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

3. Not 2 T
2 T

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

5. 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

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

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

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

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 ;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 ♂ Hypogonadism10 40 30 20
30-39
50-59
40-49
60-69
70-79
Age
# of men
435
434
333
187 86
% Symptomatic Androgen Deficiency
Araujo AB, et al. JCEM 2007;92:
BDA

14. 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:
BDA

15. 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

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

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

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

19. Free Testosterone Hypothesis
Patient Management
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 Men
Older Men
25%
bioavailable
30% tightly
bound to SHBG
70% bioavailable
75% tightly bound to SHBG
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 ;90:
BDA

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

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. No D in prostatic tissue gene markers related to prostate cancer
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) *
Serum [T] ng/dL
Setum [T] ng/g
BDA
JAMA ;296:

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 ;93:68-75.
↓ [T] = ↑ CV and total mortality in nested case-control study of > US ♂ surveyed with 7-year follow-up
Khaw KT, et al. Circulation ;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 ;167:
Recent review: Traish AM, et al. J Androl ;30:
BDA

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 & 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

32. 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 ;363:
BDA

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

34. 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

36. 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 Clin Endocrinol Metab ;90:
J Clin Endocrinol Metab ;
J Clin Endocrinol ;93:
BDA