Testosterone: Screening Older Men. Kenneth Lin, MD, MPH 40 th Fall Temple Review Course November 8, 2016

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1 Testosterone: Screening Older Men Kenneth Lin, MD, MPH 40 th Fall Temple Review Course November 8, 2016

2 Disclosure Statement I have no relevant financial relationships with any commercial interests to disclose.

3 Learning Objectives Following completion of this lecture, participants should be able to: Distinguish low-t from male hypogonadism. Weigh pros and cons of measuring testosterone levels in otherwise healthy older men. Identify gaps in the evidence about benefits and harms of testosterone supplements.

4 Case study A 70-year old male Presidential candidate with obesity and hyperlipidemia has a total testosterone level of 441 obtained during a health maintenance examination. During a previous televised debate, he vehemently denied any decreased libido or erectile dysfunction. Should this patient s testosterone level have been checked in the first place?

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7 Why screen for any disease? Common, morbid disease Significant effect on quality or length of life Acceptable and effective treatment Better outcomes if treatment begun prior to onset of symptoms Sensitive, specific, noninvasive test Harms of screening and treatment are outweighed by benefits

8 Physiology of hypogonadism in men Testosterone produced in the testes in response to luteinizing hormone (LH) produced by the pituitary gland Primary hypogonadism: failure of testes to produce sufficient testosterone Secondary hypogonadism: decreased LH production Mixed: elements of both primary and secondary

9 Symptoms of male hypogonadism In adolescents & young adults: Appear younger than chronologic age Small testes and penis Delayed puberty Difficulty gaining muscle mass In adult men: Decreased vigor and libido Depressed mood Decreased bone density and muscle mass

10 Acquired causes of primary and mixed hypogonadism Cancer Chronic glucocorticoid use Cirrhosis Chronic kidney disease COPD Diabetes HIV Hypothyroidism Orchitis/epididymo-orchitis Radiation to testes Testicular torsion or trauma

11 Low-T : is there a syndrome of testosterone deficiency in older men? Serum total and free testosterone levels decrease with advancing age In European Male Aging Study, 0.4% and 1.3% per year, respectively In Baltimore Longitudinal Study of Aging, T<325 ng/dl in 20% of men in 60s, 30% of men in 70s, 50% of men in 80s Low testosterone in older men has been associated with Decreased sexual function, bone mineral density, muscle mass & strength, hemoglobin, mood, cognitive function Obesity, higher insulin concentrations, metabolic syndrome, increased mortality

12 Benefits of testosterone supplements in men with low-t in 156 RCTs Cardiovascular health Mixed effects on angina, heart failure symptom scores, lipid profiles Sexual function Mixed effects on libido, erectile dysfunction, satisfaction Bone mineral density Increased at L-spine but not hip, no effect on fractures Muscle weakness/wasting Increased lean muscle mass but no effects on strength, function, or falls Mood and behavior Most studies showed no effect Cognitive function No effect

13 Limitations of existing RCT evidence base Small sample sizes Inclusion of men with many different causes of low T, including older age Inclusion of men with low-normal T levels Variable testosterone regimens In 2015, FDA clarified that approval for testosterone supplements is limited to men with hypogonadism due to known causes (other than aging)

14 Testosterone Trials Set of 7 RCTs initiated in response to 2003 IOM panel s recommendation to determine whether testosterone would benefit older men who had low testosterone levels for no known reason other than age and who had clinical conditions to which low testosterone might contribute Designed to assess effectiveness of T, not adverse events including CV events Initial results from Sexual Function, Physical Function, and Vitality trials published in Feb Awaiting results from cognitive function, anemia, bone density, cardiovascular status trials

15 Initial Testosterone Trials results More than 51,000 men screened to enroll 790 men over age 65 with T <275 ng/dl and evidence of sexual dysfunction, physical dysfunction, and/or reduced vitality Intervention arm received 12 months of T gel therapy to increase T levels to mid-normal range for men aged Compared to placebo group, T group reported Modest increases in sexual activity, sexual desire, and erectile function No difference in walking distance on 6-min walk test No benefit on vitality, but slightly better mood and lower severity of depressive symptoms

16 Risks of testosterone supplements (RCTs + observational studies) Lower urinary tract symptoms (LUTS) No incr. risk Prostate cancer Existing PrCa is absolute contraindication to Tx Small PSA increases, questionable significance Polycythemia Incr. risk if baseline Hct >50% Venous thromboembolism No incr. risk Cardiovascular events (next 2 slides)

17 Do testosterone supplements increase risk of cardiovascular events? (I) Dec Testosterone in Older Men with Mobility Limitations (TOM) trial halted by data & safety monitoring board 209 men enrolled, mean age 74 High prevalence of HTN, DM, HLD, obesity at baseline 23 subjects in testosterone group, vs. 5 in placebo group, had CV adverse events 2013 meta-analysis of 27 RCTs Overall OR 1.54 for CV events in patients using T (Number needed to harm = 90) In pharma-funded trials: OR 0.89 (0.50, 1.60) Non-pharma-funded trials: OR 2.06 (1.34, 3.17)

18 Do testosterone supplements increase risk of cardiovascular events? (II) 2014 cohort study of risk of MI using national claims database 55,000 men who filled a first Rx for testosterone compared to 167,000 men who filled a first Rx for PDE5-inhibitor In men >65, RR = 2.19 (1.27, 3.77) during first 90 days after filling Rx 3/ FDA required labeling change to reflect possible incr. risk of MI and stroke

19 FPs should not screen for testosterone deficiency in older men (SOR: C) Low T is associated with multiple symptoms & chronic conditions, but uncertain if causative or merely marker of poor health (SOR: C) Benefits of T supplements are mixed or unproven in men with age-related low T, even if symptoms of hypogonadism are present (SOR: B) In Testosterone Trials, average improvement in erectile dysfunction was less than that typically resulting from PDE-5 inhibitor therapy Screening may lead to net harm even if treatment works, due to potential adverse effects (SOR: C) Polycythemia Cardiovascular events (MI & stroke)

20 References Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363; Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014;9:e8505. Fugh-Berman A. Should family physicians screen for testosterone deficiency in men? No: screening may be harmful, and benefits are unproven. Am Fam Physician 2015;91: Heidelbaugh JJ. Should family physicians screen for testosterone deficiency in men? Yes: screening is worthwhile for most older men. Am Fam Physician 2015;91: Huo S, Scialli AR, McGarvey S, et al. Treatment of men for low testosterone : a systematic review. PLoS ONE 2016;11:e Petering R, Brooks N. Testosterone therapy: review of clinical applications. Am Fam Physician 2016; in press. Snyder PJ. Clinical features and diagnosis of male hypogonadism. UpToDate, Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med 2016;374:

21 References - II Snyder PJ. Overview of testosterone deficiency in older men. UpToDate, U.S. Food and Drug Administration. FDA drug safety communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. Available at: Accessed 30 August Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008;93:2737. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013;11:108.

22 Thank you!