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This Month's Question

Response by Frances Hayes, MD, Posted 11/15/07

The underlying conditions that necessitate testosterone therapy in men are usually irreversible.¹ Treatment of long duration is often required, and patient compliance is key to ensuring long-term success.^1,2 Patient adherence with testosterone therapy depends on the availability of pharmaceutical formulations that are convenient to use, promise relative independence of medical services, and ensure continuous testosterone replacement.¹ To promote optimal compliance with testosterone therapy, clinicians must involve patients in the decision-making process.²

A wide range of effective and well-tolerated treatment options are available, including testosterone gels, patches, implants, and intramuscular (IM) injections.^3-6 The goal of testosterone therapy is to restore serum testosterone levels to the normal range and to induce and maintain secondary sexual characteristics, normal sexual function, bone mineral density, muscle development, and lean body mass, while at the same time limiting side effects.⁵ Each formulation has advantages and disadvantages that may affect patient satisfaction and compliance.

Transdermal testosterone gels offer a lack of visibility, easy application, dosing flexibility, and a low rate of minimal skin irritation, resulting in favorable patient compliance.^4,5 However, gels are rather expensive and carry a risk of transference to other people through close physical contact.^3,5 Buccal formulations  may be associated with bad taste and gum irritation resulting in low patient adherence.³ Testosterone patches are somewhat large and can be cosmetically unattractive.⁶ They are expensive, can cause skin irritation at the application site, and, in some patients, may not adequately adhere to their skin.^3,5 Subcutaneous testosterone pellet implants restore physiologic testosterone levels with little fluctuation over 4 to 6 months and are generally acceptable to patients.^3,6 However, insertion of the pellets requires a minor outpatient surgical procedure, and implants are associated with unacceptably high extrusion rates.^5,6 IM injections of testosterone esters are effective and inexpensive. However, the downside of this route of administration is that the deep IM injections can be painful.⁶ In addition, currently available IM testosterone preparations cause wide variations in serum testosterone levels, into the supraphysiologic range,^3,6 which may result in concomitant fluctuations in mood, energy, libido, and sexual function.³ It is thus important for clinicians to familiarize patients with these various drawbacks when choosing a testosterone therapy that will promote optimal tolerability and compliance.

New, longer-acting testosterone formulations produce more stable testosterone levels than existing IM preparations and have few side effects, resulting in good patient adherence.^1,3,4  A novel long-acting IM formulation, testosterone undecanoate, in contrast to other testosterone esters, sustains normal testosterone levels for 12 weeks, requires less frequent injections, and produces more stable levels of energy and libido.^2-4

All patients receiving testosterone therapy must be carefully assessed and monitored for side effects.⁵ Changes in hematocrit and prostate-specific antigen (PSA) levels must also be monitored through serum evaluation.⁵

Side effects may cause nonadherence, and acute testosterone withdrawal may result in unfavorable consequences. Logically, the signs and symptoms of hypogonadism return if the patient does not adhere to therapy. A recent study by Yialamas and colleagues indicates that in young healthy men with idiopathic hypogonadotropic hypogonadism (IHH), acute testosterone withdrawal can decrease insulin sensitivity.⁷ Additionally, Lee and colleagues demonstrated that suppression of testosterone increases skeletal responsiveness to the bone-resorbing effects of parathyroid hormone (PTH) in men.⁸ Increasing skeletal sensitivity to PTH may contribute to the pathogenesis of bone loss in men with hypogonadism.⁸ To minimize nonadherence to testosterone therapy, it is critical for clinicians and patients to work together to select the testosterone formulation that ensures few side effects and optimal patient acceptability.

References

1. Gooren LJ. New long-acting androgens. World J Urol. 2003;21(5):306-310.

2. Gooren LJ, Bunck MC. Androgen replacement therapy: present and future. Drugs. 2004;64(1):1861-1891.

3. 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.

4. Byrne MM, Nieschlag E. Testosterone replacement therapy in male hypogonadism. J Endocrinol Invest. 2003;26(5):481-489.

5. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006; 91(6):1995-2010.

6. 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.

7. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92(11):4254-4259.

8. Lee H, Finkelstein JS, Miller M, Comeaux SJ, Cohen RI, Leder BZ. Effects of selective testosterone and estradiol withdrawal on skeletal sensitivity to parathyroid hormone in men. J Clin Endocrinol Metab. 2006;91(3):1069-1075.

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