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Testosterone in Aging Men; Does men opause exist?

Testosterone in Aging Men; Does men opause exist?. Brad Anawalt, MD University of Washington 12/2/ 11. Not 2 T. 2 T. Testosterone myths. Men undergo men opause ( andropause ) Testosterone is the root of all evil A little testosterone is good, a lot is better. BDA.

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Testosterone in Aging Men; Does men opause exist?

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  1. Testosterone in Aging Men; Does menopause exist? Brad Anawalt, MD University of Washington 12/2/11

  2. Not 2 T 2 T

  3. Testosterone myths • Men undergo menopause (andropause) • Testosterone is the root of all evil • A little testosterone is good, a lot is better BDA

  4. Testosterone physiologic effects • Brain: cognition, mood, sex • Skin: hair, healing • Bone: bone growth and strength • Blood: red blood cell production • Muscle: strength • Fat: decreased fat • Immune system: poorly understood BDA

  5. Common symptoms & effects of male hypogonadism • Weakness • Fatigue • Decreased sexual function • Decreased sense of well-being • Depression • Osteoporosis • Loss of facial and body hair • Gynecomastia (↑ breast tissue) BDA

  6. Effects of T on athletes

  7. Testosterone pharmacologic effects • Brain: cognition, mood, sex • Bone: bone growth and strength • Blood: red blood cell production • Muscle: strength • Fat: decreased fat BDA

  8. “It’s lost all meaning in the steroid era.”

  9. Very-high dosage T  bench press in 10 weeks Testosterone dosage = 6-8 times normal NEJM 1996;335:1-7

  10. Epidemiology of ♂ hypogonadism Based on “low” serum T levels alone • < 5% in 20s & 30s • 12% in 50s • 19% in 60s • 28% in 70s • 49% in 80s Harman SM, et al. JCEM. 2001;86:724-731. BDA

  11. Definition of male hypogonadism Syndrome of decreased androgen effect (usually  T production) and/or sperm production Diagnosis depends on serum androgens + clinical evidence of inadequate tissue androgen effect BDA

  12. 40 30 20 10 0 Age 30-39 40-49 50-59 60-69 70-79 # of men 435 434 333 187 86 Prevalence of Symptomatic ♂ Hypogonadism % Symptomatic Androgen Deficiency Araujo AB, et al. JCEM 2007;92:4241-4247 BDA

  13. Prevalence of Symptomatic ♂ Hypogonadism • Large population study in UK (2010) • Hypogonadism = threshold [T] when symptoms (sexual dysfunction) become increasingly common • Prevalence of hypogonadism is ~ 2% in middle-aged and older men • • ↑ prevalence with ↑ age, obesity & illnesses Wu FW, et al. N Engl J Med 2010;363:123-135. BDA

  14. Effects of aging on the gonadal axis of men • Testes make less testosterone • Hypothalamus & pituitary do not respond normally to lower blood testosterone levels BDA

  15. Feldman HA, et al. J Clin Endocrinol Metab 87:589-598, 2002 D in Reproductive Hormones as ♂ age 1709 ♂ (40-70 years) followed for 7-10 yrs BDA

  16. Wu FCW, et al. J Clin Endocrinol Metab. 2008;93:2737-2745 Obesity & aging synergistically  [T] Free [T] (pmol/L) BMI > 30 = 10-15 yr of aging! n = 3200 BDA

  17. “Will I still be able to not exercise?”

  18. Free Testosterone Hypothesis • Free T is the hormonally active form • T bound to SHBG is inactive • T bound to albumin is bioactive (“weakly bound”) • Tissue-mediated dissociation of T from albumin BDA

  19. Testosterone: Younger vs Older Men Normal Young Men Older Men 25% bioavailable 30% tightly bound to SHBG 75% tightly bound to SHBG 70% bioavailable BDA

  20. Common causes of altered SHBG • Low SHBG • Obesity • Diabetes mellitus • Metabolic syndrome • Corticosteroids • Anabolic steroids • Hypothyroidism • High SHBG • Aging • Medications • (anti-epileptics) • Cirrhosis, hepatitis • Estrogens • Hyperthyroidism BDA

  21. > 25% men with low total testosterone levels have normal free testosterone levels

  22.  sexual function with  T dosage in older ♂ J Clin Endocrinol Metab. 2005;90:3838-3846 BDA

  23.  strength with  T dosage in ♂ 100 P < 0.001 for dose Young * Old 80 * 60 Δ leg press strength (kg) 40 20 0 -20 25 50 125 300 600 IM T enanthate (mg/week) BDA J Clin Endocrinol Metab. 2005;90:678-688

  24. Risks of T rx for ♂ hypogonadism • Clinical Outcomes • Acne ( in younger ♂) •  red blood cell production (in older ♂) • Markers of clinical outcomes • Prostate: small  PSA & prostate volume • CV:  HDL (“good cholesterol”) • (greater  HDL in younger ♂) Male Pattern Blindness BDA

  25. Median serum [T]  but no Δ in prostate [T] with im T rx in older hypogonadal ♂ No D in prostatic tissue gene markers related to prostate cancer (Ki67, AR, CD34, PSA) * Setum [T] ng/g Serum [T] ng/dL BDA JAMA. 2006;296:2351-2361

  26. Risks of androgen therapy: cardiovascular disease • Epidemiology: • MI: ♂ > women… BUT • ↑ MI in ♂ with low T vs.♂ with normal T • Change in surrogate markers with testosterone treatment • Mixed effects on lipids •  HDL (primarily seen with oral androgens) • Not seen in older ♂ treated with non-oral T • LDL (“bad” cholesterol) •  lipoprotein (a) ( another “bad” cholesterol) • Testosterone ↑ coronary vasodilation • Testosterone  body fat • Testosterone  insulin sensitivity? BDA

  27. Epidemiological data: ↓ [T] = ↑ CAD events • ↓ [T] = ↑ CV and total mortality in study of 794 ♂ followed for up to 20 yrs (mean = 12 yrs) • Laughlin GA, et al. J ClinEndocrinolMetab. 2008;93:68-75. • ↓ [T] = ↑ CV and total mortality in nested case-control study of > 11000 US ♂ surveyed 1993-1997 with 7-year follow-up • Khaw KT, et al. Circulation. 2007;116:2694-2701 • BUT some conflicting data such as… • ↓ [DHT] and [SHBG], but not [T], associated with ischemic heart disease in Male Massachussetts study of > 1600 ♂ followed for > 15 yrs. • Araujo AB, et al. Arch Intern Med. 2007;167:1252-1260 • Recent review: Traish AM, et al. J Androl. 2009;30:477-494. BDA

  28. Androgen ablation therapy may  MI & DM • Cohort study of 1372 ♂ with prostate cancer • Earlier fatal MI in ♂ with 6 mos of  androgen vs 0 mos • Only true for ♂ > 65 yrs J Clin Oncol 2007;25:2420-2425 • Observational study of > 70,000 ♂ with prostate cancer •  DM (HR = 1.34 & orchidectomy & 1.44 for GnRH agonist) •  CAD in ♂ treated with GnRH agonist (HR = 1.16) J Clin Oncol 2006;24:4448-56 Biologically plausible: Androgen deprivation =  fat,  muscle & ?  insulin resistance

  29. TOM Trial • Study of 274 elderly ♂ (mean age = 74) • Low [T] • Most had hypertension • ~ 50% obese, 25% diabetes mellitus • 6 months of high dosage testosterone gel or placebo x 1 yr • Results • ↑↑ leg strength with testosterone • ↑ chest strength with testosterone • ↑ speed of walking upstairs with a load • ↑ cardiovascular events with tesosterone • 29 vs. 5 cardiovascular events Bhasaria, et al. N Engl J Med. 2010;363:109-122 BDA

  30. Variation in response to treatment Individual variation • Differences in androgen receptor J ClinEndocrinolMetab. 2007;92:3844-3853 • Differences in metabolism (older ♂ metabolize T slower) J ClinEndocrinolMetab. 2006 • Other differences • e.g., coactivators, repressors, etc BDA

  31. Conclusions • There is no male menopause • Many aging men have low serum [T] levels • May due to poor overall health, obesity • Diagnosis of hypogonadism is tricky in older men • Some men will benefit from testosterone rx • Determining who will benefit …is an art not a science • Different responses based on dose & individual BDA

  32. Differences in dose response with T Rx in younger vs. older ♂ • Benefits •  muscle &  fat in dose-dependent manner in ♂ of all ages •  sexual function in ♂ of all ages • Young ♂  response from low to physiological dosages • Older ♂  response from low to pharmacological dosages • Harms • Lower tolerance for  dosages in older ♂ •  hct & edema in older ♂ •  acne & ↓ HDL in younger ♂ • J ClinEndocrinolMetab. 2005;90:678-688 • J ClinEndocrinolMetab. 2006; • J ClinEndocrinol. 2008;93:914-919 BDA

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