Daily testosterone formulations include transdermal gels, transdermal patches, and buccal bioadhesive tablets.^1,2

• Transdermal testosterone gel (1%) applied once-daily to nongenital skin provides serum testosterone levels in the physiologic range over the 24-hour dosing period for most men.^1-3 The two available testosterone gel formulations in hydroalcoholic base are not bioequivalent, varying in bioavailability, with one providing significantly greater peak serum concentrations of testosterone (total testosterone, free testosterone, and dihydrotestosterone).⁴
• Evening application of one or two 5-mg nongenital testosterone patches to the skin of the back, thigh, or upper arm away from pressure areas generally achieves serum testosterone levels within the normal range.^1,2
• Application of one 30-mg bioadhesive tablet to the buccal mucosa every 12 hours normalizes serum testosterone levels for most hypogonadal men.^2,5,6
• Some men using testosterone gel or transdermal patches experience skin irritation at the application site.^1,2 Another concern with testosterone gel is direct skin-to-skin transfer to another person who does not require testosterone therapy (eg, a partner or a child).² In one trial, 16% of hypogonadal men using the buccal bioadhesive tablet reported gum-related adverse events, including edema, gingivitis, inflammation, and blistering.⁶

Longer acting formulations include subcutaneous testosterone pellets and intramuscular injection of testosterone enanthate, testosterone cypionate, and testosterone undecanoate.²

• Subcutaneous implantation of six to twelve 75-mg pellets is common (W. J. G. Hellstrom, written communication, May 2009). The prescribing information specifies implanting two 75-mg pellets for each 25 mg testosterone propionate required weekly.⁷ Approximately one third of testosterone pellet material is absorbed in the first month, one fourth in the second month, and one sixth in the third month. ⁷ Treatment effect may last from 3 to 6 months (W. J. G. Hellstrom, written communication, May 2009).⁷ Insertion and removal of the pellets requires minor surgery, with the potential adverse effects of extrusions, bleeding, and infections.^8,9 Additionally, great care should be taken when estimating the amount of testosterone needed, because pellet implantation is much less flexible than oral medication or intramuscular injection.⁷
• Intramuscular injection of testosterone enanthate or testosterone cypionate (100-300 mg) in slow-release, oil-based vehicles achieves testosterone levels in the supraphysiologic range within 72 hours, and levels decrease slowly into the hypogonadal range by the end of the dosing interval.^1,2,8 Frequent intramuscular injections (once every 1, 2, or 3 weeks or once a month) are required, and the wide variations in serum testosterone levels can lead to a roller-coaster effect characterized by undesirable swings in mood, energy, libido, and sexual function, which some patients may find disagreeable.^1,2,10,11
• Intramuscular injection of testosterone undecanoate, a long-acting formulation, achieves eugonadal physiologic testosterone levels with fewer injections compared to other intramuscular formulations.^10,12 A 1000-mg formulation is available in more than 80 countries, and a 750-mg depot formulation is in development in the United States.¹² Long-term safety and efficacy of the 1000-mg formulation of testosterone undecanoate has been demonstrated in hypogonadal men treated for more than 8 years.¹³ In the United States, a 24-week trial with 130 hypogonadal men found that intramuscular injection of 750 mg testosterone undecanoate at 0, 4, and 14 weeks resulted in normal serum testosterone levels during weeks 14 to 24 in 94% of patients.¹² More than 92% of patients had a maximum concentration below 1500 ng/dL during treatment.¹²

Factors considered when selecting a testosterone therapy include pharmacokinetics, price, patient preference, insurance coverage, ease of administration, side effects, serum testosterone levels, perceived efficacy, and patient adherence.^2,8

Response by Wayne J.G. Hellstrom, MD
Because hypogonadism is a chronic condition often warranting long-term testosterone therapy,^10,14 it is important to select a form of testosterone that meets individual patient needs.^2,8 To optimize adherence to testosterone therapy, patients should be involved in the decision-making process and fully understand the benefits and risks of the prescribed medication.^8,15 Patients are more likely to adhere to treatment if they believe that something is wrong, that a medication will improve it, and that the benefits of treatment outweigh the risks and  justify the cost.¹⁵ To select the testosterone formulation that best suits a patient’s needs, the medication’s efficacy, safety, tolerability, pharmacokinetic profile, and route, frequency, and convenience of administration should be considered along with the patient’s preferences and lifestyle.^2,8 Ideally, the medication selected should be safe, effective, and easy for the patient to use.

References

1. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8(6):439-456.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
3. Testim [prescribing information]. San Antonio, TX: Auxilium Pharmaceuticals Inc; 2006.
4. Marbury T, Hamill E, Bachand R, Sebree T, Smith T. Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim^TM, compared to AndroGel^®. Biopharm Drug Dispos. 2003;24(3):115-120.
5. Korbonits M, Slawik M, Cullen D, et al. A comparison of a novel testosterone bioadhesive buccal system, Striant, with a testosterone adhesive patch in hypogonadal males. J Clin Endocrinol Metab. 2004;89(5):2039-2043.
6. Wang C, Swerdloff R, Kipnes M, et al. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab. 2004;89(8):3821-3829.
7. Testopel [prescribing information]. Rye, NY: Bartor Pharmacal Co Inc; 2007.
8. Gooren LJG, Bunck MCM. Androgen replacement therapy: present and future [review]. Drugs. 2004;64(17):1861-1891.
9. Cavender RK. Subcutaneous testosterone pellet implantation procedure for treatment of testosterone deficiency syndrome. J Sex Med. 2009;6(1):21-24.
10. Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opin Pharmacother. 2005;6(10):1751-1759.
11. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring [review]. N Engl J Med. 2004;350(5):482-492.
12. Morgentaler A, Dobs AS, Kaufman JM, et al. Long acting testosterone undecanoate therapy in men with hypogonadism: results of a pharmacokinetic clinical study. J Urol. 2008;180(6):2307-2313.
13. Schubert M, Zitzmann M, Yassin AA. Intramuscular testosterone undecanoate for the treatment of male hypogonadism—review of recent data [review]. J Mens Health Gend. 2006;3(4):356-362.
14. Gooren LJG. Advances in testosterone replacement therapy. Front Horm Res. 2009;37:32-51.
15. Shea SC. The “medication interest model”: an integrative clinical interviewing approach for improving medication adherence—part 2: implications for teaching and research. Prof Case Manag. 2009;14(1):6-15.

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