Best Practices to Improve Patient Outcomes

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1 Best Practices Pearls Practical Primary Care Strategies for Diagnosing and Managing Hypogonadism in Men Utilize lab testing in appropriate patients who have complaints consistent with the often subtle signs and symptoms of hypogonadism Select testosterone replacement therapy based on patient preference and safety in patients with hypogonadism Matt T. Rosenberg, MD Medical Director Mid-Michigan Health Centers Jackson, MI Martin Miner, MD Co-director, Men's Health Center Clinical Associate Professor of Family Medicine & Urology Brown University, Providence, RI Miriam Hospital Providence, RI Monitor the effectiveness and side effects of testosterone replacement therapy in your patients being treated for hypogonadism with testosterone replacement therapy How is Hypogonadism Defined by Endocrine Society? A clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and the normal number of spermatozoa caused by the disruption of one or more levels of the hypothalamic-pituitary-testicular (HPT) axis Why Do We Need Testosterone? The Myth of Testosterone The Reality of Testosterone Physiological Effects of Testosterone in Male Adults Maintains reproductive tissues Stimulates spermatogenesis Stimulates and maintains sexual function Increases body weight and nitrogen retention Increases lean body mass Maintains bone mass Promotes sebum production, and axillary and body hair growth Stimulates erythropoiesis Bagatell CJ, Brenner WJ. N Eng J Med. 1996;334:

2 Cumulative Survival Prevalence of Low Testosterone (%) Practical Primary Care Strategies for Diagnosing and Managing Hypogonadism in Men Hypogonadism Is Underdiagnosed and Undertreated Prevalence of Low Testosterone (<300 ng/dl) Increases with Age 60% Baltimore Longitudinal Study on Aging 1 Hypogonadism in Males Study 2 Boston Area Community Health Survey 3 50% 46% 50% 40% 40% 40% 39% Low testosterone in 19% of men 60 years and older Low testosterone in 39% of men 45 years and older 24% of men age years had biochemical hypogonadism 30% 20% 34% Only 5%-35% of hypogonadal males actually receive treatment 4,5 5.6% of men were symptomatic 10% 0% Total 1 Harman SM, et al. J Clin Endocrinol Metab. 2001;86: Mulligan T, et al. Int J Clin Pract. 2006;60: Araujo AB, et al. J Clin Endocrinol Metab. 2007;92: Seftel AD. Int J Impot Res. 2006;18: Gooren LJ, et al. Aging Male 2007;10: Adapted from: Mulligan T, et al. Int J Clin Pract. 2006;60(7): Patient Age Range (years) The Dilemma Is That Low Testosterone Levels Are Associated with an Increased Mortality Improved Survival in Men with Coronary Heart Disease 1 VA Puget Sound 8-year study of 858 men BAT >2.6 nmol/l 0.95 (n=736) Low T <250 ng/dl or a free T <0.75 ng/dl 0.9 BAT <2.6 nmol/l (n=194) Shores MM, et al. Arch Intern Med. 2006;166(15): All-cause mortality was 34.9% in men with low T and 20.1% in men with normal T Log rank, P=.007, HR 2.2 ( ) Survival Time (days) BAT = bioavailable testosterone. Malkin CJ, et al. Heart. 2010;96: The Dilemma Natural process? Medically significant condition resulting in detriment to quality of life and adversely affecting the function of multiple organ systems? Chemical marker of generalized disease? Nonconclusive evidence that these diseases are helped with testosterone Importance of Screening and Diagnosis of Hypogonadism in Men Matt T. Rosenberg, MD Medical Director Mid-Michigan Health Centers Jackson, MI Surampudi PN, et al. Int J Endocrinol. 2012; [Epub ahead of print]. 2

3 Who Should Be Screened for Low Testosterone? Patient Presentation The Endocrine Society recommends screening for androgen deficiency only in men who present with consistent signs and symptoms of low testosterone levels Subjects with the following conditions should be screened: Sellar mass, radiation to the sellar region, or other diseases of the sellar region Treatment with medications that affect testosterone production or metabolism, such as glucocorticoids and opioids HIV-associated weight loss End-stage renal disease and maintenance hemodialysis Moderate to severe COPD Infertility Osteoporosis or low-trauma fracture, especially in a young man T2DM Harvey, a 58-year-old Caucasian man, presents with a chief complaint of fatigue He reports that he often wakes up in the middle of the night and is unable to go back to sleep He feels depressed and finds it difficult to concentrate at work COPD = chronic obstructive pulmonary disease. HIV = human immunodeficiency virus. Patient Evaluation and Medical History Current Medications Harvey has been married for 37 years and has 2 adult children He works long hours at his accounting firm and frequently eats fast food for lack of time. He has no time to exercise and has been sleeping poorly Medical history: T2DM Hypertension Dyslipidemia Metformin 500 mg twice daily Linagliptin 5 mg daily Enalapril 10 mg daily Atorvastatin 10 mg daily Physical Examination Laboratory Results Neck: No thyromegaly Lungs: Clear Cor S1S2S4 Genital: testes descended, no masses, no varicocele, normal size (15-18 g); no prostate nodule palpated Feet: no ulcers Neurologic: mild decreased sensation to 10-g monofilament; no visual field cuts Skin/hair: normal beard, normal male pattern hair in genital axilla No gynecomastia Height: 5 9 Weight: 217 lbs BMI: 32 kg/m 2 BP: 140/80 mmhg A1C: 6.8% at his last check-up 6 months ago Cr: 1.3 mg/dl PSA: 1.7 ng/ml TC: 210 mg/dl LDL-C: 110 mg/dl HDL-C: 35 mg/dl TG: 250 mg/dl Microalbumin: undetectable GFR: 50 ml/min BMI = body mass index. A1C = glycated hemoglobin. Cr = creatinine. GFR = glomerular filtration rate. HDL-C = high-density lipoprotein cholesterol. LDL-C = low-density lipoprotein cholesterol. PSA = prostate-specific antigen. TC = total cholesterol. TG = triglyceride. 3

4 Patient Presentation Patient Evaluation and Medical History Harvey, a 58-year-old Caucasian man, presents with a chief complaint of fatigue He reports that he often wakes up in the middle of the night and is unable to go back to sleep He feels depressed and finds it difficult to concentrate at work Harvey has been married for 37 years and has 2 children He works long hours at his accounting firm and frequently eats fast food for lack of time. He has no time to exercise and has been sleeping poorly Medical history: T2DM Hypertension Dyslipidemia Physical Examination Symptoms and Signs Suggestive of Hypogonadism: FACTS Neck: No thyromegaly Lungs: Clear Cor S1S2S4 Genital: testes descended, no masses, no varicocele, normal size (15-18 g); no prostate nodule palpated Feet: no ulcers Neurologic: mild decreased sensation to 10-g monofilament; no visual field cuts Skin/hair: normal beard, normal male pattern hair in genital axilla No gynecomastia Height: 5 9 Weight: 217 lbs BMI: 32 kg/m 2 BP: 140/80 mmhg No symptoms are unique to hypogonadism Screening with testosterone level is appropriate when presented with symptoms Diagnosis of hypogonadism is made when one or more symptoms are combined with low testosterone concentration Symptoms and Signs Suggestive of Hypogonadism Symptoms and Signs Suggestive of Hypogonadism (cont d) More-specific Symptoms and Signs Incomplete of delayed sexual development Reduced libido Decreased spontaneous erections Breast discomfort, gynecomastia Loss of body hair (axillary or pubic), reduced shaving Very small (< 5mL) or shrinking testis Inability to father children (azoospermia, oligospermia) Height loss, osteoporosis, low trauma fracture, low BMD Hot flushes, sweats Less-specific Symptoms and Signs Decreased energy, motivation, initiative, and self-confidence Feeling sad or blue, depressed mood, dysthymia Poor concentration and memory Sleep disturbance, increased sleepiness Mild anemia (normochromic, normocytic, in the female range) Reduced muscle bulk and strength Increased body fat, BMI Diminished physical or work performance BMD = bone mineral density. 4

5 Chronic Illness Lowers Testosterone Levels T2DM, metabolic syndrome, hypertension, obesity Steroid use Moderate-to-severe COPD Sellar mass, radiation to the sellar region, or other diseases of the sellar region End-stage renal disease, maintenance hemodialysis HIV-associated weight loss Hypogonadism and Chronic Opioid Use Up to 86% of men treated with chronic opioids may have hypogonadism Chronic opioid use affects the endocrine system, increasing the risk of testicular hypogonadism, hypothyroidism, and osteoporosis Men requiring chronic opioid therapy: Should be assisted in eliminating chronic use of opioids unless absolutely necessary and supervised by an appropriate healthcare provider Require routine testosterone, thyroid hormone levels, and BMD assessments May benefit from TRT if serum levels are decreased TRT = testosterone replacement therapy. Reddy RG, et al. BMJ. 2010;341:c4462. Woody GM, et al. NIDA Res Monogr. 1988;81: Common Comorbidities of Hypogonadism Screening for Low Testosterone Condition Odds Ratio Obesity 2.38 Diabetes 2.09 Hypertension 1.84 Hyperlipidemia 1.47 Osteoporosis 1.41 Asthma/COPD 1.40 ADAM Questionnaire 1. Do you have a decrease in 6. Are you sad and/or grumpy? libido (sex drive)? 2. Do you have a lack of 7. Are your erections less energy? strong? 8. Have you noticed a recent 3. Do you have a decrease in deterioration in your ability to strength and/or endurance? play sports? 9. Are you falling asleep after 4. Have you lost height? dinner? 10. Has there been a recent 5. Have you noticed a deterioration in your work decreased enjoyment of life? performance? The patient may have low testosterone if the answer is yes to question 1 or 7, or at least 3 of the other questions Aging Male Symptoms questionnaire is a similar questionnaire 3 These questionnaires have limited sensitivity in detecting actual androgen deficiency; further physical examinations and hormonal measurements should be obtained in patients with suspected low testosterone Mulligan T, et al. Int J Clin Pract. 2006;60: Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64: Morley JE. Metabolism. 2000;49: Chueh KS, et al. J Androl. 2012;33: The Hypothalamic-Pituitary-Testicular Axis HYPOTHALAMUS GnRH Making the Lab Diagnosis ANTERIOR PITUITARY FSH LH Sertoli cells Leydig cells TESTIS Seminiferous tubules Spermatozoa Testosterone FSH = follicle-stimulating hormone. GnRH = gonadotropin-releasing hormone. LH = luteinizing hormone. 5

6 Testosterone in the Blood Not All Testosterone is Available Testosterone bound to SHBG Free Bound to Albumin BAT Testosterone bound to albumin Free Testosterone Bound to SHBG Not Available SHBG = sex hormone-binding globulin. What Is Considered to Be a Low Serum Testosterone Level? Making the Diagnosis Total testosterone <300 ng/dl* Free testosterone <50 pg/ml Bioavailable testosterone <70 ng/dl Symptoms Low TT <300 ng/dl Remeasure morning TT >300 ng/dl <300 ng/dl *Total testosterone is the most frequently used lab test for the diagnosis of hypogonadism in the medical literature Patient with suspected low T History and physical exam Measure morning TT Levels Normal TT >300 ng/dl Seek other causes Normal TT Refer to endocrinologist Low TT Diagnosis of hypogonadism Brawer MK. Rev Urol. 2004;6:S9-S15. AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8: TT = total testosterone. Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6): Arver S, et al. Front Horm Res. 2009;37:5-20. ASA Position Statement. J Androl. 2006;27(2): Rosner W, et al. J Clin Endocrinol Metab. 2007;92(2): Primary Hypogonadism: Hypergonadotropic Hypogonadism What occurs? Testicular dysfunction Normal hypothalamic/pituitary function What results are seen? Low testosterone levels Impairment of spermatogenesis Elevated gonadotropin levels Possible cause? Karyotype to rule out Klinefelter s Secondary Hypogonadism: Hypogonadotropic Hypogonadism (cont d) What occurs? Normal testicular function Hypothalamic/pituitary dysfunction What results are seen? Low testosterone levels Impairment of spermatogenesis Low or low-normal gonadotropin levels Possible cause? Infiltrative disease (eg, check iron, TIBC) Age-related androgen deficiency Seftel A. Int J Impot Res. 2006;18(3): Surampudi PN, et al. Int J Endocrinol. 2012;2012: TIBC = total iron-binding capacity. Seftel A. Int J Impot Res. 2006;18(3): Surampudi PN, et al. Int J Endocrinol. 2012;2012:

7 Combined Primary and Secondary Mixed Hypogonadism What occurs? Testicular dysfunction Hypothalamic/pituitary dysfunction What results are seen? Low testosterone levels Impairment of spermatogenesis Low or low-normal gonadotropin levels (variable) Possible causes: Age-related androgen deficiency, alcohol. Glucocorticoids, chronic infections (HIV), hemochromatosis, systemic disease Harvey s Laboratory Results First TT: 230 ng/dl Second TT: 243ng/dL LH: 7.2 IU Seftel A. Int J Impot Res. 2006;18(3): Surampudi PN, et al. Int J Endocrinol. 2012;2012: Summary of 2010 Endocrine Guidelines Considerations in Choosing an Optimal Testosterone Modality and Importance of Monitoring Martin Miner, MD Co-director, Men's Health Center Clinical Associate Professor of Family Medicine & Urology Brown University, Providence, RI Miriam Hospital Providence, RI Diagnose Measure Treatment Goals Only in men with consistent signs and unequivocally low serum testosterone levels Do not screen in general population; however, consider measurement in disease conditions with high prevalence Morning total testosterone level Confirm abnormal level and, if in question, assess free or bioavailable testosterone Induce and maintain secondary sex characteristics as well as sexual function Improve sense of well-being Improve muscle mass and strength, and BMD Therapeutic Trial Concept In the presence of a clinical picture of androgen deficiency and borderline serum total or free testosterone levels, a short (eg, 3 months) therapeutic trial may be justified Consider discontinuing testosterone treatment if no clinical improvement Contraindications in Using Testosterone Male breast cancer Prostate cancer: but not absolute Known allergic reactions or sensitivities to substrates used in all types of TRT Wang C, et al. J Andrology. 2009;30(1):1-9. Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):

8 Precautions in Using Testosterone BPH or LUTS Edema in patients with preexisting cardiac, renal, or hepatic disease Gynecomastia Precipitation or worsening of sleep apnea Azoospermia; testicular atrophy Erythrocytosis Results of Therapy: FACTS Restore sexual functioning and libido Restore sense of well-being Prevent loss or improve bone density Restore muscle mass and strength Improves mood BPH = benign prostatic hyperplasia. LUTS = lower urinary tract symptoms. Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6): Seftel A. Int J Impot Res. 2006;18(3): Surampudi PN, et al. Int J Endocrinol. 2012; [Epub ahead of print]. Results of Therapy: Expert Opinion, Not Expert Evidence Improvement in insulin resistance Decrease abdominal fat Decrease cardiovascular risk factors Decrease overall mortality Common Sense in Initiating Testosterone Joint decision of informed patient and provider Short-acting preparations are better in the beginning to assess tolerability Start low and go slow Mårin P, et al. Eur J Med. 1992;1(6): Kapoor D, et al. Eur J Endocrinol. 2006;154(6): Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6): Shores MM, et al. J Clin Endocrinol Metab ;97(6): Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6): Treatment Options Intramuscular Injections Intramuscular injections Transdermal patches Transdermal gels Buccal tablets Subcutaneous pellets Pros History (available for 50 years) Self administration Inexpensive Flexibility of dosing Pain Cons Frequency of injections (every 2-4 weeks) Symptomatic peaks and troughs resulting in variations in breast tenderness, libido, emotional stability, energy 8

9 Transdermal Patches Transdermal Gels Pros Cons Pros Cons Non-scrotal patches Scrotal patches Application sites (upper arms, shoulder, axilla) Transfer to others (risk is minimized with high-dose, low-volume preparations) Night-time application results in good approximation of normal circadian plasma testosterone levels Skin irritation Low skin irritation Invisibility of application Low skin irritation Flexibility of dosing Flexibility of dosing Various concentrations Buccal Tablets Subcutaneous Pellets Pros Cons Pros Cons Application site Relative invisibility Application site Inadvertent loss of tablet History (started in 1940s) Relative invisibility Painful application Surgical procedure unlikely to be used by primary care physician Bypass first-pass hepatic metabolism Gum and buccal irritation, alteration in taste Long acting Slow release Long acting Inconvenient removal Slow release Twice-daily dosing No dose titration No dose titration Procedure can result in infection, fibrosis, or pellet extrusion Monitoring Therapy (Part 1) Monitoring Therapy (Part 2) Symptoms Measuring Testosterone Evaluate response 3-6 months after treatment initiation and then annually 3-6 months after initiation Aim to raise level into mid-normal range Monitoring guidelines depend on chosen therapy Hematocrit Check at 3-6 months, then annually Prostate Urologic Consultation DRE at 3 months, then yearly In men >40 years, check baseline PSA, at 3-6 months and then in accordance with guidelines PSA increase >1.4 ng/ml in any 12-month period PSA velocity of >0.4 ng/ml-yr after 6 months of therapy Detection of abnormality on DRE AUA/IPSS score of >19 Osteoporosis Measure BMD after 1-2 years Adverse Effects At each visit Can be formulation specific AUA = American Urological Association. DRE = digital rectal examination. IPSS = International Prostatic Symptom Score. 9

10 Physicians Rated Reason Against Testosterone Therapy as Very Important (%) Practical Primary Care Strategies for Diagnosing and Managing Hypogonadism in Men Measuring Testosterone: When to Check Risks of Testosterone?? Injectable Testosterone Enanthate or Cypionate Transdermal Patches Buccal Tablets Transdermal Gels Testosterone Pellets Measure level midway between injections Assess level 3-12 hours after application Assess immediately before or after application of fresh system Any time after patient has been on for a week Measure at end of dosing interval Adjust pellets or interval Potential Urologic Adverse Effects of Testosterone Replacement Potential Systemic Adverse Effects of Testosterone Replacement Worsening of LUTS Rise in PSA Testicular atrophy/infertility Progression of undiagnosed prostate cancer Erythrocytosis Acne and oily skin Gynecomastia Male pattern balding (familial) Growth of breast cancer Induction or worsening of obstructive sleep apnea Edema in patients with preexisting cardiac, renal, or hepatic disease Bhasin S, et al. J Endocrinol Metab. 2010;95(6): Bhasin S, et al. J Endocrinol Metab. 2010;95(6): Provider Concerns Regarding Testosterone Prostate Cancer and Testosterone Therapy: FACTS Brazil Saudi Arabia South Korea Spain 42 United Kingdom Assumed PCa Risk Assumed BPH Risk Budgetary Reasons Fear of causing prostate cancer leaves many appropriate patients untreated No evidence of causality of testosterone use and development of prostate cancer Testosterone will stimulate growth of existing prostate cancers Obtain consult for any concern: PSA abnormal per guidelines Abnormal prostate exam PCa = prostate cancer. Adapted from: Gooren LJ, et al. Aging Male. 2007;10(4): Gooren LJ, et al. Aging Male. 2007;10(4): Rhoden EL, Morgentaler A. N Engl J Med. 2004;350(5): Raynaud JP. J Steroid Biochem Mol Biol. 2006;102(1-5): Wang C, et al. J Androl. 2009;30(1):1-9. Carroll P, et al. Urology. 2001;57(2):

11 Prostate Cancer in Trials of TRT Historical Origin of Provider Concerns Study Duration (months) Prostate Cancer Placebo Testosterone Haijar et al. (1997) 24 0/27 0/45 Sih et al. (1997) 12 0/15 0/17 Dobs et al. (1999) 24-2/33-1/33 Snyder et al. (1999) 36 0/54 1/54 Snyder et al. (2000) 36-0/18 Wang et al. (2000) 6-0/76-0/73-1/78 Kenny et al. (2001) 12 0/33 0/34 Conclusion was based on one patient! Table adapted from: Rhoden EL, Morgentaler A. N Engl J Med. 2004;350(5): Huggins C, et al. Cancer Res. 1941;1: Reprinted by: J Urol. 2002;167: BPH and Testosterone Therapy: FACTS Patients with BPH treated with testosterone are at increased risk of worsening signs or symptoms Correlation of voiding volume to prostate size is poor Prostate size may increase in first 6 months, but generally to normal volume seen in eugonadal men Monitoring is strongly advised Testosterone Deficiency and Cardiovascular Disease Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6): Wang C, et al. J Androl. 2009;30(1):1-9. Hijazi RA, et al. Annu Rev Med. 2005;56: Miner MM, et al. Cleve Clin J Med. 2007;74:S38-S46. Rhoden EL, Morgentaler A. N Engl J Med. 2004;350(5): This is Controversial Testosterone and CV Risk in Men: A Systemic Review and Meta-analysis of Randomized Placebo Controlled Trials Many American men have embarked on a perilous course of overtreatment Testosterone is now being prescribed to men who are simply reluctant to accept the fact that they are getting older Drug companies have shamelessly pushed the notion Dangers of seeking a quick fix for aging Authors point out that many of the studies had limitations: limited reporting of methods; few patients; brief duration only 4 trials followed patients 1 year, 9% loss to follow-up; trials failing to report data on measured outcomes Results: exogenous testosterone given to men with low T levels had insignificant changes in blood pressure, glycemia, and lipid parameters Odds ratio between testosterone therapy and any cardiovascular event was 1.82 (95% CI = ) but not statistically significant Conclusion of Authors Testosterone was not associated with important CV events patients and clinicians need large randomized trials of men at risk for CV disease to better inform the safety of long-term testosterone use New York Times Editorial Board. February 5, 2014 CI = confidence interval. CV = cardiovascular. Hadda RM, et al. Mayo Clin Proc. 2007;82:

12 0.80 Survival by Testosterone Treatment, % MVC (Nm) Practical Primary Care Strategies for Diagnosing and Managing Hypogonadism in Men Testosterone Therapy Effects: Systematic Review and Meta-analysis Relationship Between Changes in TT Levels and in MVC in the Testosterone-treated Group Meta-analysis of 51 studies Follow-up ranged from 3 months to 3 years No significant effect on mortality, prostate, or CV outcomes Testosterone treatment was associated with: Significant increase in hemoglobin (WMD, 0.80 g/dl; 95% CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01). Decrease in HDL (WMD, mg/dl; 95% CI, to -0.13). These findings are of unknown clinical significance Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up WMD = weighted mean difference. OR = odds ratio. Fernández-Balsells MM, et al. J Clin Endocrinol Metab. 2010;95(6): In patients with heart failure treated with testosterone, there was a significant direct relationship between the increase in plasma levels of testosterone and the increase in maximal isometric muscle strength MVC = maximal voluntary contraction. Caminiti G, et al. J Am Coll Cardiol. 2009;54(10): r=0.58, P= TESTOSTERONE (ng/ml) Survival of Treated vs Untreated Testosterone-deficient Men in VA Population: Does TRT Improve Mortality? TOM Trial: Study Design 1031 men aged >40 years, testosterone <250 ng/dl Mortality: 10.3% treated, 20.7% untreated (P<.0001) VA = US Department of Veterans Affairs. At risk, n Untreated Treated Shores MM, et al. J Clin Endocrinol Metab ;97(6): Untreated Treated Log rank P= Time Since Testosterone Test Date (months) Effect of testosterone therapy on lower-extremity strength and physical function in older, hypogonadal men with limitations in mobility Men aged 65 y (mean, 74 y) with serum TT ng/dl or FT <50 pg/ml 209 participants randomized to receive testosterone gel or placebo for 12 months Testosterone gel titrated from 50 to 150 mg/d, based on serum testosterone level After dose adjustment, 16 men received 150 mg/d, 61 received 100 mg/d, and 29 received 50 mg/d Mean serum testosterone levels achieved were 574 (403) ng/dl in treatment group and 292 (160) ng/dl in placebo group Both groups had high prevalence of hypertension, obesity, diabetes, hyperlipidemia, and CVD CVD = cardiovascular disease. FT = free testosterone. Basaria S et al. N Engl J Med. 2010;363(2): TOM Trial: Outcomes Show Benefit TOM Trial: Safety Testosterone preferred Leg-press strength Chest-press strength Leg-press power Chest-press power Total lean mass ALST Grip strength Unloaded gait speed Loaded gait speed Unloaded stair climb Loaded stair climb Lift and lower Treatment Effect, SD Units Absolute treatment differences (testosterone vs placebo arms) are plotted for primary and secondary outcomes in units normalized to baseline standard deviation of measurement. Data are point estimates with 95% confidence intervals. ALST = appendicular lean soft tissue. SD = standard deviation. Adapted from: Travison TG, et al. J Gerontol A Biol Sci Med Sci. 2011;66(10): In treatment arm, hematocrit and hemoglobin levels increased significantly, and HDL and LDL levels decreased TOM trial reported more cardiovascular AEs 23 men receiving testosterone vs 5 receiving placebo Cardiovascular AEs had variable clinical importance Based on significantly increased incidence of cardiovascular AEs in treatment arm, data and safety monitoring board recommended cessation of enrollment and testosterone therapy: Termination of study in December 2009 AE = adverse event. Basaria S, et al. N Engl J Med. 2010;363(2):

13 Proportion of events (%) Proportion of events (%) Proportion of events (%) Practical Primary Care Strategies for Diagnosing and Managing Hypogonadism in Men Association of TRT with Mortality, MI, and Stroke Proportion of All Events after Statistical Modeling: VIGEN Study Study Design Retrospective VA study of men with low testosterone levels (<300 ng/dl) who underwent coronary angiography no TRT TRT 25.7 Population Results 1223 patients started testosterone after a median of 531 days following angiography 7486 patients received no testosterone 3 years after coronary arteriography, the Kaplan-Meier estimated cumulative percentages with events were 19.9% in the control group vs 25.7% in the TRT group Absolute risk difference of 5.8% at 3 years after coronary angiography No difference in effect among those with and without coronary artery disease at 1 year at 2 years at 3 years MI = myocardial infarction. Vigen R, et al. J Am Med Assoc. 2013;310(17): Vigen R, et al. J Am Med Assoc. 2013;310(17): Proportion of All Events in Patients with Hypogonadism (%) with or Without TRT: VIGEN Study Increased Risk of Non-fatal MI Following Testosterone Prescription No TRT TRT Study Design Retrospective cohort study of the risk of acute non-fatal MI in the 90 days following testosterone prescription Population 55,593 patients started testosterone compared to 167,279 prescribed PDE5 inhibitors Results In men <65 years, excess risk was confined to those with prior heart history, relative risk (RR) of 2.9 ( ) In men >65 years, the 2-fold increased risk was associated with testosterone prescription regardless of CV history 0 0 Death MI Stroke All Events PDE5 = phosphodiesterase type 5. Vigen R, et al. J Am Med Assoc. 2013;310(17): Frinkle WD, et al. PLoS One Jan 29;9:e Endocrine Society Statement Regarding Cardiovascular Risk Longer, large-scale prospective randomized controlled trials on testosterone therapy are needed Physicians and patients should have a conversation about the risks and benefits of using testosterone It may be prudent not to administer testosterone therapy to men who have had a cardiovascular event (MI, stroke, or acute coronary syndrome) in the preceding 6 months. Testosterone Deficiency and Diabetes Medscape Medical News. Available at: Accessed April 18,

14 All-cause Mortality (%) Practical Primary Care Strategies for Diagnosing and Managing Hypogonadism in Men Effects on Insulin Resistance From Testosterone Therapy Effects on A1C from Testosterone Therapy: BLAST Study Study Design A 12-month, multicenter, prospective, randomized, double-blind, placebo-controlled study Study Design 30-week double-blind, placebo-controlled study of long-acting testosterone undecanoate Population 220 men with hypogonadism with T2DM and metabolic syndrome Population 211 males with T2DM Results Significantly improved insulin resistance in all patients (by 15.2% at 6 months and by 16.4% at 12 months) Significantly improved HDL ( mmol/l) and LDL-C ( mmol/l), lipoprotein a (-0.31 mmol/l) in selected groups Significantly improved sexual health (increase of 4.8 on IIEF) Results Significantly improved A1C at 6 and 18 weeks Significant reduction in waist circumference, weight and BMI related to achieving adequate serum testosterone levels Significance not reached in patients with depression IIEF = International Index of Erectile Function. Jones TH, et al. Diabetes Care. 2011;34(4): Hackett G, et al. J Sex Med. 2013;10: TRT and Survival in Patients with T2DM 6-year follow up of hypogonadal men with T2DM (TT <300 ng/dl; n=238) 25 P= Conclusions TRT Untreated Muraleedharan V, et al. Eur J Endocrinol Oct 21;169(6): Conclusions Conclusions (cont d) Hypogonadism is very prevalent, underdiagnosed and undertreated Hypogonadism is associated with major illnesses such as metabolic syndrome, T2DM, and increased mortality Indications for referral include change in DRE or PSA, HCT, worsening of voiding symptoms or infertility There is no increased risk of prostate cancer from TRT Currently, there is not enough evidence to clearly state that the benefits of TRT outweighs the risks in the aging male A candid discussion with the patient is essential 14

15 Best Practices Pearls Utilize lab testing in appropriate patients who have complaints consistent with the often subtle signs and symptoms of hypogonadism Select testosterone replacement therapy based on patient preference and safety in patients with hypogonadism Monitor the effectiveness and side effects of testosterone replacement therapy in your patients being treated for hypogonadism with testosterone replacement therapy 15