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This Month's Question

Response by Martin Miner, MD, Posted 03/15/08

Testosterone is a key component in maintaining a man’s general sense of well-being, but the exact relationship between testosterone and well-being remains unclear. Studies have shown that, when serum testosterone levels decline to hypogonadal levels, a wide range of psychological symptoms occur, including mood disturbances, depression, and poor self-esteem.¹ Men with untreated hypogonadism tend to score poorly on depression, anger, fatigue, and confusion scales.² A prospective evaluation of 157 men presenting to a sexual dysfunction clinic demonstrated that overt depression symptoms, defined by a Center for Epidemiologic Studies Depression Scale score of  ≥22, are strongly associated (P<.05) with hypogonadism.³

The primary goal of testosterone therapy is to restore hormones to physiologic levels to alleviate the signs and symptoms of hypogonadism.⁴ A growing body of evidence shows that testosterone therapy for men with hypogonadism produces positive effects in many psychological parameters, including mood, feelings of vitality, and general sense of well-being.^4,5 Although randomized trials examining the relationship between testosterone therapy in men with hypogonadism and depression symptoms have been small in number and shown somewhat conflicting results, there has been some suggestion that testosterone therapy may improve mood.^6,7

Large fluctuations in serum testosterone levels can occur between testosterone treatments with available preparations, including gels and intramuscular injectables.^8,9 Substantial vacillations in serum testosterone levels often are associated with mood and energy swings. This is well-documented for intramuscular testosterone enanthate, which produces supraphysiologic testosterone levels shortly after initial administration that decline to the subphysiologic range before the next injection.^9,10 Transdermal testosterone gels administered on a daily basis may cause serum testosterone levels to rise shortly after administration to the supraphysiologic range. Average daily fluctuations in serum testosterone levels of more than 700 ng/dL may occur with testosterone gel therapy,⁸ although mood changes and energy swings have not been associated.

Testosterone undecanoate (TU), which is available in more than 70 countries, is a long-acting intramuscular injection. This depot formulation allows for consistent delivery of testosterone over time, avoiding daily fluctuations in testosterone levels.¹¹ Patients receiving TU therapy report improvements in mood, vigor, and feelings of depression.^12,13 Unlike other testosterone formulations, TU is administered by a clinician, with regulated follow-up office visits, which would support patient adherence to therapy.

Considering the favorable pharmacokinetic profile of TU, its positive impact on psychological parameters, and possible improvement in patient adherence, TU may be an appropriate therapeutic option for patients with hypogonadism and associated psychological symptoms.

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. Burris AS, Banks SM, Carter CS, Davidson JM, Sherins RJ. A long-term, prospective study of the physiologic and behavioral effects of hormone replacement in untreated hypogonadal men. J Androl. 1992;13(4):297-304.

3. Makhlouf AA, Mohamed MA, Seftel AD, Neiderberger C. Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction. Int J Impot Res. 2007:1-5.

4. 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.

5. Wang C, Swerdloff RS, Iranmanesh A, et al; and Testosterone Gel Study Group. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2839-2853.

6. Seidman SN, Spatz E, Rizzo O, Roose SP. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. J Clin Psychiatry. 2001;62(6):406-412. Cited by: Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(1):105-111.

7. Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(1):105-111.

8. Androgel [package insert]. Marietta, GA: Solvay Pharmaceuticals Inc; 2007.

9. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab. 1980;51(6):1335-1339.

10. Nakazawa R, Baba K, Nakano M, et al. Hormone profiles after intramuscular injection of testosterone enanthate in patients with hypogonadism. Endocr J. 2006;53(3):305-310.

11. Schubert M, Minnemann T, Hűbler D, et al. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab. 2004;89(11):5429-5434.

12. Zitzmann M, Saad F, Nieschlag E. Longterm experience of up to 8.5 years with a long-acting formulation of testosterone undecanoate in substitution therapy of hypogonadal men. Presented at: 88th Annual Meeting of the Endocrine Society; June 24-27, 2006; Boston, MA. Poster P2-547.

13. Saad F, Kamischke A, Yassin A, et al. More than eight years’ hands-on experience with the novel long-acting parenteral testosterone undecanoate [review]. Asian J Androl. 2007;9(3):291-297.

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