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Male Hypogonadism and Testosterone Replacement

Male Hypogonadism and Testosterone Replacement. John W. Ragsdale, III, MD Associate Professor July 11 2019. Goals and Objectives. Review basic testosterone bio-physiology Evaluate current guidelines Review the evidence around the risk and benefits testosterone therapy

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Male Hypogonadism and Testosterone Replacement

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  1. Male Hypogonadism and Testosterone Replacement John W. Ragsdale, III, MD Associate Professor July 11 2019

  2. Goals and Objectives • Review basic testosterone bio-physiology • Evaluate current guidelines • Review the evidence around the risk and benefits testosterone therapy • Discuss initiation and surveillance of testosterone therapy • Consider the prostate and testicular cancer survivor

  3. Have you been asked about testosterone therapy?Are you comfortable knowing/explaining the risks and benefits?Do you feel comfortable managing male hypogonadism?

  4. Annual testosterone drug revenue in the U.S. in 2013 and 2018 (in billion U.S. dollars) Note: United States; 2013 and 2014 Further information regarding this statistic can be found on page 8. Source: Time ID 320301

  5. external genitalia/ prostate gland /sexual hair/baldness epiphyseal closure and bone length/strength conversion to dihydrotestosterone Conversion to Estradiol Kidney for Erythropoietin Production 5 alpha reductase Aromatase Testosterone Conversion to Estradiol Aromatase Lean muscle mass normal sexual function decrease body fat

  6. Screening 

  7. Screening Guidelines • Recommends against universal  screening  • Screen only men with symptoms AND signs consistent with testosterone deficiency • Screen only men unequivocally and consistently low serum T concentrations • 250-300 ng/ dL • Recommend repeated morning fasting concentrations (caveat to this coming up) • Discuss risks and benefits in men over 65  • Check FSH & LH initially : Why?

  8. Signs Mild anemia Decreased spontaneous erection Gynecomastia Small/shrinking testes Infertility/low sperm count Height loss  Increased body fat, BMI

  9. Symptoms Symptoms: • Decreased energy, motivation, self confidence • Feeling sad or blue • Poor concentration • Sleep disturbance • Reduced muscle tone/strength • Reduced sexual desire • Breast discomfort

  10. Screening Testosterone Deficiency In defense of Screening • The Hypogonadism in Males study evaluated 2,162 men in primary care outpatient practices and found that 38.7% of men 45 years and older had hypogonadism. • T levels inversely related to glucose intolerance and DM and metabolic syndrome (The Massachusetts Male Aging Study) • BACH survey found that only 12% of symptomatic men with hypogonadism were being treated Obtained from Heidelbaugh, AAFP editorial Vol 91, No 4 Feb 2015

  11. Why morning & fasting levels? • It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level? • So according to an article in JPF in 2015– probably not for men over the age of 45

  12. Primary Vs. Secondary Failure:Organic Causes  • Primary (testicular) • Low Testosterone • High FSH & LH • Causes • Male Menopause • 5 alpha reductase deficiency • Klinefelter’s • Alcohol • Secondary (Central) • Low testosterone • Low FSH & LH • Causes • Pituitary Adenoma • Kallman Syndrome • Intracranial radiation • Pituitary surgery

  13. Primary Vs. Secondary Failure:Functional Causes • Primary (testicular) • High FSH & LH • ESRD • Medications • Secondary (Central) • Low FSH & LH • Hyperprolactinemia • Opioids, alcohol, THC • Severe obesity • Comorbidities

  14. The test: Testosterone: What exactly is “Free and Total" ?

  15. Diagnosis • Only make diagnosis with consistent signs and symptoms • At least 2 morning fasting levels drawn before 10 am which are unequivocally low • (? Need of morning fasting in men over 45) • Not to be made during an acute illness • FSH and LH can be helpful

  16. Special Populations • Long term use of opiates especially methadone, suboxone • Suppress the hypothalamic/pit- gonadal axis • Long term can lead to osteoporosis • GnRH analogs (androgen deprivation therapy e.g. Lupron) • Increased risks of fatigue, fractures, CV events, diabetes • HIV

  17. Special Populations: Older Men (>50) • Ok to Offer men with symptoms and low testosterone a course of treatment • Not ok to offer older men with low T and no particular symptoms (again – no universal screening) • Discuss the uncertainty of benefit in these men depending on their symptoms

  18. Special Populations: middle aged men looking for fountain of youth • A single and not repeatedly low testosterone is NOT sufficient for a diagnosis • Do not prescribe on a trial basis (post-treatment hypogonal status can be harrowing) • Long term therapy may lead to testicular atrophy and / or decreased spermatogenesis / loss of fertility

  19. Testosterone Replacement Therapy: what is does…

  20. Best Study to Date: Effects of Testosterone Treatment in Older Men • In symptomatic men raising testosterone levels for 1 year from moderately low to mid-normal range for men 19-40 improved • Sexual function –modest benefit which waned • Mood – small gains • Depressive symptoms – small gains • Did not improve • Vitality • Walking distance • Number of participants too few to draw conclusions about risks Snyder PJ etal, NEJM, Vol 374 No 7 Feb 2016 pp 611-624

  21. Best Study to Date: Effects of Testosterone Treatment in Older Men • Limited number of patients make it hard to generalize results • Cannot assume benefit or lack of benefit • Cannot assume adverse event profile would be different in • Younger men • Men with higher testosterone levels • Different clinical characteristics Snyder PJ etal, NEJM, Vol 374 No 7 Feb 2016 pp 611-624

  22. Clinical Benefits • Virilization / sexual function • Muscle strength/fat free mass: increased bench press by 22%, squat strength by 45%, fat free mass increased by 5% • Bone Density : average increase of 30% in a study of 72 men

  23. Testosterone and Cardiovascular Disease Robert A. Kloner, MD, PHD,a,b Culley Carson III, MD,c Adrian Dobs, MD,d Stephen Kopecky, MD,eEmile R. Mohler III, MDf J Amer Col Card VOL . 6 7 , NO . 5 , 2 0 1 6

  24. ED & Testosterone Replacement • Testosterone supplementation does not improve the response to sildenafil (Viagra) in men with erectile dysfunction and low testosterone levels • Level of evidence 1 B • Unknown whether testosterone replacement alone is as effective as sildenafil for the treatment of erectile dysfunction

  25. CV risk and testosterone: controversy rages on • Patients with coronary artery disease had lower T levels than controls • Rosano GM, Sheiban I, Massaro R, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. IntJImpot Res 2007;19:176–82 • Study observed that both serum T levels and SHBG levels were inversely related to the incidence of adverse major CV events • Ohlsson C, Barrett-Connor E, Bhasin S, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol 2011;58:1674–81 • Observed a significant negative correlation between the level of total T and the Framingham Risk Score. • Lee WC, Kim MT, Ko KT, et al. Relationship between serum testosterone and cardio-vascular disease risk determined using the Framingham Risk Score in male patients with sexual dysfunction. World J Men's Health 2014;32:139–44

  26. CV Risk and Testosterone • Adverse Effects of Tesoterstone Administration Basaria S, Coviello AD, Travison TG, et al.Adverse events associated with testosterone administration. N Engl J Med 2010;363:109–22 • Stopped early (23 CV events vs. 5 in Placebo) • Limitations: older men with limitations in mobility and high disease burden • Small sample size made broader inferences about safety impossible

  27. CV Risk and Testosterone • Association of testosterone therapy with mortality,  myocardialinfarction, and stroke in men with low testosterone levels. Vigen R, O’Donnell CI, Barón AE, et al. JAMA 2013;310:1829–36. Three year study  • Retrospectivecohort analysis of men with low T levels(<300 ng/dl) who underwent coronary angiograms in the Veterans Affairs system. • Primary outcome: MI, mortaility oand Stroke • Results: 19.9% in the No-T group, 25.7% • BUT: Raw data showed an event rate of less than half of the group receiving T therapy .

  28. CV Risk and Testosterone • Cohort study of 1031 males >40 with testosterone less than 250ng/dl and no history of prostate cancer were followed for 4 years • Mortality in T-treated men was 10.3 % • Mortality in undertreated men 20.7% • Shores  MM, Smith  NL, Forsberg  CW, Anawalt  BD, Matsumoto  AM.  Testosterone treatment and mortality in men with low testosterone levels.  J Clin EndocrinolMetab. 2012;97(6):2050-2058.

  29. Trials on Either side, In short – the jury in still out. We need a large RCT to help clarify what is best.

  30. Contra-Indications

  31. Contra-indications to starting Testosterone therapy • Palpable Prostate nodule • Those with Active breast or prostate Cancer • PSA over 4 • PSA greater than 3 in high risk men • AAM, first degree relative with prostate caner • Hct over 50% • Untreated severe sleep apnea • Uncontrolled or poorly controlled heart failure • Those desiring fertility

  32. Contra-indications to starting Testosterone therapy • Significant bother LUTS IPSS (international prostate symptoms score) score greater than 19 • Men with Low testosterone owing to nothing: (e.g. follow up from a random testosterone screen from another source) with repeatedly normal values subsequently

  33. Testosterone replacement therapy and Prostate Cancer • Metastatic prostate Cancer… contraindicated • BUT H/o prostate cancer • Greater than 5 years out from completion of treatment • Confirmed PSA <0.1 for the duration • Clear conversation and informed decision making – patient preference and desires

  34. Men/survivors of other cancers • There is no consensus in the literature and therapy should be applied on individualized basis across all cancer diagnoses • Testicular cancer: in most patients: after 5 years are considered “cured” and a trial of testosterone therapy with markers and symptoms we‘ve already reviewed can be considered

  35. Risks of Testosterone Therapy • Elevated hematocrit, hemoglobin • Slight decrease in HDL • Significance of these findings is not currently known

  36. Getting Started Meds and Options

  37. Formulations Skin patch (transdermal): Androderm is a skin patch worn on the arm or upper body. It's applied once a day. Gels: AndroGel and Testim come in packets of clear testosterone gel. AndroGel, Axiron, and Fortesta also come in a pump that delivers the amount of testosterone prescribed by your doctor. Natesto is a gel applied inside the nose. Mouth patch Injections and implants: both formulations exist… Pills out of favor due to hepatotoxicity

  38. How to Get started: initial therapy • 5 – 10 grams of 1% gel applied daily (1-2 pumps) upper arm / torso) • Allows for relatively stable concentrations • Patient preferred • May be higher cost

  39. Surveillance What do you need to look out for?

  40. Surveillance • Visits every 3-6 months • Maintain levels at mid-normal range • 400-700 ng/dl one week after injection • Bone mineral density every 1-2 years • DRE annual at 50 for avg. risk • DRE starting 40 for higher risk • Fam Hx Pros Ca, AA

  41. Testosterone Surveillance: Particular • If receiving injections: • Check midway and value should be mid normal (500-600) • With transdermal • Measure any time • Gel: results can vary, check it twice at different times of the day

  42. Surveillance: labs to be drawn every 6 months for one year, then annually • CBC • PSA • LFTs: testosterone is metabolized here • Testosterone Free and Total

  43. Red/yellow flags (likely need consultation • Serum rise in PSA 1.5 or greater in 12 months • Abnormal DRE (must do DRE every year)

  44. Things to include in your note for surveillance • Worsening LUTS – ask about BPH symptoms • Use the IPSS in your note (?) • Worsening apnea (although OK to take testosterone if on CPAP • BMD every 2-3 years

  45. Treatment endpoint • Maintain secondary sexual characteristics • Improvement of sexual function • Sense of well being • Bone mineral density • T levels in the mid-normal (400-700)

  46. Summary/ Conclusions • Testosterone has a role in therapy of true symptomatic hypogonadism in both young and older men • There appear to be no major concerns for using T in young, healthy men with specific indications for TRT. • The use of T in older men and those with known coronary artery disease is controversial. • Asymptomatic, middle-aged and older men without a history of heart disease should be counseled about the uncertain CV risk

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