Current Data and Considerations Novel Testosterone Formulations

Current Data and Considerations Novel Testosterone Formulations 1

Hypogonadism: Treatment Safety and Prostate Health 2

Monitoring for Testosterone Therapy DRE 1,2 PSA Parameter Voiding/IPSS 1,2 Hemoglobin Hematocrit 1,2 Breast examination 1,2 Sleep apnea 1,2 Frequency Baseline, at 3 and 6 months, yearly thereafter Baseline; prostate-related symptom assessment every 6 to 12 months Baseline, at 3 and 6 months, yearly thereafter 1,2 Baseline, at 3 and 6 months, yearly thereafter Baseline and follow-up Baseline and as needed clinically Comment Biopsy if abnormal baseline and if abnormal during treatment Biopsy if PSA >4. ng/ml 1,2 Biopsy if PSA increases 1. ng/ml or greater within any 12-month period 1 Repeat PSA measurement for PSA increase of.7 to.9 ng/ml 2 Detect possible hematocrit >54% Detect gynecomastia Ask about fatigue during the day and disordered sleep DRE=digital rectal examination. IPSS=International Prostatic Symptom Score. PSA=prostate-specific antigen. 1. Bhasin S et al. J Clin Endocrinol Metab. 26;91:1995-21. 2. Rhoden EL, Morgentaler A. N Engl J Med. 24;35:482-492. Because testosterone (T) affects various organs and tissues, men receiving T therapy should be evaluated at baseline and at follow-up visits, generally at 3 and 6 months after the initiation of therapy and yearly thereafter. 1 Baseline assessments should include a digital rectal examination (DRE) and blood tests to measure prostate-specific antigen (PSA) and the hemoglobin or hematocrit. Voiding symptoms can be assessed by obtaining a history or using an instrument such as the International Prostatic Symptom Score. Patients should also be questioned regarding symptoms of sleep apnea. If the PSA is >4. ng/ml or the DRE is abnormal, a prostate biopsy should be performed. 1,2 At follow-up, urinary symptoms and the presence or exacerbation of sleep apnea or gynecomastia should be monitored. Because increased T levels appear to stimulate erythropoiesis, hemoglobin or hematocrit should be monitored during replacement therapy. 1,2 The risk of erythrocytosis appears to vary with the type of T formulation. 1 DRE should be repeated at follow-up visits. If PSA is >4. ng/ml 1,2 or increases by 1. ng/ml in a year, 1 a prostate biopsy should be performed or the patient should be referred to a urologist. For increases in PSA levels of.7 to.9 ng/ml in 1 year, the PSA measurement should be repeated in 3 to 6 months, and a biopsy should be performed if a further increase is detected. 2 1. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 24;35:482-492. 2. 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. 26;91:1995-21. 3

Potential Class Adverse Effects of Testosterone Treatment Adverse Effect Prostate cancer 1-8 Benign prostatic hyperplasia 1-6 Testicular atrophy or infertility 1-6 Sleep apnea 3,5,7 Acne and oily skin 1-6 Gynecomastia 1-6 Fluid retention 1-6 Comment Controversial; no causal relationship established Infrequently worsened in men with mild or moderate LUTS; avoid in men with severe LUTS (weak data) Common, especially in young men; usually reversible when treatment stops Infrequent; controversial Infrequent Infrequent Rarely of clinical significance; of concern only in men with class III or IV heart failure, chronic renal insufficiency, or severe liver disease 1. Delatestryl [package insert]. Lexington, Mass: Indevus Pharmaceuticals, Inc.; 25. 2. Depo-Testosterone [package insert]. Kalamazoo, Mich: Pharmacia Corporation; 22. 3. AndroGel [package insert]. Marietta, Ga: Solvay Pharmaceuticals, Inc.; 27. 4. Androderm [package insert]. Corona, Calif: Watson Pharma, Inc.; 25. 5. Striant [package insert]. Livingston, NJ: Columbia Laboratories, Inc.; 23. 6. Halotestin [package insert]. Kalamazoo, Mich: Pharmacia Corporation; 22. 7. Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab. 26;91:1995-21. 8. AACE Hypogonadism Task Force. Endocr Pract. 22;8:439-456. In the United States, product labels for testosterone replacement formulations contain standard warnings regarding prostatic hypertrophy and prostatic hyperplasia, suppression of spermatogenesis, acne and oily skin, gynecomastia, and fluid retention. 1-6 In addition, the product labeling for the testosterone buccal system includes a warning that treatment of hypogonadal men with testosterone esters may potentiate sleep apnea, especially in patients with risk factors such as obesity or chronic lung disease. However, the Endocrine Society Clinical Practice Guideline for testosterone therapy notes that this condition arises infrequently in young hypogonadal men. 5,7 With regard to prostate cancer, the American Association of Clinical Endocrinologists guidelines for the treatment of hypogonadism in adult males state that, despite anecdotal reports, no causal relationship has been established between testosterone treatment and prostate cancer. 8 1. Delatestryl [package insert]. Lexington, Mass: Indevus Pharmaceuticals, Inc.; 25. 2. Depo-Testosterone [package insert]. Kalamazoo, Mich: Pharmacia Corporation; 22. 3. AndroGel [package insert]. Marietta, Ga: Solvay Pharmaceuticals, Inc.; 27. 4. Androderm [package insert]. Corona, Calif: Watson Pharma, Inc.; 25. 5. Striant [package insert]. Livingston, NJ: Columbia Laboratories, Inc.; 23. 6. Halotestin [package insert]. Kalamazoo, Mich: Pharmacia Corporation; 22. 7. 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. 26;91:1995-21. 8. AACE Hypogonadism Task Force. Medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 22 update. Endocr Pract. 22;8:439-456. 4

Formulation-Specific Adverse Effects Formulation Injectables Pellet implants Testosterone cypionate/enanthate Testosterone undecanoate* Topical Topical gel Testosterone patch system Oral Buccal system Potential infections or expulsion Mood fluctuations or changes in libido; pain at injection site Excessive erythrocytosis Pain at injection site Dermal testosterone transference Skin irritation Adverse Effect Alterations in taste and irritation of gums and oral mucosa *In development in the United States. Data from Bhasin S et al. J Clin Endocrinol Metab. 26;91:1995-21. Formulation-specific adverse effects can occur with testosterone replacement therapy. Testosterone pellets are implanted in an office-type minor surgical procedure, which carries the risk of infection or expulsion. Intramuscular injections of testosterone cypionate, enanthate, or undecanoate (in development in the United States) may cause pain at the injection site. Testosterone cypionate or enanthate may cause fluctuations in mood or libido and excessive erythrocytosis, particularly in older patients. The testosterone topical gel can potentially be transferred to the patient s partner. Patients should cover the application site with clothing and wash skin and hands with soap before having skin-to-skin contact. Transdermal testosterone patches may cause skin irritation at the application site. The testosterone buccal system may cause alterations in taste and gum irritation. 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. 26;91:1995-21. 5

Results From Long-Term Safety Study* of Testosterone Undecanoate IM Serum trough testosterone levels within normal range Individual dosing intervals ranged from 1 to 14 weeks Patients treated for up to 8.5 years Patients reported restoration of sexual function and positive mood changes No report of mood fluctuations Hemoglobin and hematocrit within normal range Prostate size <3 ml PSA concentrations <2. µg/l Bone density improved *N=22 patients aged 3 to 65 years (mean 43.8 ± 8 years), study duration 8.5 years. Zitzmann M et al. Presented at: ENDO 26; Boston, Mass; June 24 to 27, 26. Abstract P2-547. Twenty-two hypogonadal patients aged 3 to 65 years (mean age 43.8 years) were treated with the long-acting ester testosterone undecanoate injected in a dosage of 1, mg at intervals of 1 to 14 weeks. Patients reported restored sexual function, improved vigor, and decreased depression. Fluctuations in mood often seen with short-acting testosterone preparations were not reported. Although treatment was associated with elevations in hemoglobin and hematocrit, values remained within normal limits. Prostate size remained less than 3 ml, and prostate-specific antigen (PSA) values were 2. µg/l. Quantitative computed tomography of the lumbar spine showed improvements in bone density. Testosterone undecanoate was well tolerated. The only adverse effect was moderate local irritation at the injection site that did not last more than 3 days. 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. Poster presented at ENDO 26, Boston, Mass; June 24-27, 26. 6

Prostate Health Assessment DRE PSA Consult with urologist if PSA >4. ng/ml PSA velocity >.4 ng/ml/year (using PSA level after 6 months of therapy) Detection of prostate abnormality on DRE AUA prostate symptom score >19 AUA=American Urological Association. DRE=digital rectal examination. PSA=prostate-specific antigen. Bhasin S et al. J Clin Endocrinol Metab. 26;91:1995-21. The Endocrine Society Clinical Practice Guideline recommends a digital rectal examination (DRE) of the prostate and measurement of prostate-specific antigen (PSA) before initiating testosterone therapy. A urologic consultation is recommended if the PSA is >4. ng/ml, the PSA velocity is >.4 ng/ml per year (using the PSA level after 6 months of testosterone therapy), a prostatic abnormality is detected on DRE, or the patient has an American Urological Association prostate symptom score of >19. 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. 26;91:1995-21. 7

Prostate Cancer Incidence in Testosterone Therapy Studies (Controlled) Age (y) Study Authors Duration (months) Patients Receiving T (n) Mean Range PCa Cases (n) Route of Administration Kenny et al. (21) 1 12 24 76 65-87 Patch Wang et al. (2) 2 6 227 Not available 19-68* 1 Gel, patch Snyder et al. (1999) 3 36 54 73.1 >65 1 Patch Dobs et al. (1999) 4 6 66 44.3 (gel) 44.9 (IM) 22-65 3 Gel, IM Sih et al. (1997) 5 12 17 65 51-79 IM *3.9%-8.2% aged 65 in the 3 original treatment groups. PCa=prostate cancer. T=testosterone. 1. Kenny AM et al. J Gerontol A Biol Sci Med Sci. 21;56A:M266-M272. 2. Wang C et al. J Clin Endocrinol Metab. 2;85:2839-2853. 3. Snyder PJ et al. J Clin Endocrinol Metab. 1999;84:1966-1972. 4. Dobs AS et al. J Clin Endocrinol Metab. 1999;84:3469-3478. 5. Sih R et al. J Clin Endocrinol Metab. 1997;82:1661-1667. Studies of hypogonadal men receiving testosterone therapy using transdermal, topical, intramuscular injection, or a combination of these preparations have demonstrated a low frequency of prostate cancer. A compilation of published prospective studies of testosterone replacement revealed only 5 cases of prostate cancer among 388 men (~1.%) followed for 6 to 36 months. 1-5 According to Rhoden and Morgentaler, this prevalence rate is similar to that in the general population. 6 1. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 21;56A:M266- M272. 2. 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. 2;85:2839-2853. 3. Snyder PJ, Peachey H, Hannoush P, et al. Effects of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:1966-1972. 4. Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. 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. 5. Sih R, Morley JE, Kaiser FE, Perry HM III, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997;84:1661-1667. 6. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. New Engl J Med. 24;35:482-492. 8

Prostate Cancer Incidence in Testosterone Therapy Studies (Non-Controlled) Study Authors Duration (months) Patients Receiving T (n)* Mean 59.6 6.4 Not available Age (y) Range PCa Cases (n) Route of Administration Wang et al. Not Not 36 123 3 Gel (24) 1 available available Schubert et 41.1 23-64 IM TU 3 36 al. (24) 2 36.3 18-62 IM TE Rhoden et al. (23) 3 Gerstenbluth et al. (22) 4 Snyder et al (2) 5 12 Mean 3.2 36 2 (PIN+) 55 (PIN-) 54 14 42-77 42-76 22-78 1 1 IM, gel IM, gel IM Patch *n=total number of patients remaining at end of study. Median=51. PCa=prostate cancer. PIN+=prostatic intraepithelial neoplasia without frank cancer. PIN =PIN with benign prostate biopsy. 1. Wang C et al. J Clin Endocrinol Metab. 24;89:285-298. 2. Shubert M et al. J Clin Endocrinol Metab. 24;89:5429-5434. 3. Rhoden EL, Morgentaler A. J Urol. 23;17:2348-2351. 4. Gerstenbluth RE et al. J Androl. 22;23:922-926. 5. Snyder PJ et al. J Clin Endocrinol Metab. 2;85:267-2677. These non-controlled studies of hypogonadal men receiving testosterone (T) therapy also demonstrate a low incidence of prostate cancer. Among 32 men receiving either a transdermal, topical, or intramuscular T formulation for 12 to 36 months, only 5 cases of prostate cancer were detected (1.7%). 1-5 After their retrospective study of 54 men, Gerstenbluth et al also conducted one of the longest follow-up evaluations of a significant number of hypogonadal men. They performed a subset analysis of 19 men who continued T therapy for at least 36 months (mean, 58.5 months). No patient in this follow-up group was diagnosed with prostate cancer, suggesting that, after 4 to 5 years of sustained T therapy, risk of prostate cancer did not increase. 4 1. Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 24;89:285-298. 2. Schubert M, Minnemann T, Hübler 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. 24;89:5429-5434. 3. Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol. 23;17:2348-2351. 4. Gerstenbluth RE, Maniam PN, Corty EW, Seftel AD. Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement. J Androl. 22;23:922-926. 5. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2;85:267-2677. 9

Relationship of PSA Levels to Prevalence of Prostate Cancer Total PSA (ng/ml).5.6 to 1. 1.1 to 2. 2.1 to 3. 3.1 to 4. Probability of Prostate Cancer (%) 6.6 1.1 17. 23.9 26.9 N=2,95 men aged 62 to 91 years. PSA=prostate-specific antigen. Reprinted with permission from Thompson IM et al. N Engl J Med. 24;35:2239-2246. The prevalence of prostate cancer was determined in 2,95 men (aged 62 to 91 years) in the placebo arm of the Prostate Cancer Prevention Trial who never had a prostate-specific antigen (PSA) level >4. ng/ml or an abnormal annual digital rectal examination result during 7 years in the study. Prostate cancer was diagnosed in 15.2% (449) of the 2,95 men, and 14.9% (67) of these cancers were high grade (Gleason score of 7 or higher). As shown here, the prevalence of prostate cancer increased as the PSA level increased, ranging from 6.6% among men with a PSA.5 ng/ml to 26.9% among men with a PSA of 3.1 to 4. ng/ml. Although PSA levels 4. ng/ml are generally considered normal, these findings show that prostate cancer is not uncommon in men with these levels. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level 4. ng per milliliter. N Engl J Med. 24;35:2239-2246. 1

Effect of Testosterone Therapy on Prostate Tissue in Men With Late-Onset Hypogonadism Study Design BIOPSY 17 screened 48 enrolled* 6-month, randomized, controlled trial (Feb 3 - Nov 4) 44 randomized RE-BIOPSY Testosterone 21 15 mg IM every 2 weeks 4 completed Placebo 19 *4 excluded (prostate cancer on first biopsy). 1 discontinuation (erythrocytosis). 2 discontinuations (1 GI cancer, 1 moved), 1 excluded (elevated baseline testosterone level). GI=gastrointestinal. Data from Marks LS et al. JAMA. 26;296:2351-2361. 2 prostate cancers 4 prostate cancers To determine the effects of testosterone (T) therapy on prostate tissue, a randomized, double-blind, placebo-controlled trial was conducted in men aged 44 to 78 years with screening T levels <3 ng/dl and related symptoms. Of 17 men screened, 48 men met enrollment criteria, but 4 were found to have prostate cancer. Thus, 44 men were randomized to receive 15 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. A total of 4 men (21 T therapy, 19 placebo) had prostate biopsies performed at baseline and at 6 months and qualified for the per-protocol analysis. One man assigned to T therapy discontinued early because of erythrocytosis. Two men assigned to placebo discontinued early, 1 because of gastrointestinal cancer and 1 who moved away, and a third man assigned to placebo was excluded from the analysis because of an elevated baseline T level found at the end-of-study batch analysis. Re-biopsy at 6 months detected prostate cancer in 2 of 21 men in the T therapy group and 4 of 19 men in the placebo group. In each group, 1 man had a Gleason grade 7 cancer; each man showed a modest increase in serum prostate-specific antigen during the trial. The other cancers were Gleason grade 6 lesions. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 26;296:2351-2361. 11

Effect of Testosterone Therapy on Prostate Tissue in Men With Late-Onset Hypogonadism Serum Levels Testosterone Dihydrotestosterone 1,5 Serum (ng/dl) 1, 5 Serum (ng/dl) 1 5 Baseline 6 Months Baseline 6 Months Baseline 6 Months Baseline 6 Months Placebo Active =outlier. Reprinted with permission from Marks LS et al. JAMA. November 15, 26;296:2351-2361. Copyright 26 American Medical Association. Serum levels of testosterone (T) and dihydrotestosterone (DHT) were determined in morning blood samples collected at baseline and during study visits at 6 weeks, 3 months, and 6 months. Baseline and 6-month data are compared here. After 6 months of T therapy, serum T levels increased to the mid-normal range (median at baseline, 282 ng/dl; median at 6 months, 64 ng/dl), with no significant change in serum T levels in placebo-treated men. Serum DHT increased from a median of 28 ng/dl at baseline to a median of 47 ng/dl after 6 months of T therapy, but decreased slightly in the placebo group from 28 ng/dl to 26 ng/dl. Overall, average increases in the T therapy group were 138% for T and 65% for DHT. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 26;296:2351-2361. 12

Effect of Testosterone Therapy on Prostate Tissue in Men With Late-Onset Hypogonadism Prostate Tissue Levels Testosterone Dihydrotestosterone 25 4 Tissue (ng/g) 15 1 5 Tissue (ng/g) 2 1 Baseline 6 Months Baseline 6 Months Baseline 6 Months Baseline 6 Months Placebo Active =outlier. Intraprostatic concentrations of testosterone and dihydrotestosterone did not differ after therapy despite substantial changes in serum concentrations. Reprinted with permission from Marks LS et al. JAMA. November 15, 26;296:2351-2361. Copyright 26 American Medical Association. Determinations of prostate androgens (testosterone [T] and dihydrotestosterone [DHT]) were performed on quick-frozen biopsy cores (5-1 mg). As shown here, intraprostatic concentrations of T and DHT did not differ after therapy despite increases of 138% and 65%, respectively, in serum concentrations. The median T level was.91 ng/g at baseline and 1.55 ng/g (P=.29) after 6 months of T therapy, and the median DHT level was 6.79 ng/g at baseline and 6.82 ng/g posttreatment (P=.51). Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 26;296:2351-2361. 13

Occult Prostate Cancer in Men With Low Testosterone Levels Objective Determine prevalence of prostate cancer in men with low TT or FT levels Design Prostate biopsy in consecutive patients Patients Men (n=345) with low TT or FT levels, with normal DRE examination and PSA levels 4. ng/ml DRE=digital rectal examination. FT=free testosterone. PSA=prostate-specific antigen. TT=total testosterone. Morgentaler A, Rhoden EL. Urology. 26;68:1263-1267. The prevalence of prostate cancer was determined in 345 consecutive men with a prostate-specific antigen (PSA) level of 4. ng/ml who underwent digital rectal examination (DRE) and prostate biopsy before initiating testosterone (T) therapy. All of the men had low serum levels of total T (184 men, 53.3%), defined as <3 ng/dl, or free T (327 men, 94.8%), defined as <1.5 ng/dl. All of the men had a PSA 4. ng/ml, and 7.1% had normal findings on DRE. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4. ng/ml or less. Urology. 26;68:1263-1267. 14

Prostate Cancer Prevalence in Hypogonadal Men With PSA Levels of 4. ng/dl Men With Prostate Cancer (%) 4 35 3 25 2 15 1 5 5.6 17.1* 26.4* 36.4 to 1. (n=162) 1.1 to 2. (n=97) PSA (ng/ml) 2.1 to 3. (n=53) 3.1 to 4. (n=33) *P<.5 vs men with PSA of to 1. ng/ml. P<.5 vs men with PSA of to 1. and 1.1 to 2. ng/ml. Reprinted with permission from Morgentaler A, Rhoden EL. Urology. 26;68:1263-1267. Biopsy revealed prostate cancer in 52 (15.1%) of the 345 men. As shown here, the relationship between cancer risk and increasing PSA level was linear. Men with a PSA level of 3.1 to 4. ng/ml had the highest rate of prostate cancer 36.4% whereas the rate of prostate cancer was about 11% among men with a PSA level of 2. ng/ml. Even men with a PSA level of 1. had a cancer rate of 5.6%, indicating that no level of PSA was without risk. In addition, the risk of prostate cancer increased with lower testosterone levels. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4. ng/ml or less. Urology. 26;68:1263-1267. 15

Low Testosterone Levels Associated With High-Grade Prostate Cancer 5 4 41 43 37 Testosterone (ng/dl) 3 2 28* 1 5 (n=34) 6 (n=33) 7 (n=51) 8 (n=38) Gleason Score *P<.1. Data from Schatzl G et al. Prostate. 21;47:52-58. Another study of 156 patients newly diagnosed with prostate cancer found an association between low testosterone (T) levels and high-grade cancer. Fifty-two of the patients (33%) had a serum T level <3 ng/dl. As shown here, the mean T level was significantly lower in men with Gleason scores 8 than in those with Gleason scores 5 (28 ng/dl vs 41 ng/dl, P<.1). Schatzl G, Madersbacher S, Thurridl T, et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate. 21;47:52-58. 16

Hypogonadal Men Treated With Testosterone After Radical Prostatectomy Patient No. (Age, years) Year of Prostatectomy Gleason Score/Surgical Margin Pre- Prostatectomy PSA Serum T Before Treatment T Start T Formulation Serum T After Treatment 1 (7) 1993 6/Neg 6.6 269 22 Patch 214-26 2 (5) 1991 6/Pos 5.2 Not available 1991 Depot Not available 3 (66) 21 7/Neg 4.4 51 22 Gel 214 4 (64) 22 6/Neg 5.3 5 22 Gel 37 5 (67) 1995 6/Neg Not available Not available 2 Depot 74 6 (55) 22 6/Neg 4.7 Not available 22 Patch 563 7 (64) 1994 6/Neg Not available 19 1998 Patch 545 PSA=prostate-specific antigen. T=testosterone. This table was published in Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 24;172:92-922. Copyright by American Urological Association 24. A retrospective review of clinical records from 2 private urology practices identified 7 hypogonadal men who were treated with an androgen preparation after curative radical prostatectomy. Before treatment, all 7 men had clinical symptoms of hypogonadism and low levels of serum testosterone. Details of each case are summarized here. After follow-up ranging from 1 to 12 years, no evidence of local recurrence or distant spread of prostate cancer was found in the 7 men who received testosterone. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 24;172:92-922. 17

Testosterone Therapy After RRP in Patients With Prostate Cancer Objective Study hypogonadal patients treated with RRP to determine whether testosterone therapy could be efficacious and safe without causing recurrent prostate tumor Method Hypogonadal patients (n=1) previously treated with RRP presented with low TT and symptoms of hypogonadism Baseline data Mean age: 64 years Mean PSA: pre-op =7 ng/ml, post-op <.1 ng/ml Mean T: pre-op =469 ng/dl, post-op =197 ng/dl Gleason score: 6-8 Results Mean T increased significantly from 197 ng/dl to 591 ng/dl (P=.2) No detectable increase in PSA (all were <.1 ng/ml) PSA=prostate-specific antigen. RRP=radical retropubic prostatectomy. T=testosterone. TT=total testosterone. Agarwal PK, Oefelein MG. J Urol. 25;173:533-536. A retrospective review of patients with cancer confined to the prostate who were treated for hypogonadism after radical retropubic prostatectomy was undertaken to determine whether testosterone (T) replacement therapy could be effective and safe without causing recurrent prostate tumor. Ten patients who underwent radical retropubic prostatectomy between 1993 and 23 were identified. Postoperatively they had no clinical or prostate-specific antigen (PSA) evidence of disease but presented with complaints of decreased libido, erectile dysfunction, lack of energy, cognitive impairment, hot flashes, or a combination of these symptoms. Baseline serum PSA was measured to exclude recurrent prostate cancer, and baseline serum T levels were determined to confirm hypogonadism. The mean age of the men was 64.3 years. Preoperatively, PSA was 7. ng/ml and T (available in 5 patients) was 469 ng/dl. Gleason scores obtained from prostate adenocarcinoma specimens ranged from 6 to 8. Postoperative values for PSA and T were <.1 ng/ml and 197 ng/dl. Patients received either topical T gel or patch or intramuscular testosterone cypionate and were followed every 2 months. After starting T replacement therapy, mean serum T increased significantly from 197 ng/dl to 591 ng/dl (P=.2). The median duration of T replacement therapy was 19 months. No patient had detectable PSA (>.1 ng/ml). Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol. 25;173:533-536. 18

Testosterone Therapy After Treatment of Early Prostate Cancer With Brachytherapy Testosterone Levels and Follow-Up Variable Testosterone (ng/dl) Range Median Before testosterone therapy With testosterone therapy* 3 to 255 365 to 1,373 188 498 Duration (years) Testosterone therapy Follow-up.5 to 8.5 1.5 to 9. 4.5 5. *Testosterone therapy started.5 to 4.5 years after brachytherapy. N=31. CANCER, Vol. 19, No. 3, 27, p. 538. Copyright 27 American Cancer Society. This material is reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. Records of 31 men who underwent prostate brachytherapy from 1996 to 24 and received subsequent testosterone (T) therapy for hypogonadism were reviewed to assess the risk of biochemical failure or prostate cancer recurrence. The duration of T therapy after prostate brachytherapy ranged from.5 to 8.5 years (median 4.5 years), with a follow-up ranging from 1.5 to 9. years (median 5. years). T therapy was initiated from.5 to 4.5 years (median, 2. years) after brachytherapy. Median serum testosterone levels were 188 ng/dl before T therapy and rose to 498 ng/dl with T therapy. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 27;19:536-541. 19

Recent PSA Levels in Men Receiving Testosterone After Brachytherapy PSA (ng/ml) <.1 <.5 <1. No. of Patients (%) 23 (74.2) 3 (96.7) 31 (1) PSA=prostate-specific antigen. CANCER, Vol. 19, No. 3, 27, p. 538. Copyright 27 American Cancer Society. This material is reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. One patient had transient increases in prostate-specific antigen after testosterone therapy, followed by decreases. The most recent prostate-specific antigen levels were <.1 ng/ml in 23 men (74.2%), <.5 ng/ml in 3 men (96.7%), and <1. ng/ml in all 31 men. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 27;19:536-541. 2

Summary Eugonadal testosterone levels are a critical component of men s overall health and sexual well-being Clinical benefits of testosterone therapy may include improvements in libido, erectile function, mood, bone mineral density, and body composition No evidence indicates that testosterone therapy increases prostate cancer risk but careful monitoring of prostate health is mandatory Some evidence indicates that men with low testosterone levels may have increased risk of prostate cancer and of high-grade prostate cancer Men who have been treated for prostate cancer must receive individualized treatment and be monitored carefully Follow-up visits are essential to assess efficacy and safety Eugonadal testosterone (T) levels are a critical component of men s overall health and sexual well-being. Clinical benefits of T therapy in hypogonadal men may include improvements in libido, erectile function, mood, bone mineral density, and body composition. Clinical experience to date has shown no evidence to suggest that T therapy increases the risk of prostate cancer. However, careful monitoring of prostate health during T therapy is mandatory. Some evidence suggests that men with low T levels may have an increased risk of prostate cancer and of high-grade prostate cancer. After treatment for prostate cancer, men experiencing symptoms of hypogonadism need to be treated on an individual basis and monitored very carefully. Follow-up visits are essential to monitor efficacy and safety for patients who are currently receiving or who have previously received T therapy. 21