Testosterone in Aging Men; Does menopause exist?

Brad Anawalt, MD University of Washington 12/2/11

2 T Not 2 T

Testosterone myths

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

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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

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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)

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Effects of T on athletes

Testosterone pharmacologic effects

• Brain: cognition, mood, sex • Bone: bone growth and strength • Blood: red blood cell production • Muscle: strength • Fat: decreased fat

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

Very-high dosage T  bench press in 10 weeks 60 50 40 30 20 10 0

Couch potato Couch potato + T Weighlifting Weighlifting + T

Testosterone dosage = 6-8 times normal NEJM 1996;335:1-7

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.

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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

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Prevalence of Symptomatic ♂ Hypogonadism 40 30

% Symptomatic Androgen Deficiency

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

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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.

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

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

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Obesity & aging synergistically  [T] Free [T] (pmol/L) BMI > 30 = 10-15 yr of aging!

n = 3200 Wu FCW, et al. J Clin Endocrinol Metab. 2008;93:2737-2745

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“

Will I still be able to not exercise?

”

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

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Testosterone: Younger vs Older Men

Normal Young Men Older Men

30% tightly bound to SHBG 70% bioavailable 25% bioavailable 75% tightly bound to SHBG

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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

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

 sexual function with  T dosage in older ♂

15 10 5 0 -5 25 mg 50 mg 100 mg 300 mg Weekly T enanthate dosage 600 mg

J Clin Endocrinol Metab. 2005;90:3838-3846

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

strength with



T dosage in

♂ 100 80 Young Old P < 0.001 for dose

*

Δ leg press strength (kg) 60 40 20

*

0 -20 25 50 125 300 IM T enanthate (mg/week) 600 J Clin Endocrinol Metab. 2005;90:678-688

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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

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Median serum [T]



but no Δ in prostate [T] with im T rx in older hypogonadal

♂ No D 900 800 700 600 500 400 300 200 100 0 in prostatic tissue gene markers related to prostate cancer (Ki67, AR, CD34, PSA)

*

Baseline serum [T] Treatment serum [T]

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JAMA. 2006;296:2351-2361

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?

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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;93:68-75.

• ↓ [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.

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Androgen ablation therapy may



MI & DM

• Cohort study of 1372 ♂ – Earlier fatal MI in ♂ with prostate cancer 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

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

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Variation in response to treatment

Individual variation • Differences in androgen receptor J Clin Endocrinol Metab. 2007;92:3844-3853 • Differences in metabolism (older ♂ metabolize T slower) J Clin Endocrinol Metab. 2006 • Other differences – e.g., coactivators, repressors, etc

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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

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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 ♂ – Older ♂   response from low to physiological dosages 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;90:678-688 J Clin Endocrinol Metab. 2006; J Clin Endocrinol. 2008;93:914-919

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