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What effects do the various chronic testosterone therapies have on serum testosterone levels?
Response by Christina Wang, MD

Low testosterone levels adversely affect many dimensions of overall health, reducing bone density and increasing the risk of metabolic syndrome1-7; producing depressed mood, low energy, and impaired cognition1,2; and manifesting as decreased libido, reduced sexual activity, and erectile dysfunction. Testosterone supplementation is recommended for men with low testosterone levels who are symptomatic.1

Several formulations are available for testosterone supplementation, each with its own dosing and pharmacokinetic characteristics.2 The US Food and Drug Administration (FDA) recently recommended that testosterone supplements in development achieve average serum concentrations (Cavg) of testosterone within the normal range (300-1000 ng/dL) for ≥75% of subjects and maximum serum concentrations (Cmax) of testosterone <1500 ng/dL in more than 85% of patients, with <5% at 1800 to 2500 ng/dL and none ≥2500 ng/dL (US Food and Drug Administration, oral communication, 2008).

Transdermal patches, buccal tablets, and topical gel formulations are intended for daily use.
  • Transdermal testosterone patches for application to nonscrotal skin have enhanced permeability.2 Evening application of 1 or 2 patches produces testosterone levels that approximate the circadian rhythm of healthy young men and provide normal-range testosterone concentrations.1,2,8,9 With a half-life of approximately 70 minutes for the patches, serum testosterone levels fall to hypogonadal levels within 24 hours after cessation of treatment.8 During steady state, levels of dihydrotestosterone (DHT)—the biologically active major metabolite of testosterone—remain in the normal range.1,8,10
  • Two formulations of transdermal testosterone 1% in a hydroalcoholic gel for topical application are available. Both products applied to nongenital skin restore and maintain serum testosterone levels in the normal physiologic range over the 24-hour dosing period for most men.1,2,11 Systemic exposure to testosterone and DHT is highly variable.11 Serum DHT levels are higher and the ratio of testosterone to DHT is lower than in eugonadal men.1 The two formulations are not bioequivalent, with significant differences in the Cmax and area under the curve (0-24 h) for both testosterone and DHT.11
  • Bioadhesive 30-mg tablets applied twice daily to the buccal mucosa normalize serum testosterone levels in hypogonadal men.1,12 DHT levels also remain in the physiologic range.12 Buccal delivery is transdermal rather than oral and, thus, circumvents the rapid gastrointestinal-hepatic metabolism12 that has prevented development of oral products.2
Implanted and injectable testosterone formulations have longer durations of effect.
  • Four to six 200-mg testosterone pellets surgically implanted under the skin maintain serum testosterone levels in the normal physiologic range for 4 to 6 months.1,13 After a short burst within 48 hours of implantation, testosterone levels plateau for about 2 months and then gradually drop to hypogonadal levels. DHT levels also rise, peaking after about 2 months. Maximum concentrations of DHT rise above the upper limit of normal, and the ratio of testosterone to DHT decreases significantly after implantation.
  • Testosterone enanthate or testosterone cypionate 100 to 200 mg by intramuscular injection maintains average serum concentrations of testosterone in the desired physiologic range for up to 14 days.1,14,15 Testosterone levels rise above normal immediately after injection, then gradually decline to the hypogonadal level by the end of the dosing period. Higher doses produce longer-term effects but also higher peaks and lower nadirs.
  • A longer-acting injectable formulation in development, testosterone undecanoate (TU) 750 mg, was found to restore serum testosterone concentrations to normal physiologic levels (Cavg between 300 and 1000 ng/dL) in 94% of subjects and maintain them within the Cmax recently established by the FDA for the entire 10-week dosing period.16,17 DHT levels remained in the low-normal range.
  1. Bhasin S, Cunningham GR, Hanes 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.
  2. 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.
  3. Kuchuk NO, van Schoort NM, Pluijm SMF, Smit JH, de Ronde W, Lips P. The association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women. Clin Endocrinol (Oxf). 2007;67(2):295-303.
  4. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91(3):843-850.
  5. Shabsigh R, Arver S, Channer KS, et al. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome [review]. Int J Clin Pract. 2008;62(5):791-798.
  6. Pitteloud N, Mootha VK, Dwyer AA, et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005;28(7):1636-1642.
  7. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27(5):1036-1041.
  8. Androderm [package insert]. Corona, CA: Watson Pharma Inc; 2005.
  9. McClellan KJ, Goa KL. Transdermal testosterone. Drugs. 1998;55(2):253-258.
  10. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J Clin Endocrinal Metab. 1992;74(3):623-628.
  11. Marbury T, Hamill E, Bachand R, Sebree T, Smith T. Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim™, compared to AndroGel®. Biopharm Drug Dispos. 2003;24(3):115-120.
  12. 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.
  13. Jockenhövel F, Vogel E, Kreutzer M, Reinhardt W, Lederbogen S, Reinwein D. Pharmacokinetics and pharmacodynamics of subcutaneous testosterone implants in hypogonadal men. Clin Endocrinol. 1996;45(1):61-71.
  14. Snyder PJ. Clinical use of androgens. Annu Rev Med. 1984;35:207-217.
  15. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab. 1980;51(6):1335-1339.
  16. Morgentaler A, Dobs AS, Kaufman JM, et al. Safety, efficacy, and pharmacokinetics of testosterone undecanoate long-acting injection in the treatment of hypogonadism: results of a phase 3 clinical trial. Poster presented at: Annual Meeting of the American Urological Association; May 17-22, 2008; Orlando, FL.
  17. Swerdloff RS, Wang C, Dobs AS, et al. Pharmacokinetics of a long-acting testosterone injection, testosterone undecanoate, on serum total testosterone and other sex hormones in the treatment of hypogonadism at steady state: results from a phase 3 clinical trial. Poster presented at: Annual Meeting of the American Urological Association; May 17-22, 2008; Orlando, FL.

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