9/2/2016. Faculty. Learning Objectives. Disclosures. Prevalence of Hypogonadism. Prevalence of HG (cont)

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1 Faculty Testosterone Replacement Therapies: Mitigating Cardiometabolic Risks Associated with Hypogonadism Pamela Ellsworth, MD Professor of Urology University of Massachusetts Medical School Vice Chair, Department of Urology University of Massachusetts Memorial Medical Center Worcester, MA Disclosures Dr. Ellsworth has disclosed no relevant financial relationships with any commercial interests. Learning Objectives Explain the bidirectional relationship between low testosterone levels and cardiometabolic syndrome Apply timely hypogonadism screening and diagnostic techniques for symptomatic and at-risk male patients, including those with cardiometabolic symptoms Outline clinical data on available TRT, comparing efficacy, safety, and routes of administration Apply informed clinical decision making to the individualized management of hypogonadism, incorporating guideline recommendations for TRT initiation and monitoring Promote adherence to long-term therapy to ensure optimal patient outcomes TRT = testosterone replacement therapy. Prevalence of Hypogonadism Prevalence of HG (cont) Circulating T in men decreases by 0.4% to 2.0% per year from the third decade onward Prevalence of HG is 12% to 38% in men aged >45 years Increases with age 35% to 40% in men with diabetes mellitus 20% of men aged >60 years have serum TT <320 ng/dl with variation between different populations 24% men aged >60 years have serum TT <300 ng/dl (10.4 nmol/l) T = testosterone; HG = hypogonadism; TT = total testosterone Gray A, et al. J Clin Endocrinol Metab. 1991;73: Orwoll ES, et al. J Clin Endocrinol Metab. 2006;91: Wu FC, et al. J Clin Endocrinol Metab. 2008;93: Mulligan T, et al. Int J Clin Pract. 2006;60: Dhindsa S, et al. Diabetes Care. 2010;33: Kaufman J, et al. Endocr Rev. 2005;26: Borst S, et al. Am J Physiol Endocrinol Metab. 2015;308:E1035- E1042. EMAS 2599 men (mean BMI, 27 kg/m 2 ) Aged years observed for 5 years Prevalence of Secondary HG (low T and low/normal LH): 11.6% Primary HG (low T and increased LH): 2% Compensated HG (Nl T and increased LH): 9.5% Older men more likely to have primary HG (RRR=3.04; P<.001) and compensated HG (RRR=2.41; P<.001) BMI of >30 kg/m 2 associated with secondary HG Sexual side effects more prevalent in secondary and primary HG Physical side effects more prevalent in compensated HG SINGLE MOST POWERFUL PREDICTOR OF LOW T: OBESITY EMAS = European Male Ageing Study; BMI = body mass index; LH = luteinizing hormone; RRR = relative risk ratio. Hackett G. Ther Adv Urol. 2016;8(2): Tajar A, et al. J Clin Endocrinol Metab. 2010;95(4):

2 HG Impacts Health and Quality of Life Social impact/emotional/cognitive Decreased energy Depressed mood Sexual dysfunction Cognitive dysfunction Physical impact Loss of muscle mass and strength Increased fat mass Decreased energy Reduced bone mineral density fracture and frailty Maggi M, et al. J Sex Med. 2007;4: Increased Risk of Morbidity and Mortality with HG Morbidity Depression Osteoporosis CVD MetS/type 2 diabetes mellitus Sexual dysfunction CVD = cardiovascular disease; MetS = metabolic syndrome. Maggi M, et al. J Sex Med. 2007;4: Carruthers M. Aging Male. 2009;12: Shores MM, et al. Arch Intern Med. 2006; Araujo AB, et al. J Clin Endocrinol Metab. 2011;96: Increased Risk of Morbidity and Mortality with HG (cont) Reduced Survival in Men with Low Testosterone Levels Mortality US study men aged >40 over a mean follow-up of 4.3 years Mortality rate of 20% in men with normal T (>250 ng/dl) Mortality rate of 35% in men with low T Increased risk of mortality by 88% in men with low T Low T levels associated with all-cause and CV death Cumulative Survival *P=.001 vs normal levels Men with a normal testosterone level (n=452) Men with an equivocal testosterone level (n=240) Men with a low testosterone level (n=166) Survival, years CV = cardiovascular. Maggi M, et al. J Sex Med. 2007;4: Carruthers M. Aging Male. 2009;12: Shores MM, et al. Arch Intern Med. 2006; Araujo AB, et al. J Clin Endocrinol Metab. 2011;96: Unadjusted Kaplan-Meier survival curves for the three testosterone-level groups in men aged 40 years. Normal = 2 measurements of >250 ng/dl; low = 2 measurements of <250 ng/dl; equivocal = 1 low and 1 normal testosterone levels. Shores MM, et al. Arch Intern Med. 2006;166: Testosterone Deficiency and CVD Low T has been associated with increased mortality MMAS: Men with low T nearly twice as likely to die of all causes and CVD compared to those with normal testosterone EPIC-Norfolk study: Baseline T levels inversely related to deaths from all causes, CVD, and malignancy after controlling for confounders Ranchero Bernardo study: Low TT predicted an increased risk of CV mortality (hazard ratio, 1.38) as did low bioavailable T levels Challenges in Defining Androgen Deficiency Symptoms: Non-specific and modified by age, comorbidities, severity and duration of androgen deficiency, variation in androgen sensitivity, and prior T therapy Threshold T level below which symptoms of androgen deficiency and adverse health outcomes occur and TRT improves outcomes in general population not known MMAS = Massachusetts Male Aging Study; EPIC = European Prospective Investigation Into Cancer in Norfolk. Wu FC, et al. N Engl J Med. 2010;363(2): Stellato RK, et al. Diabetes Care. 2000;23(4): Oh J, et al. Diabetes Care. 2002;25: Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):

3 Symptoms and Signs Suggestive of HG in Adult Males Reduced sexual desire and activity Decreased spontaneous erections Breast discomfort, gynecomastia Loss of body hair Very small or shrinking testes Low or azoospermia Height loss, low trauma fracture, Low bone mineral density Hot flushes, sweats Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6): Decreased energy, motivation, initiative, self-confidence Feeling sad or blue, depressed mood Poor concentration and memory Sleep disturbance, increased sleepiness Mild anemia Reduced muscle bulk and strength Increased body fat, BMI Diminished physical or work performance What Testosterone Level Defines HG? 30% of such men with initial mildly low T have normal T on repeat evaluation TT is usually all that is needed Check FT or bioavailable T when TT is near lower limit of normal and when altered SHBG levels suspected Endocrine Society consensus TT <200 ng/dl indicates HG TT of 200 to 400 ng/dl may suggest that therapy would be beneficial TT >400 ng/dl unlikely to reflect androgen deficiency SHBG = sex hormone-binding globulin. Swerdloff RS. The Endocrine Society, CME Series, The Practice Committee of the ASRM. Fertility Sterility. 2004;81(3): Brambilla DJ, et al. Clin Endocrinol (Oxf). 2007;67(6): Distribution of Testosterone According to AACE Hypogonadism Task Force 68% 2% 30% SHBG Tightly Bound ALBUMIN Weakly Bound FREE Bioavailable = albumin bound + free Conditions That May Affect SHBG Levels Decreased SHBG concentration Moderate obesity Nephrotic syndrome Hypothyroidism Use of glucocorticoids, progestins, androgenic steroids Acromegaly Diabetes mellitus Increased SHBG concentration Aging Hepatic cirrhosis and hepatitis Hyperthyroidism Anticonvulsants Estrogens Human immunodeficiency virus AACE Hypogonadism Task Force. AACE Guidelines. Endocr Pract. 2002;8(6): Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6): Younger Who Is at Risk? Conditions in Men Who Are Considered at High Risk of Having HG Older 1. Type 2 diabetes mellitus 2. MetS 3. Moderate to severe chronic lung disease 4. Osteoporosis 5. Human immunodeficiency virus 6. History of male infertility 7. Treatment with corticosteroids, opiates (even medically prescribed), anticonvulsants 8. Alcohol abuse 9. Erectile dysfunction or loss of spontaneous erections 10. Loss of sexual desire Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6): Seftel AD, et al. Mayo Clin Proc. 2015;90(8):

4 HG and Obesity and MetS Evaluation Low T correlated with insulin resistance May be attributable to effect of T on adiposity Low T increases fat mass and decreases lean body mass, leading to increased adipose tissue Adipose tissue increases aromatization of T to estradiol - decreased serum and tissue levels Estradiol produced provides (-) feedback on HG axis, further decreasing T Adiposity potentially leads to HG, which in itself promotes further adiposity History Libido, sexual function Medication use Anosmia/hyposmia, mid-line defects, cryptorchidism Testicular trauma/surgery/infection Toxin exposure: Chemotherapy, radiation therapy Other endocrine deficiencies History of osteoporosis/fracture Decreased muscle mass, poor ability to concentrate, hot flush Voiding history Corona G, et al. Hormones (Athens). 2015;14(4): Petak SM, et al. Endocr Pract. 2002;8(6): Physical Examination Blood pressure Fluid retention lower extremity edema Body hair Gynecomastia Genitalia Testicular size: Adult testes between 20 and 30 ml in volume; 4.5- x 6.5-cm long by 2.8- by 3.3-cm wide Testicular consistency: Prepubertal damage testes, small and firm; postpubertal damage testes, small and soft Varicocele Penile length: Adult penile length, cm; width in flaccid state, 3 cm DRE: Nonpalpable prostate suggests low T levels r/o nodule Laboratory Evaluation Serum T: Obtain before 11:00 am Screening TT Repeat: TT, bioavailable T (includes TT, bioavailable T, and SHBG) or FT LH, follicle-stimulating hormone, prolactin Fasting blood lipid profile Complete blood count Liver function tests Prostate-specific antigen DRE = digital rectal examination. Petak SM, et al. Endocr Pract. 2002;8(6): Miner M, et al. Postgrad Med. 2008;120(3): Free and Bioavailable Testosterone Calculator FDA-Approved TRT Treatment Options T enanthate or cypionate Scrotal T patch Non-genital transdermal system T gel 17-α-methyl T T buccal, bioadhesive, tablets T topical solution T pellets International Society for the Study of the Aging Male. Accessed June 23,

5 FDA-Approved TRT Treatment Options (cont) Formulation Regimen Pharmacokinetic Profile T enanthate or mg IM q 2 Supraphysiologic T cypionate weeks or that declines to low T mg/wk over interval TU 3 ml (750 mg) IM at Conc reaches max 7 initiation, 4 weeks days after injection and Q 10 weeks then steady decline thereafter 1% T gel Sachets, tubes, and Physiologic level T pumps 5-10 T gel - and E mg T QD Transdermal T patch Buccal, bioadhesive T tablets T pellets 1 or 2 patches QD-5-10 mg T/d nonpressure area Absorbed from bucal mucosa 30 mg BID 3-6 pellets subq, dose and regimen vary with formulation; higher doses frequently used Restores T, DHT, E2 Advantage Inexpensive; selfadmin; dose flexibility Restores T, lessfrequent injections Restores T, dose, flexibility, easy to use, minimal skin issues Ease of use, restores T Disadvantage Requires injection, peaks and troughs in T levels Requires injection, AVEED REMS program due to risk of POME and anaphylaxis Potential of skin-skin transfer, skin irritation, mod high DHT levels Some have low-nl T and need 2 patches QD skin irritation Restores T and DHT Restores T Gum-related adverse events in 16% of men T peaks at 1 month sustained for 3-6 months, varying with formulation Restores T IM = intramuscular; TU = testosterone undecanoate; E2 = estradiol; subq = subcutaneous. FDA prescribing information. Surgical incision for insertion, pellets may extrude Which Formulation of Testosterone to Use? Current market is largely long-acting injections and topical gel or solution Retrospective review of 544,115 TRT initiations based on healthcare computerized data from the United States and the United Kingdom Concluded that short-acting injections had higher event rates followed by patches and then gels No baseline levels to confirm diagnosis and no evidence of treatment compliance, only initiation Layton B, et al. JAMA Intern Med. 2015;175: Modes of TRT Different Testosterone Levels after TRT Mode of TRT administration alters metabolism of T Transdermal T (patch and gel) elevates DHT 5.46-fold IM injected T elevates DHT only 2.2-fold High expression of 5 alpha-reductase in skin vs skeletal muscle DHT = dihydrotestosterone. Borst SE, et al. Horm Metab Res. 2010;42: Inui S, et al. Exp Dermatol. 2013;22(3): Wu Y, et al. Biochem Biophys Res Commun. 2010;400(4): Borst SE, et al. AJP- Endocrinol Metab doi:10/1152/ajpendo Testosterone ng/dl Patch or gel Normal range 1400 Injection Days Adapted from Bhasin S, et al. J Clin Endocrinol Metab. 1997;82:3-8. Pharmacokinetics of TRTs Testosterone Undecanoate Testosterone Pellets Monitoring Treatment According to AACE Guidelines Morning T level 2-3 weeks of starting gel, patch, or buccal T Approximately 8 weeks if injectable form of T used Check T level midway between injections Goal ng/dl 1 week after injection Check T levels 3 to 6 months after start of therapy and periodically thereafter Baseline PSA, at 3-6 months, per prostate cancer screening HCT at baseline, 3-6 months, and then annually Discontinued if HCT >54% until decreased to safe level, then reinitiate at lower dose Lipid profile after 6-12 months, then annually McCullough AR, et al. J Sex Med. 2012;9: HCT = hematocrit. Miner M, et al. Postgraduate Medicine. 2008;120(3): Petak SM, et al. Endocrine Practice. 2002;8(6):

6 Monitoring Treatment According to AACE Guidelines (cont) DRE and prostate-related symptom assessment every 6-12 months Assess for gynecomastia, alopecia Assess for fluid retention Sleep apnea: TRT may worsen sleep apnea Impaired spermatogenesis: TRT can cause oligospermia or azoospermia, which may not be reversible Weight gain Acne Risks of Testosterone One of my patients presented to my office for a routine follow-up I walked in to see her and she was covering her mouth with a tissue I asked if she was feeling okay She said that the testosterone gel replacement I had been prescribing her husband was apparently working very well for him and for her Miner M, et al. Postgraduate Medicine. 2008;120(3): Petak SM, et al. Endocrine Practice. 2002;8(6): With That, She Pulled Away Her Tissue to Show Me the Results! Clinical Manifestations of Late-Onset HG and Response to Treatment Wein AJ. In: Campbell-Walsh Urology. 10th ed. Philadelphia, PA: Saunders- Elsevier; 2011: 812. Bidirectional Relationship between Low Testosterone and MetS: Not a Direct Link Inter-Relationship between Testosterone and MetS Traish AM, et al. J Androl. 2009;30: Jones TH. Trends Endocrinol Metab. 2010;21(8):

7 Tromsø Study Testosterone and Abdominal Obesity Population-based health survey: Started in 1974 with main focus on CVD Fourth study, Sex hormones available in random sample of 1565 men aged years Study demonstrated associations between T and components of MetS TT and FT inversely associated with BMI and WC In age-adjusted analyses, men with WC >103 cm had significantly lower TT levels compared to men with normal WC (11.0 vs 14.7 nmol/l; P<.001) Associations remained significant after adjustment for BMI as a surrogate for overall body fatness Lowest levels of TT and FT found in men with a WC in highest tertile who at same time had BMI in lowest tertile Svartberg J. Int J Impot Res. 2007;19(2): FT = free testosterone; WC = waist circumference. Svartberg J. Int J Impot Res. 2007;19(2): Tromsø Study Low T levels were independently associated with higher HbA 1c levels in age- and WCadjusted analyses Men with diabetes mellitus had lower TT levels (11.4 vs 13.1 nmol/l; P<.005) Higher endogenous T levels associated with more favorable lipid profile Higher TT levels associated with lower SBP Normotensive men had higher levels of TT and FT Differences between normotensive and HTN patients consistent within age groups HbA 1c = glycosylated hemoglobin; SBP = systolic blood pressure. Svartberg J. Int J Impot Res. 2007;19(2): Association between Testosterone and MetS Cross-sectional study of 400 men aged years from Utrecht, The Netherlands Low endogenous T levels independently associated with all separate components of MetS as well as the MetS according to NCEP Each SD (5.3 nmol/l) increase in TT was associated with 57% reduced risk of having MetS NCEP = National Cholesterol Education Program; SD = standard deviation. Muller M, et al. J Clin Endocrinol Metab. 2005;90: Association between Testosterone and MetS (cont) Kuopio Ischemic Heart Disease Risk Factor Study Men with TT in lower quartile were two-fold more likely to develop MetS compared with other men during 11-year follow-up, independent of potential confounders, such as CAD, smoking, alcohol intake, and socioeconomic status Three-fold increased risk of HG developing at the 11-year follow-up in men having MetS at baseline using either WHO or NCEP definition MetS not only a consequence of low T but may also be a cause of hypogonadism Benefits of TRT in Men with MetS TRT in hypgonadal men with type 2 diabetes mellitus and/or MetS (the TIMES2 study) Effects of T supplementation on markers of the MetS and inflammation in hypogonadal men with MetS (the double-blind, PBO-controlled Moscow study) CAD = coronary artery disease; WHO = World Health Organization; NCEP = National Cholesterol Education Program. Laaksonen DE, et al. Diabetes Care. 2004;27: Laaksonen DE, et al. J Clin Endocrinol Metab. 2005;90: PBO = placebo. Jones TH, et al. Diabetes Care. 2011; Kalinechenko SY, et al. Clin Endocrinol. 2011;75(2):275. 7

8 TRT in Hypogonadal Men with Type 2 Diabetes Mellitus and/or MetS: TIMES2 Study Multicenter, prospective, randomized, doubleblind, PBO-controlled study Transdermal 2% T gel evaluated over 12 months in 220 men with HG (TT <11 nmol/l or FT <255 pmol/l on 2 draws >1 week apart with at least two symptoms of HG) with type 2 diabetes mellitus and/or MetS Primary outcome: Mean change from baseline in HOMA-IR Secondary outcomes: Measures of body composition, glycemic control, lipids, and sexual function Efficacy results focused primarily on months 0-6 HOMA-IR = homeostasis model assessment of insulin resistance. Jones TH, et al. Diabetes Care. 2011;34(4): Kalinechenko SY, et al. Clin Endocrinol. 2011;75(2):275. MetS Results Difference between TRT and PBO in patients with MetS approached significance (TD, 13.3% [-1 to 26]; P=.069) TRT associated with significantly greater reductions from baseline in plasma levels of: Lpa (TD, µmol/l [95% CI, to ]; P=.008) LDL cholesterol (TD, mmol/l [ to ]; P=.012) HDL cholesterol (TD, mmol/l [ to ]; P=.016) Significant improvement in IIEF total score and sexual desire and intercourse satisfaction domain scores TD = treatment difference; Lpa = lipoprotein a; LDL = low-density lipoprotein; HDL = high-density lipoprotein; IIEF = International Index of Erectile Function. Jones TH, et al. Diabetes Care. 2011;34(4): TRT in Hypogonadal Men with Type 2 Diabetes Mellitus and/or MetS: TIMES2 Study AEs Most common AEs in patients with >1 AE Erythema (TRT 4%, PBO 5%) Pruritus (TRT 4%, PBO 4%) Nasopharyngitis (TRT 3%, PBO 4%) Most common AEs leading to discontinuation Skin disorder Subcutaneous tissue disorder CV events occurred more commonly with PBO (10.7 vs 4.6%; P=.095) HCT increased by L/L for TRT vs L/L for PBO Hemoglobin increased by g/dl vs g/dl for PBO AE = adverse effect. Jones TH, et al. Diabetes Care. 2011;34(4): Effects of Testosterone Supplementation on Markers of the MetS and Inflammation in Hypogonadal Men with MetS: Moscow Study Randomized, PBO-controlled, double-blind, phase men with MetS and hypogonadism (baseline TT <12.0 nm or calculated FT <225 pm) Rx for 30 weeks with either parenteral T undecanoate (n=113; TU; 1000 mg IM) or PBO (n=71) administered at baseline and after 6 and 18 weeks 195 TU and 65 PBO completed trial Measurements: Body weight, BMI, waist circumference, HDL, LDL, C-reactive protein, interleukin-1-beta, interleukin-6, interleukin-10, and tumor necrosis factoralpha TU = T undecanoate. Kalinchenko SY, et al. Clin Endocrinol. 2010;73(5): Moscow Study Results Significant decreases in weight, BMI, and WC in the TU vs PBO group Decreased levels of leptin and insulin No changes in serum glucose or lipid profile Decrease in interleukin-1-beta, tumor necrosis factoralpha, and C-reactive protein No significant change in IL-6 and IL-10 Medication Adherence and Treatment Patterns Adherence to topical therapy low By 6 months, 34.7% had continued TRT By 12 months, 15.4% had continued TRT Approximately 50% who discontinued therapy resumed therapy IL = interleukin. Kalinchenko SY, et al. Clin Endocrinol. 2010;73(5): IL = interleukin. Schoenfeld MJ, et al. J Sex Med. 2013;10(5):

9 Medication Adherence with Topical Therapy Retrospective Medical Claims Analysis included 15,435 hypogonadal men from Thomson Reuters MarketScan Database who had an initial topical T gel prescription in 2009 and followed for 12 months Results At 6 months, only 31.1% of patients were still on therapy At 12 months, only 13.6% of men remained on therapy Approximately half of the men restarted TRT Patient Satisfaction with TRT Anonymous survey academic urology clinic 382 completed surveys Average age, years Satisfaction rates similar between gels (68%), injections (73%), and implantable pellets (70%) Injectable TRT favored because of lower cost (35% vs 21% gel users vs 19% pellet users) Pellets favored for ease of use (64% vs 44% injection users vs 43% gel users) and convenience (58% vs 26% injection users vs 19% gel users) Pellets had increased rates of satisfaction first 12 months Improvements in concentration and mood occurred at higher percentages in satisfied patients Schoenfeld MJ, et al. J Sex Med. 2013;10(5): Kovac JR, et al. J Sex Med Feb;11(2): Balancing Benefit and Risk: The CV Controversy Good Conflicting Data Bad Effects of TRT on Surrogate Markers for CV Risk Decreases in serum cholesterol noted as early as after 4 weeks (most by 3 months), maximum reached at 12 months Decrease in triglycerides at 4 weeks, maximum effect at 12 weeks LDL decreases but slower response, maximum effect at 24 months Variable effect on HDL Decline in IL-6 and TNF-α within 6 to 16 weeks and C-reactive protein at 30 weeks TNF-α = tumor necrosis factor-alpha. Kalinchenko S, et al. Clin Endocrinol (Oxf). 2010;73: Zgliczynski S, et al. Atherosclerosis. 1996;121: Jones T. Diabetes Care. 2011;34: Hackett G, et al. J Sex Med. 2011;8:430. Haffner SM, et al. Am J Epidemiol. 1996;143: Boyanov MA, et al. Aging Male. 2003;6:1-7. Impact of TRT on CVD TRT Decreased Cardiac Events/Procedures Men with chronic stable angina, ischemic threshold increased after 4 weeks with TRT Exercise capacity in men with CHF increased after 12 weeks, primarily via improvement in skeletal muscle performance PBO-controlled trial of testosterone gel vs PBO in elderly, frail men was terminated due to a greater number of cardiac events in the testosterone group More severe CAD in active treatment group Allowed for rapid escalation to 150 mg (> recommended dosing) Inadequate validation of many of the events Long-term safety: Meta-analysis of 1000 patient-years vs PBO suggests a slight decrease in MI and CVA but marked decrease in coronary interventions Calof OM, et al. J Gerontol. 2005;60A: Basaria S, et al. N Engl J Med. 2010;363: Mathur A, et al. Eur J Endocrinol. 2009;161: English KM, et al. Circulation. 2000;102: Caminiti G, et al. J Am Coll Cardiol. 2009;54: Calof OM, et al. J Gerontol. 2005;60A(11):

10 Concerns Regarding CV Risks of TRT A systematic review and meta-analysis of PBO controlled trials of TRT and CV events concluded: The effects of testosterone on CV-related events varied with source of funding...overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of CV-related events AACE: TRT and CV Risk AACE Releases New Position Statement on TRT in Men Rigorous studies have not linked testosterone replacement therapy to heart attack or stroke, and the decision to prescribe testosterone replacement therapy should be based on a full diagnostic work-up not the underlying cause of hypogonadism, according to a new position statement from the American Association of Clinical Endocrinologists The statement challenges several aspects of a recent Food and Drug Administration safety announcement warning about possible increased risks of heart attack and stroke with testosterone replacement therapy (TRT) and approving its use only for testicular, pituitary, or brain disorders that cause low testosterone, not for ageassociated hypogonadism In fact, AACE rejoined, randomized controlled trials have lacked the power to assess whether TRT increases the chances of cardiovascular events or death. Data linking TRT to cardiovascular problems come from a few retrospective studies, the major flaws of which limit their ability to assess risk. Large-scale prospective randomized controlled trials on testosterone therapy, focusing on cardiovascular benefits and risks, are clearly needed. As with therapeutics in general, common sense, experience, and an individualized approach are recommended Xu L, et al. BMC Med. 2013; 11:108. Karon A. Clinical Endocrinology News Digital Network. September 25, Goodman N, et al. Endocr Pract. 2015;21(9): Testosterone Trial in Older Men What s the Take Home? Purpose: A multi-center set of trials involving 12 clinical sites geographically distributed across the United States Primary specific aims: To test the hypotheses that T treatment of elderly men whose serum testosterone concentrations are unequivocally low and who have symptoms and objectively measured abnormalities in at least one of five areas that could be due to low testosterone (physical or sexual function, vitality, cognition, and anemia) will result in more favorable changes in those abnormalities than placebo treatment Two additional trials have been incorporated into the T trial Only men enrolled in the T trial are eligible to participate in these trials The CV trial will examine whether T treatment results in more favorable changes in CV risk factors compared to placebo Hypogonadism is common in men with obesity and MetS A bidirectional relationship exists between hypogonadism and obesity/mets Hypogonadism may be associated with morbidity/mortality, and treatment may mitigate these risks Hypogonadism is simple to evaluate Multiple therapies are available to treat hypogonadism A knowledge of benefits/risks is essential to selecting the most appropriate therapy ClinicalTrials.gov Identifier: NCT Questions? 10