Testosterone Replacement Therapy: 10 Tips

Sometimes, all it takes for a prescription product to move from relative obscurity to remarkable utility is a little dosage-form engineering. That is testosterone’s story. The number of testosterone prescriptions has followed an upward trajectory since 1999, when prescribers wrote 648,000 of them. By 2002, that number had jumped to 1.75 million prescriptions; in 2012, 2.2 million.^1,2

The primary indication for prescription testosterone is replacement therapy for a deficiency (ie, androgen deficiency syndrome or hypogonadism). Today, although a variety of testosterone formulations are available, public concern is substantial. Pharmacists need to be aware of 10 key points about testosterone replacement therapy (TRT) to allay concern and ensure patient safety.

1. Testosterone’s androgenic effects begin in the perinatal period, when sex organs develop. They continue at puberty, stimulating secondary sex characteristics such as voice deepening, beard growth, and development of axillary hair. Testosterone’s anabolic effects increase muscle mass, strength, bone density, and bone maturation throughout life.^3,4

2. The FDA has approved TRT for classic androgen deficiency caused by pathologic conditions (eg, Klinefelter’s syndrome, orchiectomy, chemotherapy). Many prescribers also use testosterone for age-related testosterone decline, which is called late-onset hypogonadism. This is an off-label use.³

The 2010 Endocrine Society Clinical Practice Guidelines did not address some populations, but the results of later studies indicate that men with metabolic syndrome or frailty may benefit from TRT based on improvements in biometrics, insulin sensitivity, muscle strength, and bone health.⁴

3. The Endocrine Society’s guidelines indicate that to diagnose testosterone deficiency in a patient, the patient must present with the following:

• Symptoms (eg, low energy, depressed mood, low sex drive, erectile dysfunction)
• A serum testosterone concentration lower than 300 ng/dL⁵

Recent findings indicate that 25% of patients prescribed testosterone did not have their testosterone levels checked before starting treatment.

4. Serum testosterone concentrations are diurnal. In young men, the concentrations are highest in the morning. Older men tend to have similar, but blunted, patterns.^6,7 Clinicians should draw serum testosterone levels between 8:00 am and 11:00 am.⁵ Patients’ serum testosterone levels vary over time, so providers should not rely on 1 test. For example, one-third of men who have low testosterone levels will have normal levels when they repeat the test.

5. Recent findings indicate that almost 20% of all new users received treatment for 30 days or less.^6,7 TRT is designed to be long-term therapy, however. The high incidence of short-term use indicates that some TRT use may be injudicious.

6. The degree and duration of testosterone deficiency influence the signs and symptoms. Restoring serum testosterone concentrations to normal range can produce beneficial effects (Table 1^8-17).^9,10

7. TRT has some risks and adverse effects (Table 2^3,18-23).

8. Testosterone is available as oral tablets that are well absorbed from the intestine, but quickly metabolized by liver enzymes. The gel, transdermal patch, buccal injection, and intramuscular injection avoid hepatic metabolism and improve delivery.^24-26 The transbuccal route avoids first-pass hepatic metabolism and mimics endogenous testosterone’s diurnal pattern, while gels elevate serum testosterone for longer durations than the transdermal patch does.²⁵ Another testosterone product available in solution form is applied to the underarms.²⁷ The viscosity of oil-based esterified testosterone injection requires good administration technique using smaller-gauge needles to reduce tissue scarring.²⁵ Subcutaneous testosterone pellet implants are also available and deliver normal serum levels of testosterone for 3 to 4 months.²⁸

9. Monitoring is critical. Table 3⁴ lists tests that clinicians should order at baseline and periodically during therapy.

Table 3. Laboratory Monitoring of Testosterone Therapy

• Testosterone levels (at baseline; repeat at 3-6 months)
• Digital rectal examinations and prostatic-specific antigen tests
• Hematocrit to screen for polycythemia
• Liver-function tests
• Lipid panel

^{Adapted from reference 4.}

10. Prescribers must consider pharmacokinetic properties, treatment burden, and therapy cost when they work with candidates for TRT.

CONCLUSION

When testosterone deficiency causes troublesome signs and symptoms, TRT can be beneficial. Pharmacists can use counseling and medication therapy management to help patients use TRT properly. Pharmacists must advise patients about skin irritation at the application or injection site and warn that direct skin-to-skin contact with women or children can transfer the product and cause adverse effects in the recipient.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy.

References

• Liverman CT, Blazer DG; Institute of Medicine (US) Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. Testosterone and aging: clinical research directions. Washington, DC: National Academies Press (US); 2004.
• Gabrielsen JS, Najari BB, Alukal JP, Eisenberg ML. Trends in testosterone prescription and public health concerns. Urol Clin North Am. 2016;43(2):261-271. doi: 10.1016/j.ucl.2016.01.010.
• 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 [news release]. Silver Spring, MD: FDA; March 3, 2015. www.fda.gov/Drugs/DrugSafety/ucm436259.htm. Accessed May 30, 2016.
• Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465-1466. doi: 10.1001/jamainternmed.2013.6895.
• Seftel AD, Kathrins M, Niederberger C. Critical update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: a systematic analysis. Mayo Clin Proc. 2015;90(8):1104-1115. doi: 10.1016/j.mayocp.2015.06.002.
• Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB. The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab. 2009;94(3):907-913. doi: 10.1210/jc.2008-1902.
• Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56(6):1278-1281.
• Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281(6):E1172-E1181.
• Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296(19):2351-2361.
• Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89(5):2085-2098.
• Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systemic review and meta-analysis. J Psychiatr Pract. 2009;15(4):289-305. doi: 10.1097/01.pra.0000358315.88931.fc.
• Shores MM, Kivlahan DR, Sadak TI, Li EJ, Matsumoto AM. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). J Clin Psychiatry. 2009;70(7):1009-1016.
• Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005;63(3):280-293.
• Knezevich EL, Knezevich JT. Testosterone deficiency in men: more common than you think. US Pharm. 2011;37(12)(suppl).
• Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93(5):1834-1840. doi: 10.1210/jc.2007-2177.
• Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 1997;82(8):2386-2390.
• Cawley MH. Testosterone replacement therapy: what to look for, when to treat. Nurse Pract. 2009;34(9):47-52. doi: 10.1097/01.NPR.0000360150.79515.a8.
• Braunstein GD. Gynecomastia. N Engl J Med. 2007;357(12):1229-1237.
• Deplewski D, Rosenfield RL. Role of hormones in pilosebaceous unit development. Endocr Rev. 2000;21(4):363-392.
• Grunstein RR, Handelsman DJ, Lawrence SJ, Blackwell C, Caterson ID, Sullivan CE. Neuroendocrine dysfunction in sleep apnea: reversal by continuous positive airways pressure therapy. J Clin Endocrinol Metab. 1989;68(2):352-358.
• Santamaria JD, Prior JC, Fleetham JA. Reversible reproductive dysfunction in men with obstructive sleep apnoea. Clin Endocrinol (Oxf). 1988;28(5):461-470.
• Cunningham GR, Toma SM. Why is androgen replacement in males controversial? J Clin Endocrinol Metab. 2011;96(1):38-52. doi: 10.1210/jc.2010-0266.
• Advisory Panel on Testosterone Replacement in Men. Report of National Institute on Aging Advisory Panel on Testosterone Replacement in Men. J Clin Endocrinol Metab. 2001;86(10):4611-4614.
• Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. 2008;299(1):39-52. doi: 10.1001/jama.2007.51.
• Snyder PJ. Clinical features and diagnosis of male hypogonadism. uptodate.com website. uptodate.com/contents/clinical-features-and-diagnosis-of-male-hypogonadism?source=see_link. Accessed June 3, 2016.
• AndroGel 1.62% [package insert]. North Chicago, IL: AbbVie; 2015.
• Axiron [package insert]. Indianapolis, IN: Eli Lilly and Company; May 2015.
• Testopel [package insert]. Malvern, PA: Auxilium Pharmaceuticals, Inc; May 2015.