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

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Presentation on theme: "Testosterone in Aging Men; Does menopause exist? Brad Anawalt, MD University of Washington 12/2/11."— Presentation transcript:

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

3 2 T Not 2 T

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

5 Testosterone physiologic effects BDA 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

6 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

7 Effects of T on athletes

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

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

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

11 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: BDA

12 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

13 Prevalence of Symptomatic ♂ Hypogonadism Araujo AB, et al. JCEM 2007;92: Age # of men % Symptomatic Androgen Deficiency BDA

14 Prevalence of Symptomatic ♂ Hypogonadism Wu FW, et al. N Engl J Med 2010;363: BDA 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

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

16  in Reproductive Hormones as ♂ age Feldman HA, et al. J Clin Endocrinol Metab 87: , ♂ (40-70 years) followed for 7-10 yrs BDA

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

18 “Will I still be able to not exercise?”

19 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

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

21 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

22 > 25% men with low total testosterone levels have normal free testosterone levels

23  sexual function with  T dosage in older ♂ J Clin Endocrinol Metab. 2005;90: BDA

24 * * Δ leg press strength (kg) Young Old  strength with  T dosage in ♂ IM T enanthate (mg/week) J Clin Endocrinol Metab. 2005;90: P < for dose BDA

25 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

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

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28 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

29 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 Clin Endocrinol Metab. 2008;93: ↓ [T] = ↑ CV and total mortality in nested case-control study of > US ♂ surveyed with 7-year follow-up Khaw KT, et al. Circulation. 2007;116: 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: Recent review: Traish AM, et al. J Androl. 2009;30:

30 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: 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: Biologically plausible: Androgen deprivation =  fat,  muscle & ?  insulin resistance

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32 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: TOM Trial BDA

33 Variation in response to treatment Individual variation Differences in androgen receptor J Clin Endocrinol Metab. 2007;92: Differences in metabolism (older ♂ metabolize T slower) J Clin Endocrinol Metab Other differences –e.g., coactivators, repressors, etc BDA

34 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 Conclusions BDA

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36 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 Clin Endocrinol Metab. 2005;90: J Clin Endocrinol Metab. 2006; J Clin Endocrinol. 2008;93: Differences in dose response with T Rx in younger vs. older ♂ BDA


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