Prevalence of Age Associated Testosterone Deficiency in Males

1. Prevalence of Age Associated Testosterone Deficiency in Males Bobby Jacob, Pharm.D. Mercer University – June 29, 2010

2. Testosterone replacement therapy (TRT)

3. Do men really age?

4. Do men really age?

5. Do men really age?

6. Program Objectives • Discuss the potential physiologic consequences of age associated testosterone deficiency • Discuss current guidelines and recommendations regarding appropriate diagnostic criteria for age associated testosterone deficiency • Discuss recent literature that has evaluated cross-sectional and longitudinal trends with respect to testosterone concentrations in males • Discuss recent literature that has evaluated the prevalence of age associated testosterone deficiency in the general population

7. Basic anatomy and physiology

8. Male Reproductive System Mescher AL. Junqueira’s basic histology text & atlas, 12 edition. McGraw-Hill company, 2010.

9. Testes Mescher AL. Junqueira’s basic histology text & atlas, 12 edition. McGraw-Hill company, 2010.

10. Testes Leydig or interstitial cells are the primary site of endogenous testosterone production (~95%) Testosterone is the primary androgen in the male Mescher AL. Junqueira’s basic histology text & atlas, 12 edition. McGraw-Hill company, 2010.

11. Systemic distribution • Regulated by protein binding in the body • 50-70% tightly bound to sex hormone binding globulin (SHBG) • 20-30% loosely bound to albumin • ~4% bound to other proteins • Only 1-3% is free, non-protein bound (biologically active) Diver MJ. Front Horm Res 2009;37:21-31

12. HPG Axis Hypothalamus stimulates release of GnRH GnRH stimulates pituitary release of LH and FSH Testosterone provides negative feedback to the HP axis AND has a stimulatory effect on spermatogensis LH interacts with receptors on Leydig cells to stimulate testosterone production FSH acts on Sertoli cells to stimulate spermatogenesis Bhasin S and Jameson JL. Disorders of the testes and male reproductive system. In: Harrison’s principles of internal medicine. EdsFauci AS, et al. McGraw-Hill Companies, 2008.

13. Definition • Male hypogonadism • Deficiency of both testosterone and spermatozoa • Primary • Secondary • Mixed Bhasin S, et al. JCEM 2010;95:2536-2559

14. Pathophysiology • Primary • Testicular dysfunction • Low testosterone, elevated LH/FSH • Secondary • Hypothalamic-pituitary dysfunction • Low testosterone, low LH/FSH • Mixed • Can be observed with age associated testosterone deficiency Bhasin S and Jameson JL. Disorders of the testes and male reproductive system. In: Harrison’s principles of internal medicine. EdsFauci AS, et al. McGraw-Hill Companies, 2008.

15. Diagnostic criteria

16. Definition • Age associated testosterone deficiency (late onset hypogonadism) • A clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels (below the young healthy adult male reference range) Wang C, et al. Int J Impotence Res 2009;21:1-8

17. Specific symptoms • Reduced libido and sexual activity • Most commonly associated with hypogonadism • Decreased spontaneous erections • Breast discomfort • Gynecomastia • Loss of body hair • Height loss • Low trauma facture • Low bone mineral density • Hot flushes, sweats Bhasin S, et al. JCEM 2010;95:2536-2559

18. Non-specific symptoms • Decreased energy or motivation • Depressed mood, dysthymia • Poor concentration or memory • Sleep disturbances • Mild anemia • Reduced muscle mass and strength • Increased body fat or body mass index • Diminished physical or work performance Bhasin S, et al. JCEM 2010;95:2536-2559

19. Serum total testosterone • Recommended measurement for diagnosis • Normal range is variable depending on laboratory • 280-300 ng/dL has been historically noted for lower limit, but we remain unclear regarding what is most clinically applicable • Follow laboratory specific reference ranges • Multiple assay types can be used • Debatable if this is the best indicator of physiologic activity • Continued difficulty in establishing standardized reference ranges for use across the country has presented challenges for clinicians • CDC is currently working on a project to standardize measurement Bhasin S, et al. JCEM 2010;95:2536-2559

20. Serum total testosterone • Influenced by many factors • Circadian rhythm • Measurement should be in the early morning • Acute/chronic illness • Measurement not recommended during these times • SHBG levels • Several chronic conditions (particularly in aging males) are associated with altered levels • Certain medications • Opioids • Steroids Bhasin S, et al. JCEM 2010;95:2536-2559

21. Other laboratory measurements • Free testosterone (FT) • Unbound, biologically active testosterone in the blood • Equilibrium dialysis is the gold standard; however, not widely available • Calculated using total testosterone (TT), SHBG, and albumin • Lower limit of normal has been suggested between 50-90 pg/dL • Bioavailable testosterone (BAT) • Free testosterone plus albumin bound testosterone • Ammonium sulfate precipitation method or calculated using TT and SHBG Bhasin S, et al. JCEM 2010;95:2536-2559

22. Variability in laboratory evaluation • Telephone survey conducted in September 2004 • Purpose was to access the state of laboratory diagnosis of hypogonadism • Directors of 25 laboratories in New England were contacted • 12 academic medical centers • 12 community practice sites • 1 national laboratory (Quest Diagnostics) • The following information was recorded • Types of assays used • Manfacturer of assay • Reference range utilized Lazarou S, et al. J Sex Med 2006;3:1085-1089

23. Variability in laboratory evaluation • Results regarding assays used • Academic • 12/12 (100%) offered assay for TT • 6/12 (50% offered assay for FT • Community • 8/12 (67%) offered assay for TT • 1/12 (8%) offered assay for FT • Eight different assays for TT; 4 different assays for FT • No laboratory performed independent validation of the manufacturer’s recommended reference range Lazarou S, et al. J Sex Med 2006;3:1085-1089

24. Variability in lowest value for reference range Lazarou S, et al. J Sex Med 2006;3:1085-1089

25. Endocrine Society recommendations • Diagnosis of testosterone deficiency should be made ONLY in men with consistent symptoms/signs and unequivocally low serum testosterone levels • Serum testosterone levels should be measured in a patient with clinical manifestations • Measurement of morning serum TT by a reliable assay should be the initial diagnostic test • Confirmation of the diagnosis by repeat measurement is recommended • Measurement of FT or BAT is recommended in men near the lower limit of normal or if SHBG variation is suspected • Screening of the general population is not recommended Bhasin S, et al. JCEM 2010;95:2536-2559

26. Longitudinal and Cross-sectional trends with aging

27. Massachusetts Male Aging Study (MMAS) • Prospective, observational study on health and aging in men from the Massachusetts area • Compare levels and cross-sectional trends • Estimate within subject longitudinal trends • 1,709 men seen at T1 (mean age 55.2±8.7 years) • 1,156 men seen at T2 (mean age 62.7±8.3 years) • Mean duration between T1 and T2 was 8.9 years • TT measured by RIA; FT calculated • Height, weight, co-morbid conditions, current prescription and non-prescription medications, alcohol intake measured at each visit • “Good health” defined as • No chronic illness, no medication use, BMI <29, alcohol use not >5 drinks daily Feldman HA, et al. JCEM 2002;87:589-598

28. MMAS Feldman HA, et al. JCEM 2002;87:589-598

29. MMAS “Good health” status added 10-15% to serum testosterone levels Did not affect longitudinal trend; significantly attenuated cross-sectional declines in TT Feldman HA, et al. JCEM 2002;87:589-598

30. MMAS Cross-sectional Feldman HA, et al. JCEM 2002;87:589-598

31. Baltimore Longitudinal Study on Aging (BLSA) • Open registration study on physiology of aging, >40 years duration with data collection at 2 year intervals • 890 men from the Baltimore area (mean age at entry 53.8±15.8 years) • TT measured by RIA • During a 6 month period in 1995 samples from each subject’s most recent visit, previous 3 visits, and closest to 10, 15, 20, 25, and 30 years were obtained Harman SM, et al. JCEM 2001;86:724-731

32. BLSA – Longitudinal Trends TT declines by 3.2 ng/dL per year Similar results seen with FT Index Cross-sectional declines seen as well Harman SM, et al. JCEM 2001;86:724-731

33. MMAS From T1 to T3, there is a substantial increase in chronic illness and polypharmacy; while there is a substantial decrease in the proportion of smokers. Travison TG, et al. JCEM 2007;92:196-202

34. MMAS Travison TG, et al. JCEM 2007;92:549-555

35. Secular decline Travison TG, et al. CurrOpinEndocrinol Diabetes Obes 2009;16:211-217

36. Secular decline - MMAS Adjustment for chronic illness, general health, medication use, smoking, BMI, employment, and marital status Travison TG, et al. JCEM 2007;92:196-202

37. Health in Men Study • Prospective, cohort investigation of community dwelling men, ≥70 years in Australia • Establish if TT and FT decline in linear fashion at the upper range of age or reach a plateau • Determine appropriateness of age adjusted reference ranges • 3,645 men participated (mean age 77.0±3.6 years) • TT measured by immunoassay; FT calculated • Physical exam performed and questionnaire given on risk factors for CV disease, medical history, and alcohol consumption Yeap BB, et al. Eur J Endocrinol 2007;156:585-594

38. Health in Men Study Yeap BB, et al. Eur J Endocrinol 2007;156:585-594

39. Health in Men Study Yeap BB, et al. Eur J Endocrinol 2007;156:585-594

40. Belgium study Longitudinal study of 221 community dwelling men over 4 years (mean age 74.0 years) Decline of 1.26% per year for TT (95% CI -2.58 to -0.01) and 2.43% (95% CI -3.78 to -1.08) for BAT Lapauw B, et al. Eur J Endocrinol 2008;159:459-468

41. Prevalence Studies

42. DETECT Study • Cross-sectional evaluation of participants in the DETECT study • Diabetes Cardiovascular Risk Evaluation Targets and Essential Data for Commitment of Treatment focused on assessment of cardiovascular risk • Estimate the prevalence of hypogonadism in primary care • 2,719 men at primary care sites in Germany (men age 58±13.4 years) • TT measured by immunoassay • Definition of “hypogonadism” • TT <346 ng/dL • TT <320 ng/dL • TT <300 ng/dL • No assessment of symptoms or breakdown by age • Physicians diagnosed co-morbid conditions based on pre-specified criteria Schneider HJ, et al. ClinEndocrinol 2009;70:446-454

43. DETECT study • Prevalence of testosterone deficiency • TT <346 ng/dL – 28.1% • TT <320 ng/dL – 22.3% • TT <300 ng/dL – 19.3% • Negative correlation between TT and the following conditions • Diabetes, dyslipidemia, cancer, metabolic syndrome, depression, ≥4 physician diagnoses, ≥6 prescription medications, acute inflammation • No correlation with coronary artery disease, heart failure, or stroke • Significantly associated with TT <300 ng/dL • Obesity, cancer, metabolic syndrome, ≥6 prescription medications, not smoking, acute inflammation • Significantly associated with TT <100 ng/dL • Age, cancer, and liver disease Schneider HJ, et al. ClinEndocrinol 2009;70:446-454

44. HIM study • Cross-sectional evaluation (industry sponsored) • Estimate the prevalence of hypogonadism in men ≥45 years in primary care • 2,165 men visiting primary care clinics in the United States (mean age 60.5±10.3 years) • TT measured RIA; FT measured by equilibrium dialysis, - hypogonadism separately defined as: • TT <300 ng/dL • FT <52 pg/mL • BAT <95 ng/dL for ages <70; BAT <60 ng/dL for ages 70 years and older • Current androgen therapy • No breakdown of data by age Mulligan T, et al. Int J ClinPract 2006;60(7):762-769

45. HIM study • Prevalence rate – 36.3% based on TT • 40% based on FT • 45% based on BAT • Each 10 year increase in age leads to a 33% increased risk of hypogonadism • 67% of hypogonadal men reported at least one symptom Mulligan T, et al. Int J ClinPract 2006;60(7):762-769

46. HIM study • Odds ratio (95% CI) for having hypogonadism associated with select conditions • Obesity 2.38 (1.93-2.93) • Diabetes 2.09 (1.70-2.58) • Hypertension 1.84 (1.53-2.22) • Dyslipidemia 1.47 (1.23-1.76) • Asthma/COPD 1.40 (1.04-1.86) • Prostatic disease 1.29 (1.03-1.62) Mulligan T, et al. Int J ClinPract 2006;60(7):762-769

47. BLSA • Longitudinal study (40 years) with sampling at 2 year intervals • 890 men from Baltimore area (mean age at entry 53.8±15.8 years) • TT measured by RIA • No assessment of symptoms • Prevalence rate measured by age decade using two criteria • TT <325 ng/dL • FT Index (TT/SHBG) <0.153 Harman SM, et al. JCEM 2001;86:724-731

48. BLSA Harman SM, et al. JCEM 2001;86:724-731

49. MMAS • Observational, cohort study of men in the Boston area • 1,709 men completed baseline assessment (T1); 1,156 men completed follow-up (T2, mean interval for follow-up was 8.6 years) • TT measured by RIA; FT calculated • Men screened for following symptoms • Decreased libido, ED, depression, lethargy, inability to concentrate, sleep disturbance, irritability, depressed mood • Criteria for androgen deficiency • ≥3 symptoms AND TT <200 ng/dL • ≥3 symptoms AND TT 200-400 ng/dL AND FT <89.1 pg/mL Araujo AB, et al. JCEM 2004;89:5920-5926

50. MMAS Araujo AB, et al. JCEM 2004;89:5920-5926