with elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations.[4] Secondary hypogonadism, or hypogonadotropic hypogonadism, is a dysfunction of the hypothalamicpituitary-gonadal axis presenting as low testosterone concentration with or without impaired spermatogenesis and with reduced or normal LH and FSH concentrations.[4]

Men typically seek treatment for hypogonadism based on the symptoms they experience with continued low testosterone levels. Per the Endocrine Society's clinical guidelines for testosterone therapy in adult men with androgen deficiency syndromes, certain symptoms, such as decreased energy, depressed mood, and reduced muscle strength, are general and not indicative of male hypogonadism initially.[4] More specific symptoms seen in hypogonadism include decreased sexual desire, loss of body hair, and breast discomfort, all of which may be alarming to patients. TRT has been shown to be beneficial in men experiencing these symptoms. However, the safety of long-term therapy has been questioned in various studies.

Cardiovascular issues with TRT were first noted in the Testosterone in Older Men with Mobility Limitations (TOM) trial and reported in the peer-reviewed journal Contemporary Clinical Trials in 2009.[5] The TOM trial assessed the effects of testosterone administration on voluntary muscle strength in older men. The trial was terminated early because of the significantly higher incidence of cardiovascular events in the testosterone group.[5]

In 2014, two separate studies assessing cardiovascular adverse events with testosterone were published.[6,7] The studies suggest that there are increased cardiovascular risks in elderly men, regardless of preexisting adverse cardiovascular history. Vigen et al reported the findings of a retrospective cohort study assessing elderly men in the Veterans Affairs healthcare system with low testosterone levels and coronary artery disease.[6] Adjusting for the presence of coronary artery disease, this study found a statistically significant increase in adverse outcomes, including risk of stroke, heart attack, and death in the group receiving TRT compared to the group with no TRT (hazard ratio [HR] 1.29, 95% CI, 1.04–1.58).[6] Finkle et al reported the results of a meta-analysis that found that men aged ≥65 years, regardless of cardiovascular history, had a twofold increased risk of heart attack (risk ratio [RR] 2.19, 1.27–3.77). It also found that men <65 years of age, with a preexisting history of heart disease, had a two- to threefold increased risk of heart attack (RR 2.90, 1.49–5.62).[7]

The studies by Finkle et al and Vigen et al have caused controversy in the field of andrology. Experts have published their objections to these findings, stating that the results from the two retrospective analyses contradict over 20 years of literature, as described in a letter to the editor in a subsequent edition of the Journal of the American Medical Association (JAMA).[8] The Endocrine Society,[9] American Urological Association,[10] and the Sexual Medicine Society of North America[11] have all released statements addressing this concern and noting the evidence supporting the contrary. Of note, there have been no prospective, randomized, controlled trials powered sufficiently to assess testosterone therapy and measure cardiovascular events as the primary outcome. There is currently a study being conducted by the National Institute on Aging to determine if testosterone treatment in men will improve their physical and sexual function, and decrease risk factors for cardiovascular disease and diabetes.[12] However, the principal investigator, Peter J. Snyder, MD, has warned that the study is not designed to evaluate whether cardiovascular risk actually increases.[13]

With these recent updates on the safety of testosterone products and changes to the established boxed warning, pharmacists are in an influential position to promote evidence-based counseling on TRT and to advocate for proper follow-up and monitoring. The remainder of this article will focus on key information pharmacists should share with patients regarding the safety and efficacy of TRT.