Feb., 2014 mens urological health cme testosterone replacement -

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  • 1. 1 CLINICAL PRACTICE Q&A A CME PROGRAM FOR MEN’S UROLOGICAL HEALTH LOW TESTOSTERONE HOME
  • 2. 2 STEERING COMMITTEE Ghalib Ahmed, MD, CCFP General Family Practitioner, Associate Clinical Professor, Department of Family Practice, University of Alberta Gerald Brock, MD, FRCSC Professor of Surgery, Urology Program Director, University of Western Ontario Chair, Office of Education, Canadian Urology Association Lydia Hatcher, MD, CCFP, FCFP Clinical Associate, Professor of Family Medicine, Memorial University of Newfoundland Murray Awde, MD, CCFP, FCFP Clinical Professor of Family Medicine, University of Western Ontario Serge Carrier, MD, FRCSC Associate Professor, Division of Urology, Department of Surgery, McGill University Jay Lee, MD, FRCSC Clinical Assistant Professor, Division of Urology, Department of Surgery, University of Calgary Anthony Bella, MD, FRCSC Greta and John Hansen Chair in Men's Health Research, Assistant Professor of Urology, Department of Surgery, Associate Scientist, Neuroscience, University of Ottawa Stacy Elliott, MD Director, BC Center for Sexual Medicine, Sexual Medicine Consultant, Men’s Health Initiative, Vancouver Coastal Health Clinical Professor, Departments of Psychiatry and Urologic Sciences, University of British Columbia HOME
  • 3. 3 3 STEERING COMMITTEE DISCLOSURES Ghalib Ahmed, MD, CCFP • Grants/Research Support: AstraZeneca, Bristol-Myers Squibb, Pfizer, Servier, Sunovion • Speaker’s Bureau/Honoraria: Abbott, AstraZeneca, Eli Lilly, Lundbeck, Merck, Pfizer, Shire • Consulting Fees: Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Lundbeck, Merck, Pfizer Murray Awde, MD, CCFP, FCFP • Grants/Research Support: Astellas, Bristol-Myers Squibb, Boehringer Ingelheim, Merck, Novartis, Otsuka, Purdue Pharmaceuticals • Speaker’s Bureau/Honoraria: Abbott, AstraZeneca, Bayer, LEO, Takeda, Nycomed • Consulting Fees: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer Anthony Bella, MD, FRCSC • Grants/Research Support: Acorda Therapeutics, Canadian Foundation for Innovation, Canadian Male Sexual Health Council, Northeastern Section American Urological Association • Speaker’s Bureau/Honoraria: Abbott, American Medical Systems, Bayer, Coloplast, Eli Lilly, Pfizer Gerald Brock, MD, FRCSC • Grants/Research Support: American Medical Systems, Eli Lilly, GlaxoSmithKline, Pfizer • Speaker’s Bureau/Honoraria: American Medical Systems, Bayer, Coloplast, Eli Lilly, GlaxoSmithKline, Pfizer • Consulting Fees: Bayer, Eli Lilly, GlaxoSmithKline, Pfizer Serge Carrier, MD, FRCSC • Grants/Research Support: Bayer, Eli Lilly, Pfizer • Speaker’s Bureau/Honoraria: Abbott, Bayer, Eli Lilly, Pfizer Stacy Elliott, MD • Speaker’s Bureau/Honoraria: Abbott, Bayer, Eli Lilly, Pfizer • Consulting Fees: Abbott, Bayer, Eli Lilly, Pfizer Lydia Hatcher, MD, CCFP, FCFP • Grants/Research Support: Servier • Speaker’s Bureau/Honoraria: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen-Ortho, Merck, Nycomed, Pfizer, Purdue Pharmaceuticals, Takeda, Valeant • Consulting Fees: AstraZeneca Jay Lee MD, FRCSC • Speaker’s Bureau/Honoraria: Abbott, Bayer, Eli Lilly, GlaxoSmithKline, Pfizer HOME
  • 4. 4 SPEAKER DISCLOSURES • Faculty: [Speaker’s name] • • • • Grants/Research Support: Speaker’s Bureau/Honoraria: Consulting Fees: Other: HOME
  • 5. 5 DISCLOSURE OF COMMERCIAL SUPPORT • This program has received financial support from Eli Lilly Canada Inc in the form of an educational grant • This program has received in-kind support from Eli Lilly Canada Inc in the form of logistical support. • Potential for conflict(s) of interest: • [Speaker/Faculty name] has received funding Eli Lilly Canada Inc. • Eli Lilly markets testosterone solution, a product that will be discussed in this program. HOME
  • 6. 6 MITIGATING POTENTIAL BIAS • All content in this presentation has been developed, reviewed and approved by the Steering Committee • All the recommendations involving clinical medicine are based on evidence from well-designed clinical trials published in peerreviewed journals • All testosterone formulations currently available in Canada will be discussed in this CME event HOME
  • 7. 7 LOW TESTOSTERONE 2 How do I decide which agent to prescribe for testosterone deficiency? 3 How should patients on testosterone therapy be monitored? 4 If untreated, what are the consequences of testosterone deficiency? 5 What are the risks associated with testosterone therapy? 6 Does testosterone therapy impact comorbid conditions? 1 How do I diagnose testosterone deficiency? HOME
  • 8. 8 LOW TESTOSTERONE 1 How do I diagnose testosterone deficiency? HOME
  • 9. 9 LEARNING OBJECTIVES • After addressing this question participants will be able to: • Identify the assessments required for the diagnosis of testosterone deficiency and integrate these into clinical practice • Evaluate the serum testosterone measurements and review the current testing recommendations • Be able to differentiate primary and secondary causes of low testosterone HOME
  • 10. 10 HOW DO I DIAGNOSE TESTOSTERONE DEFICIENCY? • Subjective testing • Objective testing 1. Morales et al. CUAJ. 2010;4:269-75. HOME
  • 11. 11 SUBJECTIVE TESTING • History and physical exam:1,2 • General health evaluation  NO acute or subacute illness • Assess signs and symptoms • Sensitive screening questionnaires correlate symptoms with biochemically low testosterone (i.e. ADAM Questionnaire)3 Click here for more info on the ADAM Questionnaire • Evaluate patients for comorbid conditions and risk factors associated with low testosterone ADAM: androgen deficiency in aging males. 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 3. Morley et al. Metabolism. 2000;49:1239-42. HOME
  • 12. 12 SYMPTOMS OF TESTOSTERONE DEFICIENCY What symptoms are characteristic of testosterone deficiency? Q Degree of Deficiency Mild Severe • • • • • • • • • • • • • • • Decreased libido Decreased vitality Fatigue Mood changes Insomnia Anemia Delayed ejaculation Flushes Erectile dysfunction Decreased muscle mass Increased visceral body fat Testicular atrophy Weakness Osteopenia/osteoporosis Loss of facial, axillary and pubic hair 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 13. 13 LOW TESTOSTERONE HIGH-RISK GROUPS • • • • • • • • • • • Type 2 diabetes Metabolic syndrome HIV-associated weight loss Treatment with opioids, glucocorticoids or ketoconazole Osteoporosis or low trauma fracture at a young age End-stage renal disease and maintenance hemodialysis Chronic obstructive pulmonary disease Infertility Sellar region mass, disease, radiation or trauma Use of street drugs Liver disease 1. Morales et al. CUAJ. 2010;4:269-75. HOME
  • 14. 14 OBJECTIVE TESTING • Serum testosterone measurement • Measure when signs and symptoms of testosterone deficiency are present: • Low libido • Sexual dysfunction • Low energy • Testosterone levels are thought to be influenced by circadian rhythm • Higher levels in the morning • Measure between 7 a.m. and 11 a.m.1,2 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 15. 15 SERUM TESTOSTERONE Total T SHBG Alb T T SHBG Alb T T Free (0.5-3%) T SHBG SHBG Alb T T T T SHBG SHBG Albumin Bound (~38%) SHBG Bound (~60%) Alb T T T Alb T Alb T Bioavailable Free Alb: albumin; SHBG: sex hormone binding globulin; T: testosterone. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 16. 16 WHICH TESTOSTERONE MEASURE? Which measure of serum testosterone should be used to diagnose testosterone deficiency? HOME
  • 17. 17 COMPARING TESTOSTERONE MEASURES Pros1,3 • Total • Testosterone • Free Testosterone Bioavailable Testosterone Cons1,2 Widely available Simple, rapid, inexpensive Minimal technical expertise • • • Relatively accurate Relatively sensitive and reproducible • • • Less frequently available Relatively expensive Technically cumbersome and difficult • • Technically simple Correlates well with symptoms • • • Less frequently available Relatively expensive Can be inaccurate due to incomplete precipitation Click on the website for a screen shot of the online tool. • Poor accuracy, sensitivity and between-laboratory comparability Interpretation greatly affected by alterations in SHBG Free and bioavailable testosterone calculator: http://www.issam.ch/freetesto.htm SHBG: sex hormone binding globulin. 1. Rosner et al. J Clin Endocrin. 2007;92:405-13; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Morales et al. CUAJ. 2010;4:269-75. Click for factors that influence SHBG HOME
  • 18. 18 TESTING RECOMMENDATIONS • Canadian consensus recommends bioavailable testosterone2,3 • Acceptable alternatives: • Calculated free testosterone • Calculated bioavailable testosterone • Total testosterone • The American Endocrine Society recommends total testosterone1 • Free or bioavailable testing should be considered in patients who are at the lower end of normal What test do you use to determine testosterone level? Q 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Morales et al. CUAJ. 2010;4:269-75; 3. Bebb. BCMJ. 2011;53:474-79. HOME
  • 19. 19 QUANTIFYING TESTOSTERONE DEFICIENCY Q What value defines testosterone deficiency? 10.4 nmol/L Average testosterone threshold. Patients below this have a greater likelihood of symptoms1 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 20. 20 LOW TESTOSTERONE If testosterone level is borderline or low, repeat testing is required for confirmation1,2 • Low testosterone requires investigation of:1 • • • • SHBG levels Serum luteinizing hormone Follicle-stimulating hormone Prolactin • Distinguish between primary and secondary causes SHBG: sex hormone binding globulin. 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 21. 21 PRIMARY VS. SECONDARY CAUSES Low serum testosterone Primary causes • Testicular origin Secondary causes • Pituitary/hypothalamic origin Results in: • Low testosterone levels • Impairment of spermatogenesis • Elevated gonadotropin levels Results in: • Low testosterone levels • Impairment of spermatogenesis • Low/low-normal gonadotropin levels Exclude: • Klinefelter syndrome Exclude: • Pituitary neoplasia • Hyperprolactinemia • Hemochromatosis • Obstructive sleep apnea • Genetic disorders associated with gonadotropin deficiency Click for comparative treatment algorithm 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 22. 22 LOW END OF NORMAL Q How would you manage a patient with testosterone levels at the low end of normal? Initiate testosterone therapy if the patient is symptomatic, evaluate response 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 23. 23 DIFFERENTIAL DIAGNOSIS What conditions present with features similar to testosterone deficiency? Q • If testosterone levels are in the normal range, consider other conditions causing fatigue: • • • • • • • • Depression Hypothyroidism Sexual dysfunction (low libido/ED) from other causes Osteoporosis Cardiovascular disease Metabolic syndrome Diabetes Anemia ED: erectile dysfunction. HOME
  • 24. 24 TAKE HOME MESSAGES • Diagnostic assessments of testosterone deficiency include: • Subjective testing: medical history, physical examination and assessment of characteristic symptoms of low testosterone • Objective testing: measure of serum testosterone levels • The American Endocrine Society recommends total testosterone • Canadian consensus recommends measuring bioavailable testosterone • Confirm any low or borderline testosterone results • Primary and secondary causes can be distinguished through measurements of SHBG, LH, FSH and prolactin FSH: follicle-stimulating hormone; LH: luteinizing hormone; SHBG: sex hormone binding globulin. 1. Morales et al. CUAJ. 2010;4:269-75. HOME
  • 25. 25 LOW TESTOSTERONE 2 How do I decide which agent to prescribe for testosterone deficiency? HOME
  • 26. 26 LEARNING OBJECTIVES • After addressing this question participants will be able to: • Assess the available formulations for the treatment of testosterone deficiency • Identify the role of a newly approved testosterone formulation • Evaluate factors that influence prescription decisions for treating testosterone deficiency HOME
  • 27. HOW DO I DECIDE WHICH AGENT TO PRESCRIBE FOR TESTOSTERONE DEFICIENCY? • • • • Safety/tolerability Efficacy Patient preference Cost/insurance coverage 1. Morales et al. CUAJ. 2010;4:269-75. HOME 27
  • 28. 28 TESTOSTERONE FORMULATIONS IN CANADA Testosterone Formulation Brand Name Oral • Testosterone undecanoate • • Andriol pms-Testosterone Intramuscular injections • Testosterone cypionate • Testosterone enanthate • • Depo-testosterone Delatestryl Testosterone patch • Androderm Testosterone topical solution • Axiron Testosterone gel • Tube • Sachet/pump • • Testim AndroGel Click for info on the testosterone pipeline HOME
  • 29. 29 CONTRAINDICATIONS TO TESTOSTERONE Absolute Contraindications • Prostate or breast cancer • Hematocrit >54% Relative Contraindications • Severe lower urinary tract symptoms (AUA/IPSS score >19) • Prostate nodule • Baseline PSA greater than 4 ng/mL, or PSA >3 ng/mL in men at high risk of prostate cancer • Uncontrolled congestive heart failure • Myocardial infarction, acute coronary event, unstable angina, or coronary revascularization procedure in the preceding 6 months • Untreated severe obstructive sleep apnea AUA: American Urological Association; IPSS: international prostate symptom score; PSA: prostate specific antigen. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Morales et al. CUAJ. 2010;4:269-75. HOME
  • 30. 30 ORAL TESTOSTERONE Product Testosterone undecanoate1,2 (Andriol, pms-Testosterone) *This Dosage 120-160 mg daily divided in 2 doses* dose should be taken for 2-3 weeks. Subsequent dosages may be reduced to 40-120 mg daily. • Pros3,4 • Convenient administration • Cons3,4 • Taken with a high fat meal • Absorption issues may lead to poor response 1. Andriol Product Monograph. Merck Canada Inc; 2. pms-Testosterone Product Monograph. Pharmascience Inc; 3. Morales et al. CUAJ. 2010;4:269-75; 4. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 31. 31 ORAL TESTOSTERONE: SAFETY/EFFICACY CONSIDERATIONS • Safety Considerations1 • No safety considerations specific to oral formulations • Efficacy Considerations1,2 • Limited efficacy due to unreliable oral bioavailability, fluctuating serum levels and short half-life • Requires multiple daily dosing 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Nieschlag et al. Hum Reprod Update. 2004;10:409-19. HOME
  • 32. 32 ORAL TESTOSTERONE: SERUM TESTOSTERONE PROFILE Mean T Concentration (ng/mL) 10 8 ― 80 mg Fed ― 80 mg Fasted 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) • T undecanoate should be taken with a normal meal or breakfast to achieve proper T levels T: testosterone. 1. Andriol Product Monograph. Merck Canada Inc. HOME
  • 33. 33 INTRAMUSCULAR INJECTIONS Product Dosage Testosterone cypionate1 (Depo-Testosterone) 200 mg every 2 weeks (max. dose 400 mg per month) Testosterone enanthate2 (Delatestryl) 100-400 mg every 1-4 weeks • Pros3,4 • • • • Relatively inexpensive Effective Long-acting Flexibility of dosing • Cons3,4 • Waning effect between injections • Requires intramuscular injection • Greatest risk of erythrocytosis 1. Depo-Testosterone Product Monograph. Pfizer Canada Inc; 2. Delatestryl Product Monograph. Valeant Canada LP; 3. Morales et al. CUAJ. 2010;4:269-75; 4. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 34. 34 INTRAMUSCULAR INJECTIONS: SAFETY/EFFICACY CONSIDERATIONS • Safety Considerations1 • • • • Pain at injection site Fluctuations in mood, energy and sexual desire Coughing episodes immediately after intramuscular injection Supraphysiologic levels can reduce HDL • Efficacy Considerations1,2 • Serum testosterone levels rise into the supraphysiologic range within 24-48 hours • Gradually decline into the hypogonadal range over the next 2 weeks HDL: high-density lipoprotein. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Nieschlag et al. Hum Reprod Update. 2004;10:409-19. HOME
  • 35. 35 INTRAMUSCULAR INJECTIONS: SERUM TESTOSTERONE PROFILE Testosterone cypionate Testosterone enanthate 1400 1200 1200 1000 ― 200 mg 800 600 400 Testosterone (ng/dL) Testosterone (ng/dL) 1400 1000 ― 200 mg 800 600 400 200 200 0 0 0 1 2–3 4–5 6–7 8–10 11–12 13–14 Time (days) 0 2 4 6 8 10 12 14 16 18 Time (days) 1. Behre et al. Testosterone: Action-Deficiency-Substitution. Cambridge; UK; 2004. HOME 20
  • 36. 36 TRANSDERMAL PATCH Product Transdermal Patch1 (Androderm) Dosage 2.5 or 5 mg patch applied daily • Pros2,3 • Ease of application • Cons2,3 • Visibility of product • Significant skin reactions • Serum testosterone may be low-normal 1. Androderm Product Monograph. Watson Laboratories, Inc; 2. Morales et al. CUAJ. 2010;4:269-75; 3. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 37. 37 TESTOSTERONE PATCH: SAFETY/EFFICACY CONSIDERATIONS • Safety Considerations1 • Frequent skin reactions at the application site • Efficacy Considerations1,2 • Serum testosterone in the mid-normal range 4-12 hours after application • Some patients require two 5 mg patches to achieve target levels 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Nieschlag et al. Hum Reprod Update. 2004;10:409-19. HOME
  • 38. 38 TESTOSTERONE PATCH: SERUM TESTOSTERONE PROFILE Testosterone (ng/dL) 2000 1600 1200 800 400 0 0 6 12 18 24 Time (hours) 1. Dobs et al. J Clin Endocrinol Metab. 1999;84:3469-78. HOME
  • 39. 39 DIRECT COMPARISON OF TRANSDERMAL PATCH TO GELS Patients with Skin Irritation1 Type of Irritation1 Gel: 50 mg/day testosterone (5 g, 1% testosterone USP)2 5.7% Erythema Gel: 100 mg/day testosterone (10 g, 1% testosterone USP)2 5.3% Erythema 65.8%* Mild erythema to intense erythema with blisters Product Patch: Testosterone transdermal delivery system (testosterone)3 *Sixteen patients discontinued product due to skin irritation. 1. Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-53; 2. AndroGel Product Monograph. Abbott Laboratories Ltd; 3. Androderm Product Monograph. Watson Labs Inc. HOME
  • 40. 40 TRANSDERMAL GELS Product Concentration AndroGel sachet1 1% testosterone Dose Application Site 1-2 sachets daily (50-100 mg daily) Shoulders +/abdomen AndroGel pump1 1% testosterone 2-8 actuations daily (12.5 mg/actuation) Shoulders +/abdomen Testim2 1-2 tubes daily (50-100 mg daily) Shoulders +/abdomen 1% testosterone • Pros3,4 • Minimal side effects • Ease of application • Flexibility of dosing • Cons3,4 • Risk of secondary exposure from gel transference 1. AndroGel Product Monograph. Abbott Laboratories Ltd; 2. Testim Product Monograph. Auxilium Pharmaceuticals, Inc; 3. Morales et al. CUAJ. 2010;4:269-75; 4. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 41. 41 TESTOSTERONE GEL: SAFETY/EFFICACY CONSIDERATIONS • Safety Considerations1 • Potential risk of gel transfer to another person who might come in close contact • Skin irritation at application site • Efficacy Considerations1,2 • Raise serum total and free testosterone concentrations into the mid-normal range in hypogonadal men over 24 hours • ̴25% of patients will require >5 g of testosterone gel to achieve target levels 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Nieschlag et al. Hum Reprod Update. 2004;10:409-19. HOME
  • 42. 42 TESTOSTERONE GELS: SERUM TESTOSTERONE PROFILE Long-term Short-term Serum T (nmol/L) 40 40 30 30 20 20 10 10 0 0 0 8 16 24 0 Time (hours) 30 60 90 90 120 150 180 Days Since Treatment Initiation ― 50 mg testosterone (5 g, 1% AndroGel) ― 100 mg testosterone (10 g, 1% AndroGel) T: testosterone. 1. Swerdloff et al. J Clin Endocrinol Metab. 2000;85:4500-10. HOME
  • 43. 43 TRANSDERMAL TOPICAL SOLUTION Product Axiron Concentration 2% testosterone Dose 2-4 actuations daily (60-120 mg daily) Application Site Axilla • NOC in Canada March 30, 2012 • Pros • Ease of application (applied to axilla with applicator) • Minimal side effects • Flexible dosing • Cons • Risk of secondary exposure from transference 1. Axiron Product Monograph. Eli Lilly Canada Inc. HOME
  • 44. 44 TRANSDERMAL TOPICAL SOLUTION: METERED DOSING SYSTEM • Testosterone topical solution is available as a metered-dose pump containing 110 mL of solution • The pump is capable of dispensing 90 mL of solution in 60 metered pump actuations • One pump actuation delivers 30 mg of testosterone in 1.5 mL of solution 1. Axiron Product Monograph. Eli Lilly Canada Inc. HOME
  • 45. 45 TRANSDERMAL TOPICAL SOLUTION: DOSING AND ADMINISTRATION Daily Prescribed Dose Each Application Requires 1 Depression of the Pump 30 mg Apply 1 application: • ONE axilla (left OR right) 60 mg Apply 2 applications: • ONE to both the left AND right axilla 90 mg Apply 3 applications: • ONE to both the left AND right axilla • Wait for the product to dry • Again apply to ONE axilla (left OR right) 120 mg Apply 4 applications: • ONE to both the left AND right axilla • Wait for the product to dry • Again apply to both the left AND right axilla • Patient should apply deodorant before testosterone topical solution 1. Axiron Product Monograph. Eli Lilly Canada Inc. HOME
  • 46. 46 TESTOSTERONE TOPICAL SOLUTION: SAFETY/EFFICACY CONSIDERATIONS • Safety Considerations1 • Potential risk of skin-to-skin transfer of testosterone solution • Skin irritation at application site • Efficacy Considerations1,2 • Provides continuous dosing (over 24-hour period) to deliver physiological levels in the normal concentration range • Steady-state serum concentrations are attained within approximately 1 week of daily dosing • Patients should avoid swimming/showering for at least 2 hours 1. Axiron Product Monograph. Eli Lilly Canada Inc. HOME
  • 47. TRANSDERMAL TESTOSTERONE SOLUTION: SERUM TESTOSTERONE PROFILE Mean (± SD) steady-state serum testosterone concentrations on Day 120 (30, 60, 90 or 120 mg testosterone) in completers Serum Total Testosterone Concentration (ng/dL) 1400 1200 Upper limit of normal 1000 800 600 400 Lower limit of normal 200 0 0 4 8 12 16 20 24 Time from Dose (hours) 1. Axiron Product Monograph. Eli Lilly Canada Inc. HOME 47
  • 48. 48 PRESCRIBING DECISIONS: PATIENT FACTORS • Patient Preference: • Mode of delivery • Frequency of administration • Daily (patch, topical solution, gel, or oral) • Bi-monthly (injectable testosterone cypionate and testosterone enanthate) • Cost/Insurance Coverage HOME
  • 49. 49 TAKE HOME MESSAGES • Several testosterone formulations are available in Canada: • • • • • Oral (testosterone undecanoate) Testosterone patch Testosterone topical solution (underarm applicator) Testosterone gel (tube, sachet/pump) Intramuscular injections (testosterone cypionate and testosterone enanthate) • Selection should be based upon safety, tolerability, efficacy and patient preference 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 50. 50 LOW TESTOSTERONE 3 How should patients on testosterone therapy be monitored? HOME
  • 51. 51 LEARNING OBJECTIVES • After addressing this question participants will be able to: • Identify and implement appropriate follow-up for a patient on testosterone therapy • Assess the time-to-symptom improvement after initial treatment for major symptoms • Recognize when referral to a specialist is required HOME
  • 52. HOW SHOULD PATIENTS ON TESTOSTERONE THERAPY BE MONITORED? • If stable... • 3-6 months in the first year • Every year thereafter • Follow-up should include: • • • • Symptom response Change in blood parameters Monitoring adverse events PSA/DRE testing DRE: digital rectal exam; PSA: prostate specific antigen. 1.Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME 52
  • 53. 53 SYMPTOM IMPROVEMENT Duration of Treatment (months) 0 3 6 12 Enhanced libido Symptom Improvement Improved emotional well-being Increased energy Reduced ED Increased strength Enhanced BMD Improved cognition Enhanced cardiovascular strength Decreased body fat Improvement in some components of MetS BMD: bone mineral density; MetS: metabolic syndrome. 1. Morales et al. CUAJ. 2010;4:269-75. HOME
  • 54. 54 CHANGES IN BLOOD PARAMETERS • Assess hematocrit levels1 • • • • Testosterone therapy increases red cell mass in a dose-dependent manner2 If hematocrit >54%, stop therapy until hematocrit decreases to safe levels Evaluate patient for hypoxia and sleep apnea Restart therapy — consider different testosterone formulation • Assess serum testosterone levels1 • Testosterone therapy aims to raise levels to the mid-normal range Q What would you do if hemoglobin levels are high? 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Coviello et al. J Clin Endocrinol Metab. 2008;93:914-19. HOME
  • 55. 55 ADVERSE EVENTS • Potential adverse events:1 • • • • • • • • • • Acne, oiliness of skin Breast tenderness Erythrocytosis Growth of metastatic prostate cancer Detection of subclinical prostate cancer Reduced sperm production and infertility Leg edema and worsening of obstructive sleep apnea* Gynecomastia* Growth of breast cancer* Male pattern balding* *Weak evidence of association. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70. HOME
  • 56. 56 FORMULATION-SPECIFIC FOLLOW-UP When To Measure Serum Testosterone: Evaluate Patient For: Oral (Andriol, Pms-Testosterone)1,2 3-5 hours after ingestion • Compliance • Taken with fat, split doses Testosterone patch (Androderm) 1,2 2-12 hours after application • Skin reactions Testosterone topical solution (Axiron)3 Any time >1 week after initiation of topical solution • Adherence to protocols which minimize transfer and maximize absorbance Testosterone gel (Testim, AndroGel) 1,2 Any time >1 week after initiation of gel use — ideally 3-4 hours after application • Adherence to protocols which minimize transfer and maximize absorbance Intramuscular injections (Delatestryl, Depo-testosterone,)1,2 Midway between injections, or at trough • • Fluctuations in mood/libido Cough after injections Testosterone Therapy Adjust dose (and/or frequency) to obtain testosterone levels in the mid-normal range 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Bebb. BCMJ. 2011;53:474-79; 3. Axiron Product Monograph. Eli Lilly Canada. HOME
  • 57. 57 PSA/DRE TESTING • Prostate health should be assessed by PSA/DRE • Recommended for men >40 years with baseline PSA >0.6 ng/mL who are initiating testosterone • PSA measurements should be obtained: • Before treatment • 3-6 months after treatment initiation • In accordance with guidelines for prostate cancer screening DRE: digital rectal exam; PSA: prostate specific antigen. 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 58. 58 WHEN TO REFER Q When should a patient be referred to a urologist? • Prostatic abnormality • If PSA becomes persistently abnormal PSA: prostate specific antigen. 1. Expert opinion of planning committee. December 1, 2012. HOME
  • 59. 59 NON-RESPONSE TO TREATMENT Q • • • • • Why might a patient not respond to testosterone therapy? Non-compliance Malabsorption (orally or through skin) Insufficient dose Unsatisfactory formulation Symptoms unrelated to testosterone deficiency  other diagnosis? 1. Morales et al. CUAJ. 2010;4:269-75. HOME
  • 60. 60 TAKE HOME MESSAGES • Follow-up should occur every 3-6 months: • • • • • • Monitor response to treatment Detect potential complications Assess need for dose adjustments Assess change in blood parameters Monitor for adverse events PSA/DRE testing • If patients do not respond to therapy, consider issues related to compliance, dosing and administration before considering another diagnosis DRE: digital rectal exam; PSA: prostate specific antigen. HOME
  • 61. 61 LOW TESTOSTERONE 4 If left untreated, what are the consequences of testosterone deficiency? HOME
  • 62. 62 LEARNING OBJECTIVES • After addressing this question participants will be able to: • Recognize the consequences resulting from untreated testosterone deficiency HOME
  • 63. IF LEFT UNTREATED, WHAT ARE THE CONSEQUENCES OF TESTOSTERONE DEFICIENCY? Low testosterone levels have been associated with: • Sexual side effects • Metabolic syndrome Click for data on the impact of low T in • Psychological effects these areas • Osteoporosis • Decreased muscle mass • Lower quality of life • Increased mortality rate • Increased cardiovascular risk T: testosterone. 1. Maggi et al. J Sex Med. 2007;4:1056-69; 2. Shelton et al. Urol Clin North Am. 2012;39:63-75. HOME 63
  • 64. 64 QUALITY OF LIFE Testosterone deficiency negatively impacts quality of life Physical functioning Emotional functioning Mental functioning Socio-emotional functioning Energy Sexual functioning Social functioning Adapted from Novak et al. 1. Novak et al. Maturitas. 2002;43:231-7. HOME
  • 65. 65 LOW T AND MORTALITY Cumulative Survival 1 Men with a normal testosterone level (n=452) Men with an equivocal testosterone level (n=240) Men with a low testosterone level (n=166) 0.9 0.8 0.7 Low endogenous testosterone levels are associated with an increased risk in mortality 0.6 0.5 0.0 2.0 4.0 6.0 8.0 10.0 Survival (years) T: testosterone. 1. Shores et al. Arch Intern Med. 2006;166:1660-5. HOME
  • 66. 66 LOW T AND CARDIOVASCULAR RISK Key Finding Keating et al. 20061 (Observational study) • 16% increase in the risk of coronary heart disease events (death or myocardial infarction) in patients on androgen deprivation therapy Tsai et al. 20072 (Observational study) • 2-fold increased risk of fatal cardiovascular events over 10-year period in men on androgen deprivation therapy Ruige et al. 20113 (Meta-analysis) • In elderly men, low testosterone predicted increased risk for cardiovascular disease and/or mortality* *It is unclear whether low testosterone has a direct negative effect, or whether it should be regarded as a ‘marker of poor health’. T: testosterone. 1. Keating et al. J Clin Oncol. 2006;24:4448-56; 2. Tsai et al. J Natl Cancer Inst. 2007;99:1516-24; 3. Ruige et al. Heart. 2011;97:870-5. HOME
  • 67. 67 TAKE HOME MESSAGES • Low testosterone levels are associated with: • • • • • • • • Impaired sexual function Increased risk of metabolic syndrome Depressed mood Decreased bone mineral density and increased risk of fractures Reduced muscle mass Decreased quality of life Increased risk of all-cause and CVD mortality Increased CV risk CVD: cardiovascular disease; CV: cardiovascular. HOME
  • 68. 68 LOW TESTOSTERONE 5 What are the risks associated with testosterone therapy? HOME
  • 69. 69 LEARNING OBJECTIVES • After addressing this question participants will be able to: • Identify the risks associated with testosterone therapy • Evaluate the evidence surrounding testosterone therapy and prostate cancer, and assess the clinical impact for prostate cancer survivors HOME
  • 70. WHAT ARE THE RISKS ASSOCIATED WITH TESTOSTERONE THERAPY? • • • • • • • • Stimulate growth of known prostate cancer Worsen symptoms of significant BPH Gynecomastia* Erythrocytosis* Testicular atrophy and infertility Skin diseases Sleep apnea Lowering of HDL* *Result of supraphysiological levels of testosterone. BPH: benign prostatic hyperplasia; HDL: high density lipoprotein. 1. Bassil et al. Ther Clin Risk Manag. 2009;5:427-48; 2. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70. HOME 70
  • 71. TESTOSTERONE THERAPY AND PROSTATE CANCER 71 • Testosterone therapy is contraindicated in men with prostate cancer 1,2 • Fear of accelerating tumour growth • Huggins and Hodges (1941): castration caused a decline in serum marker acid phosphatase3 • Testosterone caused an enhanced rate of growth of prostate cancer • Fowler et al. (1981): testosterone administration resulted in an unfavourable response in 45 of 52 men with metastatic prostate cancer4 1. Morales et al. CUAJ. 2010;4:269-75; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Huggins et al. Cancer Res. 1941;1:293-7; 4. Fowler et al. J Urol. 1981;126:372-5. HOME
  • 72. EMERGING VIEW OF TESTOSTERONE LEVELS AND PROSTATE CANCER • Prostate cancer is largely unaffected by variations in serum testosterone levels within the naturally occurring ranges1 • TESTOSTERONE DEFICIENCY may be associated with:1,2 • • • • Greater risk of prostate cancer High Gleason scores Worse stage at presentation Worse survival • No recurrence of prostate cancer upon testosterone therapy3,4 Click for data 1. Morgentaler. Urol Clin N Am. 2011;38:119-24; 2. Morgentaler.Eur Urol. 2006;50:935-9; 3. Kaufman et al. J Urol. 2004;172:920-2; 4. Khera et al. J Sex Med. 2009;6:1165-70. HOME 72
  • 73. 73 REVISITING THE ORIGINAL EVIDENCE • Increase in serum testosterone after androgen deprivation results in an increase in PSA, even in men without cancer1 • Huggins and Hodges: only 1 patient without prior androgen deprivation1,2 • Fowler et al: 4/52 men did not have prior androgen deprivation3 • 1 patient had an unfavourable result • 3 patients continued to receive testosterone with no apparent negative effect Suggests that the effect of testosterone on prostate cancer may be more benign than originally thought PSA: prostate specific antigen. 1. Morgentaler et al. Urol Clin N Am. 2011;38:119-24; 2. Huggins et al. Cancer Res. 1941;1:293-7; 3. Fowler et al. J Urol. 1981;126:372-5. HOME
  • 74. 74 TESTOSTERONE THERAPY IN PROSTATE CANCER SURVIVORS Q How should a patient who has been successfully treated for prostate cancer be managed for testosterone deficiency? • Testosterone therapy may be considered on an individualized basis, in patients who have undergone radial prostatectomy and:1,2 • Have been disease free for >2 years* • Have undetectable PSA levels • No general recommendation due to lack of randomized-controlled trials1 *Individualized approach for patients disease free for <2 years, with severe symptoms (i.e. suicidal). PSA: prostate specific antigen. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Bebb et al. BCMJ. 2011; 53:474-79. HOME
  • 75. 75 TESTOSTERONE THERAPY IN PATIENTS WITH BPH-LUTS • Testosterone is contraindicated in men with severe BPH-LUTS (IPSS >19)1 • Original consensus: testosterone therapy may worsen symptoms of BPH1,2 • Current view: testosterone therapy improves LUTS in men with low testosterone and mild BPH3 • No compelling data to suggest that testosterone therapy contributes to worsening of LUTS or promotion of urinary retention3 Click for data BPH: benign prostatic hyperplasia; IPSS: International Prostate Symptom Score; LUTS: lower urinary tract symptoms. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 2. Bassil et al. Ther Clin Risk Manag. 2009;5:427-48; 3. Shigehara et al. Aging Male. 2011 Mar;14:53-8. HOME
  • 76. 76 TAKE HOME MESSAGES • Risks are associated with testosterone therapy and should be discussed and monitored in patients • Prostate cancer is largely unaffected by variations in serum testosterone levels within the naturally occurring ranges • Testosterone therapy may be considered on an individualized basis, in patients who have undergone radial prostatectomy and • Have been prostate cancer free for >2 years • Have undetectable PSA levels PSA: prostate specific antigen. HOME
  • 77. 77 LOW TESTOSTERONE 6 Does testosterone therapy impact comorbid conditions? HOME
  • 78. 78 LEARNING OBJECTIVES • After addressing this question participants will be able to: • Recognize the benefits of testosterone therapy on sexual function, including the role of testosterone therapy in PDE5 inhibitor non-responders • Assess the impact of testosterone therapy on cardiovascular events • Evaluate the benefits of testosterone therapy in patients with HIV and the implications on clinical practice • Assess the role of testosterone therapy in improving quality of life and pain in chronic opioid users PDE5: phosphodiesterase type 5. HOME
  • 79. 79 DOES TESTOSTERONE THERAPY IMPACT COMORBID CONDITIONS? Testosterone therapy can impact: • Sexual function • Cardiovascular disease • HIV • Chronic narcotic use HOME
  • 80. 80 IMPACT ON SEXUAL FUNCTION Testosterone therapy can result in moderate improvements to all aspects of sexual function1 1. Isidori et al. Clin Endocrinol (Oxf). 2005;63:381-94. HOME
  • 81. 81 TESTOSTERONE AND SEXUAL DYSFUNCTION • Testosterone therapy has been evaluated in context of: • • • • Erectile function Libido Ejaculatory function Overall sexual satisfaction • Testosterone therapy results in moderate improvements to all aspects of sexual function Click for data 1. Isidori et al. Clin Endocrinol (Oxf). 2005;63:381-94. HOME
  • 82. 82 IMPLICATIONS FOR CLINICAL PRACTICE • Testosterone therapy benefits men with underlying sexual dysfunction • Clinicians should consider testosterone therapy for:1 • Men with low testosterone and libido • Men with ED and low testosterone, after evaluating cause of ED and considering established therapies 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 83. 83 ROLE OF TESTOSTERONE IN ERECTILE FUNCTION T NOS NO cGMP GMP Smooth muscle contraction Smooth muscle relaxation cGMP • Testosterone modulates NOS and PDE5 expression • Low serum testosterone levels are a predictor of poor response to PDE5i1 • Combined use of testosterone and PDE5i salvaged 37.5-92% of PDE5i failures2 Click for data cGMP: cyclic guanosine monophosphate; GMP: guanosine monophosphate; NO: nitric oxide; NOS: nitric oxide synthase; PDE5: phosphodiesterase type 5; PDE5i: phosphodiesterase 5 inhibitor; T: testosterone. 1.Park et al. BJU Int. 2005;95:366-70; 2. Buvat et al. Current Sexual Health Reports. 2008;5:135-40. HOME
  • 84. 84 TESTOSTERONE AND PDE5i: IMPLICATIONS FOR CLINICAL PRACTICE Q How do these findings relate to clinical practice? • Measure testosterone levels in PDE5i non-responders1 • Consider combination therapy when:1,2 • Testosterone deficiency is diagnosed following a consultation for ED • Poor response to PDE5i therapy alone due to unsatisfying erections in patients with low or low-normal testosterone • Poor response to PDE5i therapy alone due to sexual desire in patients with low or low-normal testosterone • No improvement on testosterone therapy alone in testosterone deficient men1 PDE5i: phosphodiesterase 5 inhibitor. 1. Buvat et al. J Sex Med. 2010;7:1627-56; 2. Buvat et al. Current Sexual Health Reports. 2008;5:135-40. HOME
  • 85. 85 IMPACT ON CARDIOVASCULAR DISEASE Testosterone therapy does not increase cardiovascular risk and has been reported to have beneficial effects on patients with angina and heart failure1-3 1. Toma et al. Circ Heart Fail. 2012;5:315-21; 2. Malkin et al. Heart. 2004;90:871-6; 3. Carson et al. J Sex Med. 2012;9:54-67. HOME
  • 86. CARDIOVASCULAR EVENTS NOT AFFECTED BY TESTOSTERONE TREATMENT Event Rate per 1,000 Patient Years 70 * 60 50 Placebo Testosterone 40 30 20 10 0 *Odds ratio significantly different from placebo. CABG: coronary artery bypass graft. 1. Calof et al. J Gerontol A Biol Sci Med Sci. 2005;60:1451-7; 2. Carson et al. J Sex Med. 2012;9:54-67. HOME 86
  • 87. 87 TOM TRIAL • Investigated testosterone administration on lower extremity strength and physical function • 209 men enrolled in the study: • Were ≥65 years of age • Had total serum testosterone levels between 3.5 to 12.1 nmol/L • Had limitations in mobility 1. Basaria et al. NEJM. 2010;363:109-22. HOME
  • 88. TOM TRIAL: TESTOSTERONE INCREASED CV RISK 88 Trial halted due to an increased risk of CV adverse events in the testosterone arm1 Risk of adverse events with testosterone therapy Total Risk Odds Ratio (95% CI) Event Category Unadjusted Adjusted MedDRA cardiac 10.6 (1.3-84.5) NA Atherosclerosis-related 7.2 (0.9-59.7) NA Cardiovascular-related 5.4 (2.0-14.9) 5.8 (2.0-16.8) Dermatologic 2.6 (1.1-6.2) 4.9 (1.7-14.6) Necessitating referral for medical evaluation 2.3 (0.98-5.3) 5.2 (1.8-14.6) MedDRA: Medical Dictionary for Regulatory Activities. 1. Basaria et al. NEJM. 2010;363:109-22. HOME
  • 89. 89 TOM TRIAL: LIMITATIONS • Study limitations:1,2,3 • • • • Small sample size Older, sicker (unique) population Study not designed to assess CVD More patients in the testosterone arm had hypertension or dyslipidemia, increasing their risk of CVD CVD: cardiovascular disease. 1. Basaria et al. NEJM. 2010;363:109-22; 2. Traish et al. Am J Med. 2011;124:578-87; 3. Bebb. BCMJ. 2011; 53:474-79. HOME
  • 90. 90 BENEFITS OF TESTOSTERONE THERAPY IN PATIENTS WITH CVD • Testosterone therapy improves exercise capacity in patients with heart failure1 • Improvements are greater than that observed with other therapies currently used for morbidity and mortality reduction in patients with heart failure • Testosterone therapy in hypogonadal men with angina significantly improved time to ischemic threshold vs. placebo2 CVD: cardiovascular disease. 1. Toma et al. Circ Heart Fail. 2012;5:315-21; 2. Malkin et al. Heart. 2004;90:871-6. HOME
  • 91. 91 TESTOSTERONE THERAPY AND HIV • 20-25% of HIV-infected men on highly active antiretroviral therapy have low testosterone levels1 • In men with low testosterone and HIV, testosterone therapy has been shown to:2 • Restore libido and energy • Alleviate depressed mood • Increase muscle mass 1. Rietschel et al. Clin Infect Dis. 2000;31:1240-4; 2. Rabkin et al. Arch Gen Psychiatry. 2000;57:141-7. HOME
  • 92. 92 IMPACT OF TESTOSTERONE THERAPY ON PATIENTS WITH HIV Mood Energy Placebo ED Testosterone Libido 0 20 40 60 80 Patients Reporting Improvements (%) • Average increase in muscle mass over 12 weeks was 1.6 kg • A 2.2 kg increase was reported for the subset with wasting at baseline 1.Rabkin et al. Arch Gen Psychiatry. 2000;57:141-7. HOME
  • 93. 93 IMPLICATIONS FOR CLINICAL PRACTICE • Short-term testosterone therapy should be considered as an adjunct to antiretroviral therapy in HIV-infected men with low testosterone levels and weight loss, to promote: • Weight maintenance • Gains in lean body mass and muscle strength • Measure bioavailable testosterone in men with HIV infection • These men have elevated SHBG Click for factors that influence SHBG SHBG: sex hormone binding globulin. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 94. 94 IMPACT ON CHRONIC OPIOID USE Testosterone therapy improves quality of life and pain indices in patients on chronic opioids 1. Daniell et al. J Pain. 2006;7:200-10; 2. Aloisi et al. Reprod Biol Endocrinol. 2011;9:26. HOME
  • 95. 95 IMPACT OF CHRONIC OPIOID USE ON TESTOSTERONE LEVELS • Chronic opioid use leads to a down-regulation of testosterone production through:1,2 • Secondary hypogonadism • Decreased hypothalamic GnRH • Decreased pituitary LH, possibly FSH • Decreased adrenal DHEAS and testosterone • Decreased testicular testosterone • Possible cortisol deficiency • Possible growth hormone deficiency • Bioavailable testosterone should be measured in chronic opioid users DHEAS: dehydroepiandrosterone sulfate; FSH: follicle stimulating hormone; GnRH: gonadatropin releasing hormone; LH: luteinizing hormone. 1. Katz et al. Clin J Pain. 2009;25:170-5; 2. Roberts et al. Clin J Pain. 2002;18:144-8. HOME
  • 96. 96 TESTOSTERONE THERAPY IMPROVES SYMPTOMS IN PATIENTS ON OPIOIDS • Testosterone therapy has been shown to improve patient quality of life, with improvements in:1 • • • • Sexual function Mood Depression Hematocrit levels • Testosterone therapy improves pain dimensions2 Click for data on the impact of testosterone therapy in opioid users 1. Daniell et al. J Pain. 2006;7:200-10; 2. Aloisi et al. Reprod Biol Endocrinol. 2011;9:26. HOME
  • 97. 97 TAKE HOME MESSAGES • Testosterone therapy has been shown to: • • • • • Improve sexual function Improve PDE5 inhibitor efficacy* Have no significant impact on CV event rates Improve libido, energy, mood and muscle mass in men with HIV Improve quality of life and pain indexes in chronic opioid users *In patients with low-normal serum testosterone levels who have previously failed on PDE5 inhibitor therapy alone. CV: cardiovascular; PDE5: phosphodiesterase type 5. HOME
  • 98. 98 LOW TESTOSTERONE 7 Supplementary Slides HOME
  • 99. 99 ADAM QUESTIONNAIRE ADAM Questionnaire1 1. Do you have a decrease in libido (sex drive)? 2. Do you have a lack of energy? 3. Do you have a decrease in strength and/or endurance? 4. Have you lost height? 5. Have you noticed a decreased ‘‘enjoyment of life’’? 6. Are you sad and/or grumpy? 7. Are your erections less strong? A positive questionnaire result is defined as a ‘‘yes’’ answer to Questions 1 or 7 or any 3 other questions 8. Have you noted a recent deterioration in your ability to play sports? 9. Are you falling asleep after dinner? 10. Has there been a recent deterioration in your work performance? • Correlates symptoms with serum testosterone levels with 88% sensitivity and 60% specificity Return to Slide 9 ADAM: androgen deficiency in aging males. 1. Morley et al. Metabolism. 2000;49:1239-42. HOME
  • 100. FREE AND BIOAVAILABLE TESTOSTERONE CALCULATOR 100 Return to Slide 15 HOME
  • 101. 101 THE INFLUENCE OF SHBG • SHBG-bound testosterone represents the majority of testosterone  it is not biologically active Factors that Influence [SHBG]1 Decrease in [SHBG] Increase in [SHBG] Obesity Aging Diabetes Hepatic cirrhosis Hypothyroidism Hyperthyroidism Nephrotic syndrome HIV infection Use of glucocorticoids, progestins and androgenic steroids Estrogens • Influences interpretation of total testosterone measurement • Use free or bioavailable measurements when altered SHBG is suspected2,3 [SHBG]: concentration of sex hormone binding globulin. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Morales et al. CUAJ. 2010;4:269-75. Return to Slide 15 HOME
  • 102. 102 TREATING PRIMARY/SECONDARY HYPOGONADISM Secondary Hypogonadism Primary Hypogonadism (pituitary/hypothalamic) Low T + Normal LH/FSH (testicular) Low T + High LH/FSH Normal Prolactin Normal PSA/DRE Abnormal PSA/DRE Define Etiology Consider TRT Treat or Refer Monitor Response Continue TRT High Prolactin Investigate or Refer Normal Abnormal PSA/DRE PSA/DRE Order MRI or Refer Investigate or Refer No Response Consider: •Compliance •Dose adjustments •Change in delivery system •Other causes •Referral Return to Slide 19 DRE: digital rectal exam; FSH: follicle-stimulating hormone; LH: luteinizing hormone; MRI: magnetic resonance imaging; PSA: prostate specific antigen; T: testosterone; TRT: testosterone replacement therapy. 1. Morales et al. CUAJ. 2010;4:269-75. HOME
  • 103. 103 FORMULATIONS UNDER INVESTIGATION • Novel testosterone formulations are being developed with better pharmacokinetic and more selective activity profiles: • Biodegradable testosterone microspheres • Long-acting testosterone esters • Buccal and auxiliary formulations • Nasal sprays Next 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70. HOME
  • 104. 104 OTHER TESTOSTERONE FORMULATIONS Testosterone pellets Buccal bio-adhesive testosterone tablets Injectable long-acting testosterone undecanoate in oil High concentration testosterone gels Testosterone in-adhesive matrix patch Next These products are currently not available in Canada. 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59. HOME
  • 105. 105 NOVEL COMPOUNDS FOR ANDROGEN THERAPY • 7-alpha-methyl-19-nortestosterone: • Greater agonist activity on muscle and gonadotrophin suppression • Less activity on the prostate • Selective androgen receptor modulators (SARMs): • May selectively exert androgen activity on muscle, bone and sexual function • Minimal action on prostate and cardiovascular system Return to Slide 26 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70. HOME
  • 106. 106 IMPACT OF LOW T Key Finding Sexual Dysfunction Corona et al. 20041 • Corona et al. 20082 • Metabolic Syndrome Kupelian et al. 20063 • Psychological effects Barrett-Connor et al. • 19994 Patients with ED and hypoactive sexual desire had a significantly lower T level Men with delayed ejaculation had the highest prevalence of testosterone deficiency Non-obese men with a low baseline T level had a 2- to 4-fold increased risk of developing MetS Bioavailable T levels were 17% lower for men with depression than levels observed in all other men Next MetS: metabolic syndrome; T: testosterone. 1. Corona et al. Int J Impot Res. 2004;16:275-81; 2. Corona et al. J Sex Med. 2008;5:1991-8; 3. Kupelian et al. J Clin Endocrin Metab. 2006;91:843-50; 4. Barrett-Connor et al. J Clin Endocrinol Metab. 1999;84:573. HOME
  • 107. 107 IMPACT OF LOW T Key Finding Osteoporosis Jackson et al. 19921 Meier et al. 20082 Muscle Mass Szulc et al. 20043 • • • Testosterone deficiency was found in 71% men with hip fracture vs. 32% of the controls Lower testosterone was associated with ↑ risk of fracture Men with low testosterone levels had a significantly lower relative appendicular skeletal muscle mass index than men with higher testosterone levels Return to Slide 61 T: testosterone. 1. Jackson et al. Am J Med Sci. 1992;304:4-8; 2. Meier et al. Arch Intern Med. 2008;168:47; 3. Szulc et al. Am J Clin Nutr. 2004;80:496. HOME
  • 108. 108 TESTOSTERONE THERAPY IN PROSTATE CANCER SURVIVORS Key Finding Kaufman et al. 20041 • • 7 men: radial prostatectomy, undetectable PSA No recurrences of prostate cancer detected over 1-12 years of therapy Agarwal et al. 20052 • • 10 men: radial prostatectomy, undetectable PSA No recurrence of prostate cancer over 19-month follow-up Sarosdy et al. 20073 • • • 31 men: brachytherapy for prostate cancer treatment Median duration of treatment 4.5 years No recurrence or prostate cancer progression Khera et al. 20094 • • • 57 men: radial prostatectomy, undetectable PSA Testosterone therapy for average 36 months  followed for average 13 months No recurrence of prostate cancer or increase in PSA values • • • 84 year old man, untreated prostate cancer Received 2 years of testosterone therapy No increase in PSA levels Morgentaler et al. 20095 PSA: prostate specific antigen. 1. Kaufman et al. J Urol. 2004;172:920-2; 2. Agarwal et al. J Urol. 2005;173:533-6; 3. Sarosdy MF. Cancer. 2007;109:536-41; 4. Khera et al. J Sex Med. 2009;6:1165-70; 5. Morgentaler. J Sex Med. 2009;6:574-7. Return to Slide 70 HOME
  • 109. TESTOSTERONE THERAPY IMPROVES LUTS 109 IN PATIENTS WITH LOW T AND MILD BPH-LUTS 18 Mean IPSS Score 16 p=0.345 p=0.034 14 12 Baseline 10 12 Months 8 6 4 2 0 Control ART Return to Slide 73 T: testosterone; ART: androgen replacement therapy; IPSS: International Prostate Symptom Score. 1. Shigehara et al. Aging Male. 2011;14:53-8. HOME
  • 110. TESTOSTERONE THERAPY IMPROVES SEXUAL FUNCTION 110 Studies with baseline T <10 nmol/L Morning Erections Testosterone therapy results in: Erectile Function Significant, moderate improvement of all aspects of sexual function in men with low or low-normal testosterone levels1 Intercourse Sexual Motivation Sexual Satisfaction Sexual Thoughts Total Erections -2 -1 0 1 2 3 4 5 All sexual domains (SMD) 6 Return to Slide 79 T: testosterone. 1. Isidori et al. Clin Endocrinol (Oxf). 2005;63:381-94. HOME
  • 111. TESTOSTERONE THERAPY AND PDE5i EFFICACY 111 Study Therapy Key Finding Rosenthal 20061 • Testosterone gel + sildenafil • After 16 weeks, 92% of men had improved potency and erection quality with combination therapy Buvat 20112 • Testosterone gel + tadalafil • Significant improvement of erectile function with addition of testosterone therapy compared to placebo when T ≤300 ng/dL Shamloul 20053 • Testosterone undecanoate + sildenafil • Patients receiving combination therapy showed significant improvement in IIEF-5 scores Hwang 20064 • Testosterone undecanoate ± sildenafil • One third of non-responders responded to testosterone therapy alone • Another third of non-responders showed response to sildenafil after normalization of testosterone Shabsigh 20055 • Testosterone gel + sildenafil • Testosterone-treated subjects had greater improvement in erectile function compared to those who received placebo. Overall combined use of testosterone and PDE5 inhibitors salvaged 37.5-92% of PDE5i failures6 Return to Slide 81 IIEF-5: international index of erectile function; PDE5i: phosphodiesterase 5 inhibitor; T: testosterone. 1. Rosenthal et al. 2006;67:571-4; 2. Buvat et al. J Sex Med. 2011;8:284-93; 3. Shamloul et al. J Sex Med. 2005;2:559-64; 4. Hwang et al. Int J Impot Res. 2006;18:400-4; 5. Shabsigh et al. J Urol. 2004;172:658-63; 6. Buvat et al. Current Sexual Health Reports. 2008;5:135-40. HOME
  • 112. 112 THE INFLUENCE OF SHBG • SHBG-bound testosterone represents the majority of testosterone  it is not biologically active Factors that Influence [SHBG]1 Decrease in [SHBG] Increase in [SHBG] Obesity Aging Diabetes Hepatic cirrhosis Hypothyroidism Hyperthyroidism Nephrotic syndrome HIV infection Use of glucocorticoids, progestins and androgenic steroids Estrogens • Influences interpretation of total testosterone measurement • Use free or bioavailable measurements when altered SHBG is suspected2,3 [SHBG]: concentration of sex hormone binding globulin; T: testosterone. 1. Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:251-70; 2. Bhasin et al. J Clin Endocrinol Metab. 2010;95:2536-59; 3. Morales et al. CUAJ. 2010;4:269-75. Return to Slide 91 HOME
  • 113. TESTOSTERONE THERAPY IMPROVES SYMPTOMS IN PATIENTS ON OPIOIDS 113 8 Mean ADSQ Score 7 Baseline 6 12 Weeks (5 mg/day) ‡ 5 4 3 2 * * * ‡ ‡ † † † 1 0 24 Weeks (7.5 mg/day) Decreased libido ED Tiredness Depressed Hot flashes/ mood night sweats Next ADSQ: androgen deficiency symptoms questionnaire. *p<0.001; †p<0.01; ‡p<0.05 1. Daniell et al. J Pain. 2006;7:200-10. HOME
  • 114. TESTOSTERONE THERAPY IMPROVES PAIN DIMENSIONS 114 p<0.01 70 60 QUID Value 50 40 Baseline 30 p<0.02 12 Months p<0.02 20 10 0 Sensory Afffective Evaluative Miscellaneous QUID parameters Total Return to Slide 94 QUID: an Italian pain questionnaire which measures the quality and intensity of the current pain experience. 1. Aloisi et al. Reprod Biol Endocrinol. 2011;9:26. HOME