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The “Truth” About Low Testosterone To treat or Not to Treat??? C. W. Spellman, DO, PhD Professor Medicine & Dir MCH Diabetes Center Department Internal Medicine, Div. Endocrinology Texas Tech University Health Science Center Odessa, Texas Hypogonadism or Life Style? “Low T:” Causes of Hypogonadism Klinefelter syndrome Kallmann syndrome Infiltrative diseases Pituitary disorder Autoimmune syndromes Radiation Tumors, head trauma Defects in androgen synthesis or action Cryptorchidism Testicular trauma Aging Obesity Type 2 Diabetes Medications: Opioids Glucocorticoids Ketoconazoles Petak SM, et al, 2002 update. Endocr Pract. 2002;8(6):440-456 Seftel A. et al, Int J Impot Res. 2006;18(3):223-228 Conditions Associated with Hypogonadism HIV-associated wasting End-stage renal disease COPD Infertility Osteoporosis Anemia Coronary artery disease Prostate cancer 1. Orwoll E, et al. Arch Intern Med 2006;166:2124–2131 2. Amin S, et al. Am J Med 2006;119:426–433 3. Ferrucci L, Maggio M, Arch Intern Med 2006;166:1380–1388 4. Ding EL, Song Y, JAMA 2006;295:1288–1299 5. Shores MM, et al. Arch Gen Psychiatry 2004; 61:162–167 6. Moffat SD, Zonderman AB, J Clin Endocrinol Metab 2002;87:5001–5007 7. Hak AE, Witteman JC, J Clin Endocrinol Metab 2002;87:3632–3639 8. Bhasin et al. J Clin Endocrinol Metab 2006;91:1995-2010 Symptoms of Low Testosterone Decreased energy or vitality, increased fatigue Reduced libido and sexual activity Erectile dysfunction Reduced muscle mass and strength Increased Fat mass Low bone mass Depression Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010 Observations Prevalence of hypogonadism in men ≥45 yr is estimated at 12-38%1,2 Hypogonadism increases with3 Age Obesity Diabetes 1Mulligan T, et al. Intl J Clin Practice. Jul 2006;60(7):762-769. SM, et al. J clin endocrinol metab. Feb 2001;86(2):724-731. 3Dhindsa S, et al. Diabetes care. Jun 2010;33(6):1186-1192. 2Harman Observations Testosterone replacement decreases1-5 TC:HDL ratio Weight Waist circumference Insulin levels Insulin resistance CRP 1Baillargeon J, et al. Ann pharmacotherapy. Jul 2 2014;48(9):1138-1144. 2Jones TH, et al. Diabetes care. Apr 2011;34(4):828-837. 3Kalinchenko SY, et al. Clin Endocrinolo. Nov 2010;73(5):602-612. 4Svartberg J, et al. J Int. Med. Jun 2006;259(6):576-582. 5Aversa A, et al. J Sex. Med Oct 2010;7(10):3495-3503. Background….. Over the last 10 years there has been a great increase In the number of men treated with testosterone for hypogonadism Rx have increased 500% s/p TV ads about “Low-T” So, now the FDA issues warnings about testosterone therapy…What’s the data? Is it safe? Who should be treated? Goal: Review the studies on testosterone replacement therapy and cardiovascular outcomes Setting the Stage for the Current FDA Recommendations “Testosterone in Older Men with Mobility Limitations” was a randomized control study1 Qu: Will testosterone therapy improve leg strength in elderly, frail men with hypogonadism and multiple comorbidities (diabetes, obesity, HTN, lipids) Enrollment never completed because there was a suspicion of increased adverse cardiovascular “like” events in the testosterone-treated group Basaria, S., et al. N Engl J Med 2010;363:109-122. Setting the Stage for the Current FDA Recommendations Examination 55,593 insurance claims by Finkle et al.1 Qu: What is the incidence of MI at 90 days after the initial Rx for testosterone? Results: Increased risk non-fatal MI men <65 with preexisting heart disease Problems: No control group No data on testosterone levels pre- or post Rx No data on cardiac risk factors in treated men 3 months is inadequate for a cardiovascular study 1Finkle WD, et al. 2014. PLoS ONE 9(1): e85805. DOI:10.1371/journal.pone.0085805 Longitudinal Observations There are no randomized control trials that address the question: Does testosterone replacement therapy change cardiovascular outcomes? However, there are many studies reporting the association of hypogonadism with increased cardiovascular events1-7 1Mulligan T, et al. Intl J Clin Practice. Jul 2006;60(7):762-769. SM, et al. J clin endocrinol metab. Feb 2001;86(2):724-731. 3Dhindsa S, et al. Diabetes care. Jun 2010;33(6):1186-1192. 4Laughlin GA, et al. J Clin Endocrinol Metabol Jan 2008;93(1):68-75. 5Tivesten A, et al. J Clin Endocrinol Metab Jul 2009;94(7):2482-2488. 6Yeap BB, et al. J Clin Endocrinol Metab . Jul 2009;94(7):2353-2359. 7Malkin CJ, et Heart. Nov 2010;96(22):1821-1825. 2Harman Association of Low Testosterone with Cardiovascular Events &/or All-Cause Mortality Author Sample Age Duration size (average) yrs T level (ng/dL) HR death or Risk death Laughlin1 794 50-90 (74) 20 240 1.4 Tivesten2 3014 (75) 4.5 25%’ile 65% † Yeap3 3443 >70 3.5 25%’ile 1.99 Haring4 1954 20-79 7.5 <250 2.3 1Laughlin GA, et al. J Clin Endocrinol Metab. Jan 2008;93(1):68-75. 2Tivesten A, et al. J Clin Endocrinol Metab. Jul 2009;94(7):2482-2488. 3Yeap BB, et al. J Clin Endocrinol Metab. Jul 2009;94(7):2353-2359. 4Haring R, et al. Euro Heart Journ. Jun 2010;31(12):1494-1501. Association of Low Testosterone and Mortality In Men with Heart disease and/or Diabetes Author Sample size Ponikowska1 153 65 +/-9 Malkin2 930 61 +/-9 T level (ng/dL) HR death or Risk death 2 240 140% † 6.9 <230 127% C Age Duration (average) yrs Araujo3 16,181 61 yrs Meta-analysis, (all cause †) 11 studies average 300-600 Increasing † 9.7 as T declines Araujo3 Meta-analysis, 11,831 (CV †) average 300-600 Increasing † 9.7 as T declines Corona4 70 meta analyses 1Ponikowska 61 yrs 7 studies Increasing † as T declines B, et al. Intl J Cardiol. Sep 3 2010;143(3):343-348. CJ, et al. Heart. Nov 2010;96(22):1821-1825. 3Araujo AB, et al. J Clin Endocriol Metab Oct 2011;96(10):3007-3019. 4Corona G, et al. Eur J Endocrinol /Eur Fed of Endo Soc. Nov 2011;165(5):687-701. 2Malkin Low Testosterone and Artherosclerosis Low testosterone is associated with increased atherosclerosis elderly men1 Low free testosterone is associated with increased carotid intimal-medial thickness2 Low total testosterone is associated with increased with age-adjusted carotid intimal-medial thickness3 1Hak AE, et al (Rotterdam Study Group) J Clin Endocrinol Metab Aug 2002;87(8):3632-3639. 2Fukui M, et al. Diabetes care. Jun 2003;26(6):1869-1873. 3Farias JM et al. J Clin Endocrinol Metab 2014 Dec;99(12):4698-4703 Randomized Trials of Testosterone Therapy No difference in cardiovascular events was reported in two small randomized control studies on testosterone Therapy (topical gel or intramuscular injection) to increase muscle strength and body composition1-4 Note: These studies addressed the effects of replacement therapy on muscle strength and body composition These studies were not powered to determine if testosterone causes adverse cardiovascular outcomes 1Srinivas-Shankar, U., et al. J Clin Endocrinol Metab 2010;95:639-650. 2Snyder, P.J., et al. J Clin Endocrinol Metab 1999;84:2647-2653. 3Jones TH, et al. Diabetes care. Apr 2011;34(4):828-837. 4Gianatti, E.J. et al. Diabetes Care 2014;37(8):2098-2107. Retrospective Studies on Testosterone Therapy Mortality in middle age and elderly men1 Mortality @ 3 yr Testosterone therapy (n=398) 10.3% No therapy (n=633) 20.7% Mortality in men with diabetes2 Testosterone therapy (n=64) No therapy (n=174) 8.4% 19.2% Medicare review3 Outcome Testosterone therapy (n=6,355) No increased No therapy (n=19,065) risk MI 1Shores MM, et al. J Clin Endocrinol Metab Jun 2012;97(6):2050-2058. 2Muraleedharan V, et al. Euro J Endocrinol / Euro Fed Endo Soc. Dec 2013;169(6):725-733. 3Baillargeon J, et al. Ann Pharmacotherapy. Jul 2 2014;48(9):1138-1144. Meta-analyses on Testosterone Therapy Corona et al1 completed a meta-analyses of 75 randomized, placebo-controlled studies Qu: What is the incidence of major CV events? Result: No difference in CV events between testosterone and placebo therapy Similar results have been reported by other Investigators2-5 1Corona G, et al. Expert Opin Drug Saf 2014;13:1327-1351. 2Calof, et al. J Gerontol A Biol Sci Med Sci 2005 60:1451-1457. 3Haddad, R.M. et al. Mayo Clin Proc 2007;82:29-39. 4Fernandez-Balsells, et al. J Clin Endocrinol Metab 2010;95:2560-2575. 5Xu, L., et al. BMC Med 2013;11:108. Does Testosterone Replacement Therapy Increase Cardiovascular Events? We will find out…..Testosterone Trial is underway! Funded by National Institutes of Health Hypothesis: Testosterone replacement therapy in men >65 yr with documented low testosterone, compared to placebo, will: improve physical, sexual and cognitive function improve vitality, low hemoglobin Decrease cardiovascular disease and diabetes 1ABOUT THE TESTOSTERONE TRIAL. http://rt5.cceb.upenn.edu/portal/page/portal/TTrial%20Portal/T-Trial%20Public%20Page%20-%20About What’s New? 2015 ENDO Endocrine Society No increased risk venous thrombosis in hypogonadal men treated with testosterone (n=102,650) versus no testosterone (n=102,650) No major adverse cardiovascular events in men treated with testosterone with documented coronary disease or recent ACS 2015 American College Cardiology No increased cardiovascular risk among testosterone users…. actually testosterone was cardioprotective Clinical Recommendations Who are Candidates for Testosterone Replacement Therapy? FDA: Testosterone is approved to treat hypogonadism due to testicular, pituitary or other CNS conditions leading to hypogonadism Testosterone is not approved to treat age-related declines in testosterone Testosterone is not approved to treat conditions like: Obesity, sexual dysfunction, depression Endocrine Society: Do not treat without biological evidence of low testosterone What is Biochemical Evidence for Testosterone Replacement Therapy? Lab Order total and free testosterone by “LC/MS” LC= liquid chromatography MS=mass spectroscopy Need sequential 2 morning (7-10 AM) studies demonstrating low testosterone on both tests Interpretation: Use the normal ranges indicated by the lab Our lab: total testosterone is 350 -1198 free testosterone is 52- 208 In our clinics we use the free testosterone value for Dx Universal Screening of Testosterone Levels is Not Recommended Endocrine Society does not recommend routine laboratory screening for low testosterone Serum testosterone should be measured in men with signs and symptoms of androgen deficiency History Proven stud, trauma, diabetes, autoimmune disease, infection, etc. Physical Examination Development, 2nd sex features, testicular volume/consistency, etc ADAM question survey symptoms1 1Morley JE, et al Metabolism 2000;49(9):1239-1242 Low Testosterone: To Treat or Not to Treat? Rule out reversible causes of low testosterone Examples: Obesity? For every 5% decrease in weight, testosterone increases ~50 ng/dL Opiates? Vicodin, Lortab, morphine… all narcotics suppress testosterone to low levels! Low T: Are Other Studies Needed? Qu: Measure prolactin? Should an MRI be obtained? Evaluate all anterior pituitary hormones? Is a DEXA scan needed? Ans: OK to measure PRL IF total testosterone is 150 ng/dL Get MRI Check anterior pituitary hormones Do DEXA scan Goals for Testosterone Therapy Therapeutic target should be a T level in mid-normal for healthy young men Total Testosterone ~550-750ng/dL Free Testosterone >52 Also important is the ratio of testosterone to estrogen Males often increase their dose…. Wrong! Too high testosterone levels decrease libido, etc If total testosterone is ~700, estrogen should be ~30 AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.pdf. How Much Testosterone1? FDA 200 to 800 mg IM per month 200 mg IM every 10-14 days (300 mg every 3 weeks?) Something to consider… Sometimes more frequent lower doses are more effective (that T:E ratio).... 100 mg IM q wk 40mg IM twice-weekly? FYI: Therapeutic replacement doses do not cause gynecomastia 1Testosterone cypionate IM injection What to Monitor? Testosterone level Hct PSA DRE Dex Baseline X X X X X 3 month X X X annual X X (X) (X) When to be Concerned… Hct >54 PSA velocity change >0.4/yr Sleep apnea OSA Cardiovascular changes CHF, etc AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.pdf. How Does Testosterone Affect PSA and Prostate? Testosterone replacement increases PSA about 30% or back to normal levels Testosterone replacement will increase prostate volume about 15% Testosterone replacement does not cause prostate cancer (It can accelerate metastatic prostate cancer) Case 54 yr old man presents with CC of fatigue, loss libido, erectile dysfunction with an unsatisfactory response to sildenafil 100 mg PMHx: T2D, HTN Meds: Lisinopril 10 mg bid Metformin 1500 mg HS Simvastatin 40 mg QOD PE VS: BP 145/90 BMI 34 No gynecomastia Testicular vol 20 ml, normal DRE Lab Normal CMP, CBC, non-HDL 98 A1C 6.9% T 220 ng/dL (280-1000) FT 33 pg/ml (35-155) LH 4.5 IU/L (2-12) FSH 6.3 IU/L (1-12) What is the next step in this patient’s evaluation? Questions…. 1. Is this patient hypogonadal? 2. Would you treatment with testosterone? 3. Should Prolactin be measured? 4. Should other anterior pituitary hormones be measured? 5. Should MRI of pituitary be done ? 6. Should bone mineral density be measured? Just for FYI: What About High Testosterone? Interesting Facts A pro bodybuilder spends $2,000 to $5,000 a week on drugs during a competition cycle. Health issues and deaths associated with bodybuilders are related not to steroids, but: a. Recreational drug use b. Diuretics and insulin Moderate and High Dose Steroid Regimens How to “Juice” Week 01-10 Testosterone enanthate IM Moderate 750mg/wk High 1000-1200 01-10 Boldenone undeclynate IM 01-10 Trenbolone enanthate IM 800mg/wk 600mg/wk 1000 800 50mg/d 100 01-08 Dianabol PO, IM 10-16 Testosterone prop IM 100mg/qod 100mg/d 10-16 Trenbolone Acetate IM 100 mg/qod 100mg/d 10-16 Masteron propionate IM 50mg/qod 100mg/d 10-16 Winstrol PO, IM 50 mg/d 08-16 Cytomel 12-16 Halotestin PO PO 25mcg/d 10mg/d 30mg Relative Activities of Steroids Dihydrotestosterone Testosterone Boldenone undeclynate Trembolone Dianabol Masteron Winstrol Halotestin Androgenic 500 100 50 500 40 25 30 850 Anabolic 500 100 100 500 200 60 350 1900 Major Steroids for Juicing Boldenone undeclynate (AKA EQ, Ganabol) Originally vet drug used to treat horses (anemia) Now available only from South america Testosterone derivative: double bond C1-2: Not aromatized: no gynecomastia, no virilization Juicers use it to build bulk Trenbolone acetate and enanthate As potent as DHT Vet product (pellet) implanted in cattle Goal: Bigger, Leaner Steaks! Major Steroids for Juicing Trenbolone acetate and enanthate, cont. #1 Favorite anabolic steroid! 19-nortestosterone: Double bond C9-11 Increases androgen receptor binding Inhibits aromatizing Increases IGF-1 Juicers use it to build bulk, build strength Side effects: Acne, hair loss, low testosterone Low HDL, high LDL Major Steroids for Juicing Dianabol 2nd steroid synthesized (testosterone was 1st) 17 alpha alkyl derivative of testosterone: Oral or injection Rapid onset 6 hrs Juicers use it for “cutting” (i.e. cut fat, preserve muscle) PROBLEM: Hepatoxic, HTN Major Steroids for Juicing Masteron (Drostanolone) Original use was for treating breast cancer Effective with temoxifen Only anabolic with anti-estrogen properties Juicers use it to “cut” Winstrol (Stanozolol) 17-alkyl derivative of testosterone: Anabolic PROBLEM: Liver Toxicity Originally used to treat anemia (increases Hct) Increases appetite, bone density Weak conversion to estrogen Juicers use it for “cutting” Major Steroids for Juicing Halotestin Most powerful anabolic and andogenic steroid Testosterone derivative: Oral drug 5 mg tablets Original use: Induce puberty in teen males Tissue/burn repair Bone fractures and osteoporosis Malnutrition, glucocorticoid wasting, anemia Breast cancer (anti-estrogen effects) Juicers use it for cutting: High fat loss! PROBLEM: “Only steroid that can cause death” “Aggression Drug” Extra Juice for the “Big Boys” Insulin Pre-workout Beginning dose 10 units + Plazma (drink) “Crazy juicers” 100 units insulin + 10,000 calories p.o. intake GH Beginning dose 6-12 units every day weeks 1-16 “Crazy juicers” 30 units every day Credits Literature review on atherosclerosis, mortality, cardiovascular risk and meta-analyses Hans S. Sartaj MD1 Sandeep Dhindsa, MD2 William C. Little, MD3 Rama Chemitiganti, MD4 1,3Division 2,4Division Cardiology, Dept Medicine, Univ Mississippi Med Ctr, Jackson MS Endocrinology and Metabolism, Dept Medicine, Texas Tech University Health Sciences Center-Permian Basin, Odessa TX