New Advances in the Treatment of Hypogonadism in the Aging Male

THE AGING MALE New Advances in the Treatment of Hypogonadism in the Aging Male Christopher P. Steidle, MD Indiana University School of Medicine at Fort Wayne, Fort Wayne, IN The signs and symptoms of low testosterone in the aging male include erectile dysfunction, decreased libido, mood disturbances such as depression, loss of muscle mass, osteoporosis, and increase in body fat. Many of these signs and symptoms were previously believed to be part of the normal aging process, and only recently has treatment of low testosterone in the aging male been shown to provide long-term physical and mental improvement. In the past, oral and injectable testosterone delivery methods had disadvantages that limited their use, but the introduction of transdermal testosterone patches has allowed testosterone to be delivered into the circulation in a consistent fashion. Long-term use of these patches over the last 3 to 10 years has been effective in maintaining sexual function and bone and muscle mass, and from short-term studies it does not appear that testosterone treatment puts men at risk for the development of prostate cancer. A new topical gel formation (Testim) has been designed to provide consistent transdermal absorption of testosterone over 24 hours after a single dose. [Rev Urol. 2003;5(suppl 1):S34-S40] © 2003 MedReviews, LLC Key words: Hypogonadism • Andropause syndrome • Testosterone replacement therapy • Erectile dysfunction • Osteoporosis he concept of hypogonadism or low testosterone is a controversial topic. The strict definition of hypogonadism is “inadequate gonadal function, as manifested by deficiencies in gametogenesis and/or the secretion of gonadal hormones."1 Only recently has the concept of treatment of low testosterone in the aging male been shown to provide long-term physical and mental improvement. Most physicians are not aware that long-term hypogonadism in the aging male is associated with the increased risk of osteoporosis, mood disturbances, and sexual dysfunction. T S34 VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY New Advances in the Treatment of Hypogonadism Table 1 Mean Change from Baseline to Day 30—Testosterone by Treatment Group Value Testim 50 mg/d Androderm 100 mg/d ng/dL Cavg Cmin Cmax Placebo 5 mg/d mean ± SD baseline 245.8 ± 81.0 224.3 ± 78.7 236.3 ± 80.9 218.6 ± 80.8 change 119.3 ± 179.8 388.6 ± 301.8† 128.3 ± 135.8 -1.5 ± 47.7 baseline 195.3 ± 68.7 179.6 ± 74.6 192.9 ± 64.9 171.6 ± 66.3 change 27.2 ± 132.3* 213.6 ± 204.7 -14.6 ± 114.4 -6.4 ± 50.9 baseline 306.2 ± 102.7 284.2 ± 90.8 292.0 ± 106.4 274.1 ± 104.0 change 234.2 ± 362.1 613.8 ± 596.5 247.9 ± 205.2 -2.6 ± 79.2 Significant versus Androderm. † † † P < .001; * P < .025 Not until the recent information and advertising explosion regarding treatment of sexual dysfunction did the topic of low testosterone become so widely discussed. The use of testosterone replacement therapy to treat the so-called “male menopause," signs and symptoms were previously believed to be part of the normal aging process. Early treatments included testosterone injections and oral preparations. The problem with the orally administered testosterone preparations is that they need to be The baby-boomer population is now getting old enough to reap the benefits of testosterone replacement. or andropause syndrome, has been gaining tremendous popularity. This popularity is no doubt a function of increased public awareness and clinician education. The baby-boomer population is now getting old enough to reap the benefits of testosterone replacement. This population, more than any other in the history of America, is desirous of therapies that enhance lifestyle. The signs and symptoms of low testosterone in the aging male are protean. They include erectile dysfunction, decreased libido, mood disturbances such as depression, loss of muscle mass, osteoporosis, and increase in body fat. Many of these alkylated in order to be absorbed and be active. These preparations need a first-pass effect through the liver, provide poor serum blood levels, and can cause a substantial profile of liver side effects including cholestasis and widely available for a long period of time, but only recently was it realized that the dosage interval should be shortened to allow a sustained serum level of testosterone. This treatment modality is complicated by the problems of dosing irregularities, including mood changes, both at the peak and trough of the dosing cycle. Additionally, patients are often unwilling to learn self-injection, and so a spouse or significant other needs to be educated in this process. Because of such problems, these treatment options were never a great success and were used mainly for men who had the most serious causes of low testosterone, such as loss of testicles from trauma or cancer. Dosage interval should be shortened to allow a sustained serum level of testosterone. liver function abnormalities. Orally administered products are not desirable for these reasons and therefore are not recommended for replacement therapy in long-term situations. Testosterone injections have been The skin and oral mucosa are considered the most favorable routes of delivery for testosterone. Not until the introduction of transdermal testosterone patches, including the Testoderm® patch (ALZA Corp., VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S35 New Advances in the Treatment of Hypogonadism continued S36 VOL. 5 SUPPL. 1 2003 Testim 700 Concentration (ng/dL) Mountain View, CA), and the nonscrotal permeation-enhanced patch with an alcohol-based reservoir system (Androderm® Watson Pharma Inc., Corona, CA) was testosterone able to be delivered into the circulation in a consistent fashion.2 Long-term use of these patches over the last 3 to 10 years has been effective in maintaining sexual function and bone and muscle mass.2 The major drawbacks to these delivery systems, however, have been skin reactions and inadequate levels of testosterone.3 Testosterone application transdermally as a hydroalcoholic gel is as effective as parenteral testosterone replacement therapy.3 A new topical gel formation (TestimTM Auxilium Pharmaceuticals, Inc., Norristown, PA) has been designed to provide consistent transdermal absorption of testosterone over 24 hours after a single dose.4 In a single dose study, the new testosterone gel has been compared to the currently marketed gel formulation, AndroGel® (Unimed Pharmaceuticals, Inc., Deerfield, IL) and produces approximately 30% higher serum testosterone levels with similar safety profiles (Figure 1). Testim was also studied in a group of 406 patients whose primary diagnosis was that of the aging male with testosterone levels under 300 ng/dL and concomitant signs and symptoms of low testosterone. Testim 50 mg and 100 mg were compared with the testosterone patch Androderm, and placebo gel.4 Patients were treated for a period of 90 days. The average age of the patients in the trial was 58 years old. Pretreatment baseline testosterone level was 233 ng/dL and baseline prostate-specific antigen (PSA) level was 1.2 ng/dL. The primary end point for the trial was maintenance of serum testosterone levels in the therapeutic range, namely 300 to 1000 ng/dL. Comparison was made to a permeation-enhanced nonscrotal patch, AndroGel 600 500 400 300 200 100 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Time (h) Figure 1. Levels of absorption over a 48-hour interval for Testim versus AndroGel. Androderm, and to placebo. Blood samples were drawn over a 24-hour period at baseline and on day 30 and day 90. Total testosterone was measured. Appropriate safety laboratory parameters were monitored. Pharmacokinetics The 24-hour pharmacokinetic profiles for total testosterone, free testosterone (FT), and dihydrotestosterone (DHT) are measured by Cavg, which is a measure of the 24-hour average testosterone concentration. This provides a view of the entire concentration of testosterone that the body sees rather than a snapshot of individual fluctuations, which can be very confusing in clinical practice. In Table 1 the findings for mean changes in serum T from baseline to day 30 are provided. The mean Cavg increase over baseline was of similar magnitude in the 50 mg/d Testim and Androderm groups (about 50%). The 100 mg/d Testim dose resulted in a 300% greater increase in testosterone versus Androderm treatment (P < .001). Also, the results demonstrated that both the 50 mg/d and 100 mg/d Testim doses resulted in significantly higher average Cmin values than Androderm at day 30. The 100 mg/d REVIEWS IN UROLOGY Testim group had a substantial increase in mean Cmin over baseline. In contrast, the Androderm group experienced a small mean decrease, an effect similar in magnitude to that seen in the placebo group. At day 30, Cmax was very similar to the changes observed with Cavg. Data on Cmax levels demonstrated a sharp dose-response curve for the 50 mg/d and 100 mg/d doses of Testim, with the 100 mg dose producing levels twice as high as those seen with the lower-dose treatments. In addition, the Cmax achieved in the 100 mg/d Testim treatment group was significantly higher (P < .001) than that of the Androderm treated group. Day 90 values provided similar evidence of the superiority of Testim in raising serum testosterone levels. The mean change from baseline in Cavg with the Testim treatment was over twofold greater than the mean change reported with Androderm. The difference between these mean changes was statistically significant (P < .001). The data demonstrate that Testim increased Cmin over baseline by an average of 106.8 ± 175.8 (SD) ng/dL. The mean change in the Androdermtreated group was a decrease from New Advances in the Treatment of Hypogonadism differences having occurred between the treatment groups. At day 90, Testim treatment resulted in a significantly greater decrease in both fat mass (FM) (P = .002) and the percent of body fat (%F) (P = .001) than was reported in the placebotreated group. The actual mean FM decrease of 0.8 kg with the Testim group represented a clinically meaningful effect after 90 days of treatment. Table 2 Mean Change from Baseline to Day 90— Body Composition by Treatment Group Value Testim Androderm 50 and 100 mg/d 5 mg/d kg TBM LBM FM %F Placebo mean ± SD baseline 94.2 ± 13.4 94.7 ± 13.6 97.6 ± 14.4 change 0.8 ± 2.6 0.5 ± 2.1 0.5 ± 1.9 baseline 61.6 ± 8.5 62.1 ± 8.6 63.9 ± 8.6 change 1.6 ± 3.3 0.9 ± 1.8 0.6 ± 1.8 baseline 29.4 ± 8.4 29.5 ± 8.4 30.5 ± 8.3 change -0.8 ± 2.1 -0.4 ± 1.8 -0.1 ± 1.5 baseline 30.9 ± 6.2 30.8 ± 6.1 30.9 ± 5.3 change -1.1 ± 2.3 , -0.5 ± 1.6 -0.2 ± 1.4 †,†† †† † †† Sexual Function * P < .025; † P < .05; significant versus Androderm †† P < .025; significant versus placebo, FM, fat mass; %F, percent fat; LBM, lean body mass; TBM, total body mass. baseline (-29.6 ± 100.0 ng/dL) greater than the decrease seen at day 30 with this treatment. The Testim-toAndroderm comparison was highly significant (P < .001). The Testim-treated group experienced a significantly (P = .003) larger mean increase from baseline for Cmax (365.4 ± 407.8 ng/dL) than did the Androderm group (234.9 ± 247.5 ng/dL). The change was clinically meaningful with the combined Testim groups (50 mg and 100 mg), resulting in an average increase in LBM of 1.6 kg or about 3%. Changes in total body mass were minimal and there was no evidence of statistically significant 4 Baseline *††,† 3.75 3.5 Body Composition Table 2 presents the mean baseline and baseline change values to day 90 for the body composition variables as measured by dual energy X-ray absorptiometry (DXA) scan. There were statistically significant differences seen between the Testimtreated group and both the Androderm- and placebo-treated groups. Testim increased lean body mass (LBM) to a greater extent than either of the control treatments (P = .048 and P = .012, respectively). With regard to sexual functioning, the men in the study who were treated with Testim 100 mg/d showed a significant improvement at day 30 over the placebo group for the number of spontaneous erections achieved, sexual desire, performance, and motivation. Additionally, Testim produced significant improvement from baseline within the treatment groups in spontaneous erections, sexual desire, motivation, and sexual performance to a statistically significant degree (P ≤ .001) (see Figure 2). Compared to Androderm and placebo the Testim 100 mg/d group experienced the greatest increase at day 30 in the number of spontaneous erections recorded (see Figure 3). * P ≤ .05 vs placebo † P ≤ .05 vs baseline P ≤ .05 vs Androderm †† 3.25 † 3 2.75 2.5 † † 2.25 2 Figure 2. Reported levels of sexual desire in patients treated with varying testosterone replacement therapies. 1.75 Sexual Desire: Overall sexual desire (0 = none, 7 = very high) Day 30 1.5 Testim 50 mg Testim 100 mg Androderm VOL. 5 SUPPL. 1 2003 Placebo REVIEWS IN UROLOGY S37 New Advances in the Treatment of Hypogonadism continued Figure 3. Reported number of spontaneous erections (days per week) in patients treated with varying testosterone replacement therapies. 2 *†,†† Baseline 1.75 * P ≤ .05 vs placebo † P ≤ .05 vs baseline †† 1.5 P ≤ .05 vs Androderm † 1.25 † † 1 0.75 Spontaneous Erections: Nighttime and daytime erections (number of days each week) Day 30 0.5 Testim 50 mg Testim 100 mg Androderm There have also been other recent studies3 suggesting a direct relationship between testosterone levels and the development and maintenance of spontaneous erections. Sexual performance is enhanced in a variety of parameters to a significant degree in men with hypogonadism who are treated with testosterone replacement therapy. One of the greatest theoretical concerns in regard to testosterone replacement therapy in men has been elevation of serum PSA and possible development of prostate cancer. A recent abstract5 reviewed the effects of testosterone replacement therapy on serum PSA levels in older hypogonadal men and concluded that there does not appear to be a short-term risk for the development of prostate cancer. This is consistent with the findings of the pivotal Testim studies; when treatment and placebo groups were reviewed, there were no statistically significant differences in changes in PSA values. It does not appear that testosterone treatment puts men at risk for the development of prostate cancer, at least in short-term studies. This is also true for changes in pro- S38 VOL. 5 SUPPL. 1 2003 Placebo static enlargement secondary to benign prostatic hyperplasia and abnormalities of urinary flow. The changes in baseline for urinary flow were very low and there was no evidence of clinically significant or relevant treatment-related effects or differences among treatment and placebo groups. Overall, the results of the study indicate4 that Testim, when compared to both the Androderm patch and a placebo gel, was similar with regard to a variety of urinary flow measurements. Another interesting finding was that compliance with Testim gel was very high, indicating that the gel is neither offensive nor irritating and is easy to apply, and suggesting that men derive a high degree of benefit from application of the gel. The Testim trial found a large dropout rate due to skin reactions in the Androderm group. This is a previously reported phenomenon, the result of skin irritation from the permeation-enhanced patch. Bone mineral density changes were not seen in the treatment or placebo groups, but this may be a consequence of the study duration, 90 days; bone mineral changes in prior studies were not seen until at least 180 days.3 Figure 4. Reported levels of sexual performance enhancement reported in patients receiving varying testosterone replacement therapies. * †, † † 1.5 * P ≤ 0.05 vs Placebo † P ≤ 0.05 vs Baseline †† Baseline P ≤ 0.05 vs Androderm † 1.25 † 1 0.75 REVIEWS IN UROLOGY Sexual Performance: Orgasm, Ejaculation, Intercourse, Masturbation, Erection in response to sexual activity. Day 30 0.5 Testim 50 mg Testim 100 mg Androderm Placebo New Advances in the Treatment of Hypogonadism Testosterone has a stimulatory effect on hematopoiesis. This has always been considered a class effect of androgen therapy and a result of the effects of testosterone on the erythropoietic system. Both renal production of erythropoietin and stem cell differentiation are affected, the effects being much more notable in the older man. In the Testim-treated group, the effect of red blood cell mass increase was clinically notable in a small percentage of the men (7%) compared to 1% in the Androderm and placebo groups. The very small difference is probably related to the higher levels of serum testosterone obtained in the Testim-treated group. The pharmacokinetics of Testim were compared directly with those of AndroGel in a head-to-head study.6 The serum concentration of all three metabolites measured, T, DHT, and FT, increased rapidly following application of either of the gels. The levels were highly variable in this short-term study following topical application of either Testim or AndroGel. The Cmax was consistently higher following the application of Testim when compared to AndroGel. Testim produced 30% higher testosterone levels with a similar safety profile when compared in this head-to-head study (see Figure 1). The AndroGel formulation, which has a hydroalcoholic base, does not have the same emollient levels.6 This may account for more skin drying and may perhaps be the explanation for the decreased absorption of AndroGel in a short term fashion. It is important to ensure that appropriate candidates for testosterone replacement are selected and to monitor appropriate safety laboratory parameters. These parameters should always include (in men) pretreatment PSAs, complete blood count (CBC), and posttreatment PSAs at various intervals. I currently recommend 2 months, 6 months, and every year thereafter. This is consistent with the current data regarding PSA and testosterone replacement therapy. I also like to monitor testosterone levels before treatment and again at 2 months following initiation of therapy, again at 6 months, and finally every year thereafter to ensure that the appropriate levels are obtained. A pretreatment CBC is important because it allows one to evaluate the presence or absence of polycythemia. A very small percentage of men may increase their red blood cell mass as a result of testosterone treatment and as a consequence of this may develop polycythemia. This is especially evident in the older population. This has been a problem with testosterone injection therapy, secondary to the fact that rapid stimulation of stem cells from repeated injections of high doses of testosterone with long intervals between doses caused more stimulation of stem cells. I believe it is important to document the pretreatment hemoglobin when considering androgen replacement therapy. Future studies with testosterone gel should include evaluation of specific subpopulations, particularly men with erectile dysfunction in whom testosterone replacement therapy is currently indicated and treatment options in women as well. As members of the aging population become more aware of the treatment options available to them, the potential to reverse many of the long-term problems associated with hypogonadism, and the impact on their health care and lifestyle, more and more men will become interested in this therapy. As we educate more clinicians with regard to the diagnosis of hypogonadism, the numbers of men Main Points • Long-term hypogonadism in the aging male is associated with the increased risk of osteoporosis, mood disturbances, and sexual dysfunction; treatment has been shown to provide long-term physical and mental improvement. • Orally administered testosterone provides poor serum blood levels and can cause a substantial profile of liver side effects including cholestasis and liver function abnormalities. Injectable preparations have dosing irregularities that can cause mood changes, both at the peak and trough of the dosing cycle; additionally, patients are often unwilling to learn self-injection. • A new testosterone topical gel formation, Testim, provides consistent transdermal absorption of testosterone over 24 hours after a single topical dose, and produces approximately 30% higher serum testosterone levels with a similar safety profile compared to the currently marketed gel formulation. • A review of the effects of testosterone replacement therapy on serum PSA levels in older hypogonadal men concluded that there does not appear to be a short-term risk for the development of prostate cancer. • In the Testim-treated group, red blood cell mass increase was clinically notable in a small percentage of the men (7%) compared to 1% in the placebo group. • A very small percentage of men may develop polycythemia, especially in older populations. VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY S39 New Advances in the Treatment of Hypogonadism continued with this diagnosis will skyrocket. It is for this reason that there needs to be continued research on new testosterone replacement therapies. I believe that Testim represents a substantial improvement over the existing patch and injection therapies and should be a major new tool in our pharmacotherapeutic armamentarium. 2. 3. 4. References 1. S40 Stedman’s Medical Dictionary. 26th ed. VOL. 5 SUPPL. 1 2003 REVIEWS IN UROLOGY Baltimore: Williams & Wilkins; 1995:836. Dobs AS, Meikle AM, Arver S, et al. Pharmacokinetics, efficacy and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999;84:3469–3478. Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85:2839–2853. Testim normalizes androgen levels in aging males with improvements in body composition and sexual function. Personal communication 5. 6. 7. from Testim Study Group. Seftel A, Gerstenbluth R, Maniam P, et al. Effect of testosterone replacement therapy on serum prostate specific antigen levels in older hypogonadal men [abstract CP 530]. Tenth World Congress of the International Society for Sexual and Impotence Research, Montreal, Canada, September 22–26, 2002. Marbury T, Hemill E, Bachard R, et al. Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formation TestimTM compared to Androgel®. Biopharm Drug Dispos. In press. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci. 2002:57;M76–M99.