1. 1 Evaluation and Treatment of Hypogonadism in Older Men Alvin M. Matsumoto, M.D. Associate Director, GRECC V.A. Puget Sound Health Care System Professor, Department of Medicine University of Washington School of Medicine GRECC National Audio Conference May 29, 2008

2. 2 Male Hypogonadism  T LH / FSH GnRH T  Inhibin B  DHT  Sexual Development  Libido, Erections  Sperm Production  Bone,  Muscle,  Fat  Mood,  Cognition  Hair, Skin  T  Sperm  E 2  Fertility Androgen Deficiency Infertility

3. 3 Hypogonadism in Older Men Outline Prevalence Challenges –Clinical diagnosis –Biochemical diagnosis Treatment considerations Low testosterone (T) in older men Low T and clinical outcomes

4. 4 Androgen Deficiency A Common Disorder Pathological Klinefelter syndrome (47,XXY)1 in 500 men Functional  T with illness or drugs –Chronic renal, liver, lung disease, type 2 DM –Wasting (cancer, HIV), malnutrition, severe obesity –Drugs (opiates, glucocorticoids)  T with aging

5. 5 Prevalence of Low T in Aging Men (T < 2.5 Percentile of Young Men BLSA) SM Harman, et al, J Clin Endocrinol Metab 86:724-731, 2001

6. 6 Male Hypogonadism Diagnosis Clinical manifestations of androgen deficiency –Symptoms and signs Consistently low T level (biochemical androgen deficiency) –Reference normal range in younger men Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

7. 7 Androgen Deficiency Prevalence Biochemical^Clinical* Prevalence 9% 50-59 yrs12%6% 60-6919%11% 70-7928%23%  8048% ^ Total T < 345 ng/dL (BLSA) * Total T < 200 or free T < 8.9 ng/dL and ≥ 3 symptoms/signs (MMAS) Araujo A, et al, J Clin Endocrinol Metab 89:5920-5926, 2004 Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001

8. 8 Clinical Androgen Deficiency Challenges Symptoms and signs −Nonspecific presentation in adults Modified by –Age –Severity and duration of T deficiency –Co-morbid illness –Previous T treatment –Androgen sensitivity of specific target organs

9. 9 21 year-old man with infantile genitalia, delayed growth, high-pitched voice, no axillary and pubic hair, and T 30 ng/dL

10. 10 Prepubertal Androgen Deficiency Symptoms and Signs Delayed puberty −Delayed growth and sexual development Eunuchoidism −Infantile genitalia −Long arms and legs vs. height −  Muscle development,  fat,  peak BMD −High-pitched voice −Sparse axillary and pubic hair

11. 11 56 year-old man with  axillary and pubic hair, erectile dysfunction,  libido, gynecomastia, and T 100 ng/dL

12. 12 76 year old man with severe back pain from compression fractures, muscle wasting and weakness, and T 90 ng/dL

13. 13 Symptoms and Signs Suggestive of Adult Androgen Deficiency  Erections  Libido and sexual activity Gynecomastia  Axillary and pubic hair Infertility, low sperm count, small testes Low trauma fracture, low BMD  Muscle bulk and strength Hot flushes, sweats Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

14. 14 Symptoms and Signs Less Specific for Adult Androgen Deficiency  Energy, motivation Depressed mood Poor concentration and memory Sleep disturbance Mild anemia  Body fat  Physical activity Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

15. 15 Severe Androgen Deficiency in Older Men GnRH Analog or Orchidectomy Model  Erections, sexual activity and desire (libido)  Energy, motivation and mood, irritability,  QOL Sleep disturbance, hot flushes, sweats  Concentration and memory  Activity, muscle mass and strength, physical performance  Fat mass, insulin resistance (  DM and CVD)  BMD (  fracture) Gynecomastia,  body hair  Hemoglobin

16. 16 Multiple Factors Affecting Bone Mass and Fracture Risk in Older Men Genetics   BMD  Androgens  Estrogens  Calcium intake  Vitamin D Medications (e.g. glucocorticoids)  GH IGF-1  Activity Immobility Co-morbid illness Alcohol Smoking Malnutrition Fracture FallsTrauma Matsumoto AM, J Gerontol Med Sci 57:M76-M99, 2002

17. 17 Biochemical Androgen Deficiency Challenges Low serum total T level −Total T most common and available −Relative to normal range in young men (<280- 300 ng/dL but assay-to-assay variability) −T levels variable Morning, on at least two occasions If  SHBG suspected, free or bioavailable T level Illness, drugs, nutritional deficiency  transiently low T

18. 18 Day-to-Day Variation in T Levels In hypogonadal men with initial T < 300 ng/dL, 30% had normal T on repeat testing 1 In older men with initial T < 250 ng/dL –20% had average T > 300 ng/dL over 6 months –If average of two samples T 300 ng/dL 2 1 Swerdloff RS, et al, J Clin Endocrinol Metab 85:4500-4510, 2000 2 Brambilla DJ, et al, Clin Endocrinol (Oxf) 67:853-862, 2007

19. 19 Circulating Testosterone Bioavailable T Total T

20. 20 Testosterone Assays Affected by changes in SHBG –Total T –Free T by analog assay (~all clinical labs) Not affected by changes in SHBG –Calculated free T and bioavailable T from total T and SHBG –Free T by equilibrium dialysis –Bioavailable T by ammonium sulfate precipitation

21. 21 Common Alterations in SHBG Affect Total and Free T Analog Levels Estrogens HIV Anabolic steroids Acromegaly Anticonvulsants Glucocorticoids/progestins Hyperthyroidism Hypothyroidism Hepatitis, cirrhosis Low protein (nephrotic) Aging Moderate obesity  SHBG  Total T  SHBG  Total T Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

22. 22 Classification of Androgen Deficiency Challenges LH and FSH levels distinguish 1 O vs 2 O hypogonadism Combined 1 O and 2 O hypogonadism –Usually predominant hormonal pattern Discrepant  LH versus FSH may suggest a pituitary tumor

23. 23 Primary Hypogonadism  T  LH / FSH  GnRH T  Inhibin B  DHT  T  Sperm  E 2

24. 24 Causes of Primary Hypogonadism  T and  LH and FSH Pathological –Klinefelter syndrome –Myotonic dystrophy, developmental disorders –Orchitis, irradiation –Castration, trauma, anorchia –Drugs (cytotoxic, ketoconazole, spironolactone) Functional –Systemic disorders (chronic liver, renal disease)* –Aging* * Combined

25. 25 Secondary Hypogonadism  T Normal-  LH / FSH  GnRH T  Inhibin B  DHT  T  Sperm  E 2

26. 26 Causes of Secondary Hypogonadism  T and Normal or  LH and FSH Pathological –Kallmann syndrome, complex genetic disorders* –Hemochromatosis* –Hyperprolactinemia –Hypopituitarism (tumor, infiltration, destruction) Functional –CNS-active drugs (opiates) –Glucocorticoids*, estrogens/progestins, GnRH-A –Acute and chronic illness*, wasting –Nutritional deficiency, massive obesity –Aging* * Combined

27. 27 78 year-old man with weight loss, anorexia, weakness, slowed gait,  memory, osteoporosis,  T 30 ng/dL,  LH 45 IU/L and FSH 2 IU/L Patient GM Normal 27

28. 28 Secondary Hypogonadism Importance Pituitary-hypothalamic tumor mass effect Deficiency of other pituitary hormones Excessive pituitary hormone secretion Some causes treatable or reversible –Illness, malnutrition, medications Infertility treatable –Gonadotropin (or GnRH) therapy

29. 29 Diagnosis of Male Hypogonadism Summary Symptoms/signs of androgen deficiency −Sex (erections) −Brain (libido, mood, memory, hot flush/sweats) −Body (muscle, bone, breast and hair) Consistently low T level x 2 Free or bioavailable T, if suspect  SHBG R/o reversible illness, drugs, nutritional deficiency LH and FSH  1 O vs 2 O hypogonadism

30. 30 Male Hypogonadism Treatment Considerations Contraindications –Prostate or breast cancer Caution –Prostate nodule, unexplained  PSA > 3 –  Hct > 50% –Untreated sleep apnea –LUTS (IPSS > 19) –Severe unstable CHF (class III or IV) Benefits > risks? Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

31. 31 T Treatment Potential Benefits and Risks BenefitsRisks Sexual development  Erections  Libido, sexual activity  Energy, mood, vitality  Muscle strength  Physical function Erythrocytosis Acne  Sperm count Prostate biopsy Gynecomastia  Breast cancer (rare)  BMD  Sleep apnea (rare) Local (pain, skin rash) Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

32. 32 T Formulations Intramuscular T –Extensive experience, inexpensive –High-normal T, fluctuations in mood or libido, pain T Patch –Low-normal T, skin irritation, expensive T Gel –Low- to high-normal T, flexibility, no irritation –Contact transfer, expensive Buccal T – Twice daily, altered taste, gum irritation

33. 33 Male Hypogonadism Monitoring Efficacy –Clinical response –T  mid-normal range –DEXA Safety –Hct @ 3-6 mo (> 52%) –DRE (nodule, induration), PSA (> 4 ng/mL or  > 1.4 ng/mL) @ 3-6 mo, then as usual –LUTS (IPSS > 19) –Daytime somnolence, sleep apnea Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

34. 34 Longitudinal  T Levels with Age Testosterone (nmol/L) Age (Years) 10 12 14 16 18 20 30405060708090 (177) (144) (151) (158) (109) (43) Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001.

35. 35 Age-Related Changes in Body Composition Forbes GB, Metabolism 14:653-663, 1970

36. 36 Olympic Weight-Lifting Performance with Aging in Masters Athletes DE Meltzer, J Appl Physiol 80:1149-1155, 1996

37. 37 Age-Related Increase in Incidence of Prostate Cancer 1991-1995 SEER age-specific rates

38. 38 Prevalence of Histological Prostate Cancer Carter HB, et al, J Urol 143:742, 1990 20-40%

39. 39 T Levels in the Aging Male Age-related alterations associated with  T –  Muscle mass and strength, and  fat mass –  Bone density and  fractures –  Sexual function, energy, mood, cognitive function Similar changes in young hypogonadal men improve with T Does  T contribute to age-related alterations? Does T Rx of older men   function and clinical outcomes, and what are the risks? –CV and prostate disease?

40. 40 T Treatment of Older Men Evidence Base Short-term controlled trials in small #’s of healthy older men –Improved body composition –In some studies,  muscle strength, BMD, sexual function and cognition –  Hematocrit,  lipids or prostate disease No long-term controlled trials to assess clinical benefits and risks.

41. 41 S Page, et al, L Tenover, J Clin Endocrinol Metab 89:503-510, 2004 Effect of T Alone and T plus Finasteride on Lean Mass in Older Men Placebo T T + F           0 -1.6 -3.2 -4.8 2412036 Months  Fat Mass (kg)           0122436 0 3 4 1 2 5  Lean Mass (kg) Months   

42. 42  Physical Performance (sec)  Right Hand Grip Strength (kg) 1 0 2 0 2 4 6 Months 0122436 120 Months 2436 Placebo T T + F                         Effect of T Alone and T plus Finasteride on Physical Performance and Hand Grip in Older Men S Page, et al, L Tenover, J Clin Endocrinol Metab 89:503-510, 2004

43. 43 Androgen Deficiency in the Aging Male Limitations of T Treatment Trials Men not clinically or biochemically androgen deficiency T treatment  T levels too high or low Small numbers (under-powered) Short-term evaluation of surrogate outcomes Outcome measures not optimal Large multi-center, randomized, placebo- controlled trial x 1 yr in older hypogonadal men planned –Physical, sexual (cognitive?) function and vitality

44. 44 Androgen Deficiency in the Aging Male Associations with Clinical Outcomes In some studies, low T levels associated with important clinical outcomes –Metabolic syndrome and diabetes mellitus –Cardiovascular disease and mortality –Fractures, falls and physical performance –Depression, Alzheimer’s disease –Anemia UNKNOWN whether T treatment will improve or prevent these outcomes Ding EL, JAMA 295:1288, 2006; Khaw KT, Circulation 166:2694, 2007; Laughlin, JCEM 93:68, 2008; Meier C, Arch Int Med 168:47, 2008; Levy, Urology, 2008; Almeida, Arch Gen Psych 65:283, 2008; Moffat, Neurology 62:188, 2004

45. 45 Increased Mortality/4 Yrs in 858 Older Male Veterans (Mean Age 61) with Consistently Low T Shores MM, et al, Arch Intern Med 166:1660-1665, 2006

46. 46 Low Total T Levels Associated with Increased Mortality/12 Yrs in 794 Community-Dwelling Men (Mean Age 71) in Rancho Bernardo Laughlin GA, et al, J Clin Endocrinol Metab 93:68-75, 2008 370 241 288 338 422 209 266 288 507 171 Median Total T (ng/dL) Highest decile (reference) Lowest decile Median~300 ng/dL Hazards ratio 11.52

47. 47 Hypogonadism in Older Men Conclusions Common disorder Nonspecific clinical findings affected by age, severity and duration of  T and co- morbidities Diagnosis confirmed by repeated  T –Accurate free T, if  SHBG suspected –R/O reversible causes LH and FSH  1 o vs 2 o hypogonadism T treatment if benefits > risks Injectable, patch, gels, buccal T available

48. 48 Hypogonadism in Older Men Conclusions Careful but not excessive monitoring needed Larger short-term studies in older men are needed –Clinical and biochemical hypogonadism –Physiological T replacement –Robust and appropriate measures Long-term randomized trial of T in older hypogonadal men is needed to assess role of androgen deficiency on important clinical outcomes (e.g. CVD, DM, fractures, depression, dementia, prostate cancer)

49. 49 Male Hypogonadism References Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2006;91:1995-2010. –Available on The Endocrine Society web site: http://www.endo-society.org http://www.endo-society.org Matsumoto AM, Vigersky R. Patient guide to androgen deficiency syndromes in adult men. –Available on The Hormone Foundation web site: http://www.hormone.org http://www.hormone.org