International Journal of Impotence Research (2007) 19, 2–24 & 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00 www.nature.com/ijir REVIEW Testosterone replacement therapy for male hypogonadism: Part III. Pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents A Seftel Department of Urology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH, USA Male hypogonadism is associated with potentially distressing adverse effects on diverse organs and tissues. These include sexual dysfunction, particularly diminished libido, as well as mood disturbances, reduced lean body mass, and increased adipose-tissue mass. A wide range of effective and well-tolerated options exists. These include relatively noninvasive therapies, such as testosterone (T) gels and T patches; slightly more invasive treatments, such as the T buccal system; and invasive therapies, such as intramuscular T injections and subcutaneous depot implants (T pellets). Testosterone replacement therapy (TRT) can be individualized to enhance patient health and well-being. Screening and ongoing monitoring are necessary to ensure both the efficacy and safety of TRT, particularly prostate safety. Investigational agents, including selective androgen receptor modulators, may offer new pharmacodynamic and/or pharmacokinetic properties that enhance outcomes of TRT. International Journal of Impotence Research (2007) 19, 2–24. doi:10.1038/sj.ijir.3901366; published online 29 September 2005 Keywords: efficacy; hypogonadism; pharmacokinetics; safety; testosterone; tolerability Introduction improvements in sexual desire and quality of life, in hypogonadal men receiving adjunctive TRT, includ- Testosterone replacement therapy (TRT) has been ing sildenafil nonresponders.3,4 administered to men with hypogonadism for dec- Contraindications to the use of exogenous testos- ades.1 The fundamental aim of TRT is to restore terone formulations, which are Schedule III con- serum T to eugonadal levels and minimize signs and trolled substances, include prostate cancer (PCa), symptoms of hypogonadism. Sexual dysfunction, breast cancer, and/or untreated prolactinoma.5 TRT particularly low libido, is among the most readily with any of the modalities described herein should reversible symptoms of male hypogonadism. The be instituted according to the screening and mon- most recent erectile dysfunction (ED) consensus itoring guidelines, which are detailed in this review. guidelines recommend evaluation of the hypotha- lamic–pituitary–gonadal axis, including total T, Topical/transdermal therapies bioavailable T (BT), and free T (FT), ‘in patients with sexual dysfunction and at risk of or suspected Testosterone topical gels (T Gels) of hypogonadism.’2 These guidelines designate Pharmacologic profiles. Two 1% hydroalcoholic testosterone as a second-line therapy. Recent studies T gels have been approved by the US Food and Drug have demonstrated significant short-term improve- Administration (FDA) for male hypogonadism: ments in erectile function, as well as longer-term s AndroGel from UniMed Pharmaceuticals (Deer- field, IL, USA) and Solvay Pharmaceuticals (Mar- ietta, GA, USA), and Testims from Auxilium Pharmaceuticals (Malvern, PA, USA).6,7 Each 5- to Correspondence: Dr A Seftel, Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, 10-g tube or packet of 1% gel contains 50–100 mg of Cleveland, OH 44106-5046, USA. T. Each gel is formulated with a skin-penetration E-mail: [email protected] enhancer and is X67.0% ethanol by volume. After Received 2 March 2005; accepted 7 June 2005; published daily (preferably morning) application of each agent online 29 September 2005 to clean, dry, intact skin of the upper arms or Testosterone replacement therapy A Seftel 3 shoulders (and/or abdomen), 10% of each dose desire and erectile function following daily treat- (5–10 mg) is absorbed into the systemic circulation ment with topical T gel 5 g of a 1% testosterone over a 24-h period. hydroalcoholic gel daily (AndroGels; Besins Inter- national, Paris, France). Following 3 months of such treatment, the mean serum T was restored to Clinical studies 1013 ng/dl and normalized in all patients. In 31 Pharmacokinetics. T gels provide longer-lasting (63%) of the 49 men, scores on both the sexual elevations of serum T compared with a transdermal desire and erectile function domains of the IIEF patch (T patch).8 In a study involving equivalent were significantly improved compared with base- doses of two T gels,9 Testim treatment was asso- line, with the sexual desire domain more than ciated with significantly higher serum T levels and doubling (from 4 to 8.9; P 0.001) and the erectile bioavailability than Androgel; the two formulations o function domain nearly doubling (from 15.0 to 26; were not biologically equivalent: both the C and max P 0.001); the final value of 26 has been associated AUC0-24 for T delivered by Testim were 30% higher o with no ED in prior studies.18 than the values for T delivered by Androgel (Table 1). A total of 17 patients did not have significant T delivered by gel formulations undergoes no first- improvements in sexual function following 3 months pass hepatic metabolism. of T-gel therapy as determined by negative responses to the Global Assessment Question (GAQ), ‘Has Efficacy. Several multicenter, randomized con- treatment improved your erections?’ However, these trolled trials have demonstrated that restoration patients did experience some improvements, with of serum T levels with T gel was associated with normalization of serum T and BT and an increase in improvements in sexual function,3,10–12 as well as the erectile function domain of the IIEF (from 13.6 to body composition, mood, and/or bone markers11–13 22 following T-gel monotherapy). Following treatment (Table 1). In one study, threshold serum T values with an adjunctive sildenafil (100 mg)-T-gel regimen (Cavg) were identified above which significant im- for a further 3 months, the mean erectile function provements were noted: 500 ng/dl for the frequency score increased to 27, which is consistent with no of sexual intercourse and 600 ng/dl for self-rated ED, and all patients answered the GAQ positively. sexual desire (Figure 1).10 The frequency of night Two patients discontinued treatment because of time erections rose significantly even when serum T urination difficulties. Nine patients reported irritation levels were low-normal (Cavg ¼ 400 ng/dl), suggest- at the T-gel application site, but no patient dis- ing that this androgenic effect may be among the continued therapy.18 earliest to be observed during TRT. Finally, a US group recently reported that treat- The benefits of adjunctive or ‘rescue’ TRT with a T ment of 18 hypogonadal men with depression using gel were shown in studies of hypogonadal men with T gel (5 g of a 1% gel; AndroGels; Unimed refractory depression14 or with moderate-severe ED Pharmaceuticals) for up to 12 weeks significantly nonresponsive to sildenafil3 (Table 1). The results improved scores on the Hamilton Rating Scale for from the study of men with ED were particularly Depression compared with baseline but not com- noteworthy because 16% of patients also had pared with a placebo phase of equal duration.19 diabetes mellitus, which frequently renders ED There were no clinically significant changes in more severe, refractory to treatment, and a greater hemoglobin, hematocrit, or prostate-specific antigen burden on quality of life.15,16 (PSA) between the T-gel and placebo phases.19 Three important studies concerning T and both sexual function and depression have been published in 2005. Studying 162 elderly (mean age ¼ 64.1 Tolerability and safety. T gels have been well years) men with ED (mean duration ¼ 45.6 months), tolerated in trials of up to 6 months. According to a Korean group reported that hypogonadism (serum the US product labeling for Testim, adverse events To300 ng/dl) was among the strongest independent (AEs) judged to be possibly, probably, or definitely predictors of a poor response to sildenafil 25–100 mg related to T gel in 0–2% of patients included for 8 weeks. Only poor pretreatment erectile func- headache, hot flushes, insomnia, increased blood tion (International Index of Erectile Function (IIEF) pressure or increased hematocrit or hemoglobin.7 erectile function domain score o17) was a stronger AEs considered to be possibly, probably, or defi- independent prognostic factor (OR ¼ 2.2; 95% nitely related to AndroGel included acne (1–8% of CI ¼ 1.45–7.33).17 patients); headache (up to 4%); as well as emotional Consistent with this report, an Israeli group lability, nervousness, gynecomastia, or mastodynia demonstrated that short-term treatment with (up to 3%).6 Application-site reactions represent the either T gel or adjunctive T gel with sildenafil most frequent complaints with both T gels, occur- has potential clinical benefits in hypogonadal ring in up to 5% of patients.6,7 men (mean age ¼ 60.7 years) with ED.18 In this study With regard to prostate safety, 2.8–18.8% of 106 of 49 hypogonadal men (mean serum T ¼ 378 ng/dl), men receiving T gel (AndroGel) 50–100 mg experi- 31 reported significant improvements in both sexual enced prostate enlargement or elevation in PSA International Journal of Impotence Research International Journal of Impotence Research 4 Table 1 T Gels: pharmacokinetics, efficacy, and safety Study Treatment Design Pharmacokinetics Efficacy Safety/tolerability Pharmacokinetics7efficacy