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ADAM Syndrome Androgen Deficiency in the Aging Man Andropause

ADAM Syndrome Androgen Deficiency in the Aging Man Andropause. “Is it not strange that desire should so many years outlive performance?” S hakespeare, W: Henry IV Part2. Norman Jensen MD MS Professor Emeritus UW Department of Medicine nmj@medicine.wisc.edu

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ADAM Syndrome Androgen Deficiency in the Aging Man Andropause

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  1. ADAM SyndromeAndrogen Deficiency in the Aging ManAndropause “Is it not strange that desire should so many years outlive performance?”Shakespeare, W: Henry IV Part2. Norman Jensen MD MS Professor Emeritus UW Department of Medicine nmj@medicine.wisc.edu Primary Care Conference, March 28, 2007

  2. ILOsIntended Learning Outcomesa.k.a., Learning Objectives • Androgen physiology • Androgen changes with aging • Syndrome of ADAM • Effects of testosterone replacement • Practice guideline

  3. Literature Search • MESH Major: Hypogonadism 5,914 OR Testosterone 24,304 = 29,507 • Limits: • Human, Male, English, Adult 19+ = 5,267 • Last 10 years = 1930 • Core clinical journals = 454 • Randomized Clinical Trials = 115 • Reviews = 25 • Meta-analysis = 1 • Practice Guideline = 0 • Total = 141

  4. Testis, gross anatomy Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:479.

  5. Normal testicular volume > 15 ml. Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:486.

  6. Testis, micro anatomy Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:479.

  7. Testis, photomicrograph

  8. Hypothalamus – Pituitary – Testis Axis Aromatase → E2 5α reductase → DHT Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:483.

  9. DHEA = popular food supplement androgen Androgen metabolism Licorice Finasteride & dutasteride Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:481.

  10. Normal androgen sources Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:482.

  11. Normal androgen levels, serum Greenspan FS, Gardner DG. Basic & Clinical Endocrinology. Lange, NY, 2004:486.

  12. Mechanism of Action, T

  13. LH and Testosterone Excretion - Diurnal Rhythms Winters SJ. Diurnal rhythm of testosterone and LH in hypogonadal men. J Andrology 1991;12:185-190. (Pittsburgh)

  14. Ovarian hormone lifetime

  15. Testosterone in aging men

  16. Prevalence of Low T by Age NEJM 2004;350:483

  17. Clinical male hypogonadism NEJM 2004;350:483 USA Prevalence = 2-4 million ~ 5% on Rx

  18. Etiology, male hypogonadism Endocr Pract 2002;8:440-456

  19. Benefits of Testosterone replacement •  Sexual dysfunction •  Bone density & Lean muscle mass • Strength, endurance, falls •  Mood and cognition •  Erythropoesis • HIV-AIDS •  sense of well-being and muscle mass • Anti-inflammatory • Metabolic:  insulin resistance, A1c, visceral adiposity, total cholesterol, BP?, pre-diabetes

  20. Potential Harms of T • IoM concluded “no compelling evidence of major adverse side effects resulting from T therapy”. • “Prostate events” • BPH ( vol), LUTS, retention, CA • Obstructive sleep apnea • Erythrocytosis

  21. CardiovascularBenefits & Harms • No clinical trial evidence of either • However, lots of observational data •  Angiogram disease with lower T • Top 1/3 serum T = 0.2 age-adjusted relative risk • Mid 1/3 serum T = 0.4 •  exercise-free angina for men on T (Heart 2004;90:871-6) •  coronary artery diameter when injected directly with T • Men on T have  antithrombin III offsetting prothrombotic factors, prothrombinase, proteins C & S. • No effects on platelets. • No  in Cardiovascular events • No effect or  Tot cholesterol, LDL, HDL •  TNFα & IL1β and IL-10 Refs: Rhoden, NEJM 2004 / JCEM 2004;89:3313-18 / Heart2004;90:871-6.

  22. ErythropoesisBenefits & harms • Hgb  15-20 in boys at puberty • Men have higher Hgb than women • Hypogonad men have lower Hgb • Corrected by T replacement in 3 months • Risk of erythrocytosis (HCT > 52) •  with pulmonary insufficiency • dose related • No case reports of thromboembolism with T • Monitor Hgb or Hct

  23. Prostate DiseaseRisks and Benefits • No benefits observed •  P volume with Rx during first 6 months;  with castration (surgical or medical) • Risks of T Rx • No  LUTS or retention • Castration causes P cancer regression • No clinical trial evidence for  growth • Case reports only • P ca prevalent at age when T is declining

  24. Effects of T ReplacementJ Clin Edocrinol Metab 2000;85:2670-77 • Case series: 18 men > 18 y/o, hypoT due to organic disease (78+-77 ng/dl), never treated. Rx T transdermal 3 years. 16 completed 12 months, 14 all 36. • Results: Serum T normalized. L2-4 BMD  7.7%+-7.6(.001), fem trochanter BMD 4.0+--5.4%(.02) (both max 24 mos), lean body mass  3.1 kg (.004), HCT  38+-3% to 43.1+-4%(.002), prostate volume  12+-6 mL to 22.4+-8.4 mL (.004), energy  49+-19%66+-24% (.01), and sexual function 24+-20% to 66 +-24% (.001). Lipids did not change. • Full effect on BMD took 24 mos, all others 3-6 mos.

  25. Bone mineralJ Clin Edocrinol Metab 2002;87:3656-61 • Case-control study: 15 men 75y/o PCA & 17 normals 70y/o • 12 months after GnRh analog rx(chemical castration): • Total hip  3.3%, distal radius  5.3% (.001) • Spine  2.8% (ns), femoral neck  2.3% (ns) •  urine N-telopeptide (<.05) • (marker of bone resorption) • No bone loss in controls. • NEJM 2001;345:948-935 – bone loss with ADT prevented by pamidronate infusions. And alendronate (Osteoporosis International 2005;16:1591-96)

  26. Physical functioningJ Clin Endocrinol Metab 2005;90:1502-1510 • RCT: 70 T<350ng/dl, >64y/o to 200 mg / 2 wks vs. placebo X 36 months, 50 completed • Results: • Significant  timed function test*, handgrip strength (160%L & 900%R), & lean body mass, •  fat mass 17%, total cholesterol 19% & LDL 22% • NS trends in HDL -15% & fasting insulin -15%.

  27. Physical functioningEuropean J Endocrinology 2006;155:867-75. • RCT: n=70, 5 mg testoderm, placebo, exercise*, no exercise, 4 arms, 12 wks, 65-85 for SF36 and dual x-ray absorptiometry scan. • Results: T + Ex,  physical function (.03), role physical (.01), general health (.049), & social functioning (.04). • * home program, 11 resistive exercises, 10 each / day, 3-4 d/wk, using elastic bands, of various strengths, followed q2wk

  28. Metabolic Syndrome • Observations • T and insulin levels inversely related • Low T predict ins. res. and future DN • Men with DM more likely hypoT, ~33% • fT low in obese men, inversely :: BMI • HyopT have  abdom obesity • Obesity  T via aromatase conversion to E2 and via  leptin • Insulin  after GnRH agonist • Insulin & sugar levels  after castration • HypoT associated with HBP, dyslipid, & Metabolic Syndrome regardless of BMI

  29. Metabolic Syndrome • Experimental studies • Castrated rats show impaired insulin sensitivity corrected with physiologic T • Healthy men with low T improved insulin sensitivity and  insulin after T replacement • T rx  insulin resistance in obese men • T rx  TChol in hypoT men with CAD, even in those on statins • A report of improved A1c on T rx

  30. Metabolic SyndromeEuropean J Endocrinology, 2006;154:899-906 • Study, RCT, xo 3-1-3, 27 men age>30, hypoT and DM2, T200mg IMq2wk. • Results: • Insulin 14% (ns), FBS 6%(.03),  A1c 4%[.3](.03)TChol 5%(.03), %body fat 3%(ns),  waist circumference (.03),  waist:hip (.01) • No change in BMI, HDL, LDL, Trig, SysBP, DiaBP • Conclusion: T  insulin resistance & glycemia in hypogonad men with DM2 • Men with DM2 & met. Syndrome should be evaluated for hypogonadism. J Urol 2005;174:827-34 (review)

  31. CognitionAging Male 2003;6:13-18. • RCT (pilot): 10 men w new dx Alzheimer’s & hypoT (<240 ng/dl), 5 rx T 200 mg / 2wks & 5 placebo & tested at 3, 6, 9, 12 months. • RESULTS: MMSE  19.4 to 23.2 (.02) – comparable to ACH inhibitors. • Clock draw test  2.2 to 3.2 (.07) • Animal studies: T enhances ACH release,  nicotinic receptors, and affects Tau protein deposition. •  brain amyloid beta-peptide after GnRH analogs (e.g. Lupron) • Observed associations of T and memory

  32. Adverse EffectsofTestosteroneRx NEJM 2004;350:485

  33. Adverse EffectsofT Rx NEJM 2004;350:484

  34. Risk of Prostate Cancerqualitative review

  35. Calof OM, Singh AB, Martin LL, et.al. Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled trials. Journal of Gerontology 2005;11:1451-1457. • 1966 – 4/2004: Testosterone (MESH), limited by human, male, >44 y/o, RCT = 417+1, 19 of which met inclusion criteria of T rx >90 days, initial low / low-normal T, medically stable. • 615 Rx’d with T, 433 placebo. • All 5 Prostate events OR = 1.78 (1.07-2.95) • None individually significant, strongest trend = Bx • Prostate cancer (PSA>4 & +Bx) OR 1.09 (0.49 – 2.49) • HCT > 50% OR 3.69 (1.82-7.51) • CV, OSA, death = not statistically different with trend for lower CV events (ex. Arrhythmia) and deaths • N = 85,862 to detect 20%  p CA for 1 year • So IoM recommends short term efficacy trials as next step

  36. Monitoring Guideline NEJM 2004;350:488 ? lipids

  37. If the PSA rises

  38. What to do until the evidence is in? • Stringent diagnostic criteria • 3 early AM total * T’s < 200 ng/dl • High LH = primary hypogonadism • NL or low LH = secondary hypogonatism • √ Serum TSH, fT4, cortisol, prolactin, & MRI brain/sella • Rx T only if above criteria met. • If T Rx, monitor serum T & sx • Goal: ? young men’s normal 500-700 vs. • Goal: ? older men’s normal 300-450 ng/dl (“prudent”) • Screen & Monitor for adverse risk & outcomes • See previous slides NEJM 2004;350:482-492, 440-442, & 2004-2006.

  39. Rx: androgen (Class III 1991) • Testosterone cipionate, 200 mg/ml./2 wk • 200 mg/ml, 10 ml. vial, $88.99, = $ 18 / month * $65.42 /ml+ • Testosterone enanthate, 200 mg/ml/2wk • * not listed $44.78 / ml+ • Testosterone topical, 5-10 gm / am • 1% gel, @ 5 gm / day = $ 210-230 / month * • Androgel and Testim $227.75/ mo+ • Testosterone transdermal patch • 2.5 – 10 mg. qhs, @ 5 mg/d “Androderm” $223.03 / mo+ ”Testaderm” $112.29 / mo + • Testosterone, oral, methyltestosterone & fluoxymesterone • Erratic absorption, less effective, cholestasis • 10-50 mg. po / day - @ 20 mg/d = $187 / month * NA • Testosterone buccal, 30 mg. q 12 h • 30 mg., #60 = $222.42, = $ 220 / month * “Striant” $213.20 / mo+ • Testosterone pellets, injected SQ, NA • 75 mg/pellet, 3-6 / 3-6 mos., “Testopel” $160 + $20/pellet + visit • 100 mg & 200 mg pellets compounded by some pharmacies * Epocrates, Drug Store.com prices + Price, UWH pharmacy

  40. Tests Available at UWH • Testosterone, Total • Testosterone Free, Adult Male * • Testosterone, Bio-available and Sex Hormone Binding Globulin, Adult Male • 5-a-Dihydrotestosterone • * ARUP uses RAI measurement adjusted by a complex formula including measures of albumin and sex hormone binding globulin and known binding constants. The R2 = 0.94 when compared to Endocrine Science’s equilibrium dialysis method. The unreliable RAI test is a direct measurement, unadjusted.

  41. ILOsIntended Learning Outcomesa.k.a., Learning Objectives • Androgen physiology • Androgen changes with aging • Syndrome of ADAM • Effects of testosterone replacement • Practice guideline

  42. Bonus factoid

  43. Licorice  Testosterone NEJM 1999;341:1158

  44. The lecture ends here! Questions? Answers $0.25Answers requiring thought $1.00Correct answers $2.50 Comments?

  45. If you want to read more … • Liverman CT, Blazer DG, eds. Testosterone and aging: clinical research directions. Washington, D.D.: National Academies Press, 2004. (IoM report) • Laumann EO, PaikA, Rosen RC. Sexual dysfunction in the US: prevalence and predictors. JAMA 1999;281:537-44. Correction 281:1174. • Rhoden EL, Morgentaler A. Risks of testosterone replacement therapy and recommendations for monitoring. NEJM 2004;350:482-92. • Calof OM, Singh AB, Martin LL, et.al. Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled trials. Journal of Gerontology 2005;11:1451-1457. • Full bibliography available on request: nmj@medicine.wisc.edu

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