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 works when indicated

When clinically indicated (ie, when a patient’s testosterone level is below 280 ng/dL and the patient is experiencing a variety of symptoms associated with hypogonadism), research has shown testosterone replacement therapy can improve sexual function, mood, and, in some cases, lean body mass and physical function.^11,13

Keep in mind that the Endocrine Society and most professional organizations strongly discourage testosterone replacement in eugonadal men.³ Because of suppression of the HPG axis, men who discontinue testosterone replacement will typically experience symptoms of hypogonadism. Consequently, testosterone replacement should NOT be given to men with symptoms associated with hypogonadism (eg, fatigue or decreased libido) who do not have a low serum testosterone level.³

Testosterone is available in various forms, including oral, parenteral, pellets, transdermal gels and solutions, and as a buccal system. (Testosterone formulations and dosing information are described in TABLE 2.²) Oral formulations are generally not recommended due to potential hepatotoxicity and adverse effects on lipids.² In addition, oral formulations have short half-lives, making it difficult to achieve and maintain normal testosterone levels.

Long-acting parenteral testosterone is effective but must be given as an intramuscular injection, usually at 2- to 4-week intervals. These preparations produce fluctuations in serum testosterone levels, with supranormal levels occurring soon after injection and subnormal levels occurring immediately prior to subsequent injections.¹⁴

Pellets that contain 75 mg of testosterone are implanted subcutaneously. The usual dose is 2 pellets (150 mg), but may be as high as 6 (450 mg). The dose can be titrated based on follow-up serum testosterone levels. The therapeutic effects of the pellets continue, on average, for 3 to 4 months, and up to as long as 6 months.

Transdermal testosterone preparations are the most commonly prescribed. These include gels, patches, and solutions. They are easy to use and achieve more stable serum levels that remain in a normal range with daily use.¹⁵

Gels. Considerations when prescribing testosterone gel forms include the possibility of spread to female partners or children, leading to virilization and precocious puberty. The gel should be applied to the skin but not the genitals, and should be covered with clothing after drying for at least 5 to 10 minutes.
Patches can be applied to the back, abdomen, or extremities. A skin rash occurs in about one-third of men who use testosterone patches and may lead to discontinuation.¹⁶
Solutions are applied to each underarm daily. The starting dose is 60 mg under each arm; the dose can be adjusted based on follow-up serum testosterone levels.
Buccal testosterone is applied to the buccal mucosa every 12 hours. It achieves therapeutic levels without large fluctuations. The tablet softens and forms to the gum, but does not dissolve and needs to be removed after 12 hours. The most common adverse effects are mucosal irritation and taste alteration.

Contraindications

Contraindications to testosterone replacement include heart failure, hepatic dysfunction (cirrhosis), prostate cancer, and breast cancer. Current guidelines also recommend not giving testosterone to men with severe lower urinary tract symptoms (due to benign prostate hyperplasia) with an International Prostate Symptom Score (IPSS) score >19.³ And, as mentioned earlier, the Endocrine Society strongly discourages testosterone replacement in eugonadal men.

After prescribing, monitoring is required

Men receiving testosterone replacement should have their testosterone levels checked at 3, 6, and 12 months after initiation of therapy, and annually thereafter.³ Therapy should be adjusted to achieve testosterone levels in the mid-normal range. Additional laboratory monitoring should include a serum hematocrit at baseline, at 6 months, and then annually if hematocrit remains in the normal range. Such testing is required because testosterone stimulates production of red blood cells from the bone marrow, which can lead to polycythemia. Discontinue therapy or reduce the dosage if a patient’s hematocrit rises above 54%, as there is a risk of thrombosis, although, in general, these events appear to be rare.^3,8

Obtain a lipid panel, liver function tests. Lipid abnormalities—primarily a decrease in high-density lipoprotein (HDL) cholesterol—may occur with testosterone replacement. Obtain a lipid panel and liver function tests at baseline and then yearly during replacement therapy.

Keep an eye on PSA. Although testosterone replacement does not increase the risk of prostate cancer, the Endocrine Society still recommends obtaining a prostate specific antigen (PSA) level and performing a digital rectal exam in men 40 years of age and older prior to initiating testosterone therapy.

Do not prescribe testosterone replacement if the patient’s PSA level is >4 ng/mL (or >3 ng/mL in high-risk groups) or if there is a palpable nodule or significant prostatic hypertrophy. Repeat the PSA in 6 months and then annually as long as testosterone therapy is continued. Further evaluation for prostate cancer is warranted if the PSA increases more than 0.4 ng/dL/year.^3,17