Applied Evidence

Does your patient really need testosterone replacement?

J Fam Pract. 2016 December;65(12):864-866,873-875

References

1. Baillargeon J, Urban RJ, Ottenbacher KJ, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173:1465-1466.

2. PL Detail-Document #311005. The use of testosterone and the aging male. Pharmacist’s Letter/Prescriber’s Letter. October 2015.

3. Bhasin S, Cunningham GR, Hayes FJ, et al. Therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95:2536-2559.

4. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010;95:1810-1818.

5. Kaufman J, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26:833-876.

6. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87:589-598.

7. American Urological Association. AUA position statement on testosterone therapy. Available at: https://www.auanet.org/education/testosterone-therapy.cfm. Accessed October 24, 2016.

8. Dohle GR, Arver S, Bettocchi C, et al. European Association of Urology. Guidelines on male hypogonadism. 2015. Available at: http://uroweb.org/wp-content/uploads/18-Male-Hypogonadism_LR1.pdf. Accessed October 24, 2016.

9. Tanna MS, Schwartzbard A, Berger JS, et al. Management of hypogonadism in cardiovascular patients: what are the implications of testosterone therapy on cardiovascular morbidity? Urol Clin North Am. 2016;43:247-260.

10. Matsumoto AM. The testis. In: Felig P, Baxter JD, Frohman LA, eds. Endocrinology and Metabolism. 4th ed. New York, NY: McGraw-Hill; 2001:635-705.

11. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016:374:611-624.

12. Loughlin KR, Klap J. Selective use of testosterone replacement therapy. J Urol. 2016;196:1340-1341.

13. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95:639-650.

14. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab. 1980;51:1335-1339.

15. Swerdloff RS, Wang C, Cunningham G, et al. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab. 2000;85:4500-4510.

16. PL Detail-Document #311005. Comparison of testosterone products. Pharmacists’s Letter/Prescriber’s Letter. October 2015.

17. Michaud JE, Billups KL, Partin AW. Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. Ther Adv Urol. 2015;7:378-387.

18. US Food and Drug Administration. Testosterone and other anabolic androgenic steroids (AAS): FDA statement - Risks associated with abuse and dependence. Available at: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm526151.htm. Accessed October 26, 2016.

19. 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;310:1829-1836.

20. 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:e85805.

21. 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;36:2706-2715.

22. Goodman N, Guay A, Dandona P, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of testosterone and cardiovascular risk. Endocr Pract. 2015;21:1066-1073.

23. Albert SG, Morley JE. Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review. Clin Endocrinol (Oxf). 2016;85:436-443.

24. Levine GN, D’Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association. Endorsed by the American Society for Radiation Oncology. Circulation. 2010;121:833-840.

25. Kloner RA, Carson C, Dobs A, et al. Testosterone and cardiovascular disease. J Am Coll Cardiol. 2016;67:545-577.

26. O’Carroll R, Bancroft J. Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry. 1984;145:146-151.

Testosterone replacement raises issues of abuse and CV risk

On October 25, 2016, the US Food and Drug Administration (FDA) approved class-wide labeling changes for all prescription testosterone products, alerting prescribers to the agent’s abuse potential and the serious cardiac and mental health adverse outcomes that have been reported as a result of such abuse. In addition, the FDA is revising the Abuse and Dependence section to include new safety information regarding the risks associated with abuse of testosterone and other anabolic androgenic steroids.¹⁸

Prior to this announcement, the FDA had mandated in 2015 that product labels include information about a possible increased risk of myocardial infarction (MI) and stroke in people using testosterone. This warning was based on 2 published studies that showed increased cardiovascular risk.^19,20 However, a third larger study showed no increase in risk.²¹ All 3 of these studies were retrospective and had methodologic limitations, including differing baseline testosterone levels, insufficient documentation of baseline levels, and inadequate monitoring of response to therapy.

A recent statement by the American Association of Clinical Endocrinologists and the American College of Endocrinology in response to the older FDA warning cites the need for randomized controlled trials (RCTs) to elucidate whether an association exists between testosterone replacement and cardiovascular risk.²²

Of note, researchers have shown that androgen deprivation therapy (ADT) in patients with prostate cancer impacts cardiovascular risk factors (ie, it increases body fat and decreases lean body mass, increases total cholesterol, and increases insulin resistance and risk of diabetes). ADT may also be associated with increased cardiovascular mortality, although data are conflicting.²³

Investigators have shown that testosterone replacement positively affects certain risk factors for cardiovascular disease (CVD) including increasing lean muscle mass and improving laboratory values associated with the metabolic syndrome.²⁴ A large retrospective cohort study of male veterans with documented low total testosterone levels who received their medical care at the Veterans Health Administration (VHA) found that those who received testosterone replacement and achieved normal testosterone levels had lower all-cause, cardiovascular, and stroke mortality than controls.²¹ The men who did not achieve normal testosterone levels also had lower all-cause mortality (but significantly less than those with normalization of serum testosterone levels), but no change in stroke or cardiovascular mortality.

Since this study was retrospective, there were significant limitations, including unknown baseline characteristics of patients in each group. The CVD risks associated with testosterone therapy in middle-aged and older men should be discussed by physicians and their patients on an individual basis. Some experts believe that patients who have had an MI, revascularization, or a stroke within the past 6 months are not good candidates for replacement therapy.²⁵

About 20% to 40% of men with erectile dysfunction have low testosterone, although testosterone replacement does not always improve the condition.Until there are better data from prospective RCTs, it may be prudent to make sure that traditional CVD risk factors including smoking, hypertension, hyperlipidemia, and diabetes have been assessed and are appropriately managed in men prescribed testosterone replacement.

Testosterone helps with ED in certain cases

Testosterone deficiency is associated with sexual dysfunction in men, including decreased libido and erectile dysfunction (ED). About 20% to 40% of men with ED will have low testosterone, although replacement does not always improve the condition.²

Current guidelines do not recommend testosterone replacement to treat ED or sexual dysfunction in the absence of a low serum testosterone level and recommend evaluating for other causes of sexual problems in men.³ In one study, men who did not have documented hypogonadism received testosterone replacement therapy for sexual dysfunction including ED or ejaculator dysfunction. These patients saw no improvement in symptoms.²⁶

CORRESPONDENCE
J. Andrew Hoover, MD, Department of Family and Community Medicine, Lancaster General Hospital, 540 North Duke Street, Lancaster, PA 17604; jhoover4@lghealth.org.