Transcript Effect of Testosterone vs Placebo on Upper Extremity

Evaluation and Treatment of
Hypogonadism in Older Men
Alvin M. Matsumoto, M.D.
Associate Director, GRECC
V.A. Puget Sound Health Care System
Professor, Department of Medicine
University of Washington School of Medicine
GRECC National Audio Conference
May 29, 2008
1
Male Hypogonadism
GnRH
T
Androgen Deficiency
 Sexual Development
 Libido, Erections
 Sperm Production
Bone,  Muscle, Fat
 Mood,  Cognition
Hair, Skin
LH / FSH
Infertility
T
T
 E2
 Sperm
 DHT
 Fertility
 Inhibin B
2
Hypogonadism in Older Men
Outline
• Prevalence
• Challenges
– Clinical diagnosis
– Biochemical diagnosis
• Treatment considerations
• Low testosterone (T) in older men
• Low T and clinical outcomes
3
Androgen Deficiency
A Common Disorder
Pathological
• Klinefelter syndrome (47,XXY)
1 in 500 men
Functional
•  T with illness or drugs
– Chronic renal, liver, lung disease, type 2 DM
– Wasting (cancer, HIV), malnutrition, severe
obesity
– Drugs (opiates, glucocorticoids)
•  T with aging
4
Prevalence of Low T in Aging Men
Percentage
(T < 2.5 Percentile of Young Men BLSA)
100
90
80
70
60
50
40
30
20
10
0
Total T <325 ng/dL
Free T Index < 0.153
20-29 30-39 40-49 50-59 60-69 70-79 ≥ 80
Age Decade
5
SM Harman, et al, J Clin Endocrinol Metab 86:724-731, 2001
Male Hypogonadism
Diagnosis
• Clinical manifestations of androgen
deficiency
– Symptoms and signs
• Consistently low T level (biochemical
androgen deficiency)
– Reference normal range in younger men
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
6
Androgen Deficiency
Prevalence
Biochemical^
Prevalence
50-59 yrs
60-69
70-79
 80
12%
19%
28%
48%
Clinical*
9%
6%
11%
23%
^ Total T < 345 ng/dL (BLSA)
* Total T < 200 or free T < 8.9 ng/dL
and ≥ 3 symptoms/signs (MMAS)
Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001
Araujo A, et al, J Clin Endocrinol Metab 89:5920-5926, 2004
7
Clinical Androgen Deficiency
Challenges
• Symptoms and signs
− Nonspecific presentation in adults
• Modified by
– Age
– Severity and duration of T deficiency
– Co-morbid illness
– Previous T treatment
– Androgen sensitivity of specific target organs
8
21 year-old man with infantile genitalia,
delayed growth, high-pitched voice, no
axillary and pubic hair, and T 30 ng/dL
9
Prepubertal Androgen Deficiency
Symptoms and Signs
• Delayed puberty
− Delayed growth and sexual development
• Eunuchoidism
− Infantile genitalia
− Long arms and legs vs. height
−  Muscle development,  fat,  peak BMD
− High-pitched voice
− Sparse axillary and pubic hair
10
56 year-old man with  axillary and
pubic hair, erectile dysfunction, 
libido, gynecomastia, and T 100 ng/dL
11
76 year old man with severe back pain
from compression fractures, muscle
wasting and weakness, and T 90 ng/dL
12
Symptoms and Signs
Suggestive of Adult Androgen Deficiency
•
•
•
•
•
•
•
•
 Erections
 Libido and sexual activity
Gynecomastia
 Axillary and pubic hair
Infertility, low sperm count, small testes
Low trauma fracture, low BMD
 Muscle bulk and strength
Hot flushes, sweats
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
13
Symptoms and Signs
Less Specific for Adult Androgen Deficiency
•
•
•
•
•
•
•
 Energy, motivation
Depressed mood
Poor concentration and memory
Sleep disturbance
Mild anemia
 Body fat
 Physical activity
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
14
Severe Androgen Deficiency in Older Men
GnRH Analog or Orchidectomy Model
•
•
•
•
•
•
•
•
•
 Erections, sexual activity and desire (libido)
 Energy, motivation and mood, irritability,  QOL
Sleep disturbance, hot flushes, sweats
 Concentration and memory
 Activity, muscle mass and strength, physical
performance
 Fat mass, insulin resistance ( DM and CVD)
 BMD ( fracture)
Gynecomastia,  body hair
 Hemoglobin
15
Multiple Factors Affecting Bone Mass
and Fracture Risk in Older Men
 Androgens
 GH
IGF-1
 Estrogens
 Calcium intake
 Vitamin D
Genetics

 BMD
 Activity
Immobility
Alcohol
Smoking
Malnutrition
Medications
(e.g. glucocorticoids)
Trauma
Falls
Co-morbid
illness
Fracture
16
Matsumoto AM, J Gerontol Med Sci 57:M76-M99, 2002
Biochemical Androgen Deficiency
Challenges
• Low serum total T level
− Total T most common and available
− Relative to normal range in young men (<280300 ng/dL but assay-to-assay variability)
− T levels variable
• Morning, on at least two occasions
• If  SHBG suspected, free or bioavailable T
level
• Illness, drugs, nutritional deficiency 
transiently low T
17
Day-to-Day Variation in T Levels
• In hypogonadal men with initial T < 300
ng/dL, 30% had normal T on repeat
testing1
• In older men with initial T < 250 ng/dL
– 20% had average T > 300 ng/dL over 6
months
– If average of two samples T < 250 ng/dL,
none had average T > 300 ng/dL2
1Swerdloff
RS, et al, J Clin Endocrinol Metab 85:4500-4510, 2000
2Brambilla DJ, et al, Clin Endocrinol (Oxf) 67:853-862, 2007
18
Circulating Testosterone
Albuminbound T
(weak)
54%
Bioavailable T
SHBG-bound
T (tight)
44%
Free T
2%
Total T
19
Testosterone Assays
• Affected by changes in SHBG
– Total T
– Free T by analog assay (~all clinical labs)
• Not affected by changes in SHBG
– Calculated free T and bioavailable T from total
T and SHBG
– Free T by equilibrium dialysis
– Bioavailable T by ammonium sulfate
precipitation
20
Common Alterations in SHBG
Affect Total and Free T Analog Levels
 SHBG
 Total T
• Moderate obesity
• Low protein (nephrotic)
 SHBG
 Total T
• Aging
• Hepatitis, cirrhosis
• Hyperthyroidism
• Glucocorticoids/progestins • Anticonvulsants
• Anabolic steroids
• Estrogens
• Acromegaly
• HIV
• Hypothyroidism
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
21
Classification of Androgen Deficiency
Challenges
• LH and FSH levels distinguish 1O vs 2O
hypogonadism
• Combined 1O and 2O hypogonadism
– Usually predominant hormonal pattern
• Discrepant  LH versus FSH may suggest
a pituitary tumor
22
Primary Hypogonadism
 GnRH
T
 LH / FSH
T
T
 E2
 Sperm
 DHT
 Inhibin B
23
Causes of Primary Hypogonadism
 T and  LH and FSH
• Pathological
– Klinefelter syndrome
– Myotonic dystrophy, developmental disorders
– Orchitis, irradiation
– Castration, trauma, anorchia
– Drugs (cytotoxic, ketoconazole, spironolactone)
• Functional
– Systemic disorders (chronic liver, renal disease)*
– Aging*
* Combined 24
Secondary Hypogonadism
 GnRH
T
Normal- LH / FSH
T
T
 E2
 Sperm
 DHT
 Inhibin B
25
Causes of Secondary Hypogonadism
T and Normal or  LH and FSH
• Pathological
– Kallmann syndrome, complex genetic disorders*
– Hemochromatosis*
– Hyperprolactinemia
– Hypopituitarism (tumor, infiltration, destruction)
• Functional
– CNS-active drugs (opiates)
– Glucocorticoids*, estrogens/progestins, GnRH-A
– Acute and chronic illness*, wasting
– Nutritional deficiency, massive obesity
– Aging*
* Combined 26
78 year-old man with weight loss,
anorexia, weakness, slowed gait, 
memory, osteoporosis,  T 30 ng/dL, 
LH 45 IU/L and FSH 2 IU/L
Patient GM
Normal
27
27
Secondary Hypogonadism
Importance
•
•
•
•
Pituitary-hypothalamic tumor mass effect
Deficiency of other pituitary hormones
Excessive pituitary hormone secretion
Some causes treatable or reversible
– Illness, malnutrition, medications
• Infertility treatable
– Gonadotropin (or GnRH) therapy
28
Diagnosis of Male Hypogonadism
Summary
• Symptoms/signs of androgen deficiency
− Sex (erections)
− Brain (libido, mood, memory, hot flush/sweats)
− Body (muscle, bone, breast and hair)
• Consistently low T level x 2
• Free or bioavailable T, if suspect  SHBG
• R/o reversible illness, drugs, nutritional
deficiency
• LH and FSH  1O vs 2O hypogonadism
29
Male Hypogonadism
Treatment Considerations
• Contraindications
– Prostate or breast cancer
• Caution
– Prostate nodule, unexplained  PSA > 3
–  Hct > 50%
– Untreated sleep apnea
– LUTS (IPSS > 19)
– Severe unstable CHF (class III or IV)
• Benefits > risks?
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
30
T Treatment
Potential Benefits and Risks
Benefits
• Sexual development
•  Erections
•  Libido, sexual activity
•  Energy, mood, vitality
•  Muscle strength
•  Physical function
•  BMD
Risks
• Erythrocytosis
• Acne
•  Sperm count
• Prostate biopsy
• Gynecomastia
•  Breast cancer (rare)
•  Sleep apnea (rare)
• Local (pain, skin rash)
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
31
T Formulations
• Intramuscular T
– Extensive experience, inexpensive
– High-normal T, fluctuations in mood or libido,
pain
• T Patch
– Low-normal T, skin irritation, expensive
• T Gel
– Low- to high-normal T, flexibility, no irritation
– Contact transfer, expensive
• Buccal T
– Twice daily, altered taste, gum irritation
32
Male Hypogonadism
Monitoring
• Efficacy
– Clinical response
– T  mid-normal range
– DEXA
• Safety
– Hct @ 3-6 mo (> 52%)
– DRE (nodule, induration), PSA (> 4 ng/mL or
 > 1.4 ng/mL) @ 3-6 mo, then as usual
– LUTS (IPSS > 19)
– Daytime somnolence, sleep apnea
33
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
Longitudinal  T Levels with Age
Testosterone
(nmol/L)
20
(177)
18
(144)
(151)
16
(109)
14
(43)
(158)
12
10
30
40
50
60
70
80
90
Age (Years)
Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001.
34
Age-Related Changes in Body
Composition
kg
90
80
70
60
50
40
30
20
10
0
Total weight (kg)
Lean body mass (kg)
Fat mass (kg)
20
30
40
50
60 70
Age (yrs)
Forbes GB, Metabolism 14:653-663, 1970
35
Olympic Weight-Lifting Performance
with Aging in Masters Athletes
Average Weight Lifting
Performance
1.2
1
Performance at Age 30 = 1
[Corrected for Body Weight]
0.8
0.6
0.4
0.2
0
30 35 49 45 50 55 60 65 70 75 80
Age (yrs)
DE Meltzer, J Appl Physiol 80:1149-1155, 1996
36
Age-Related Increase in Incidence of
Prostate Cancer
2000
Rate per 100,000
1600
African
American
Caucasian
1200
800
400
0
40- 4544 49
5054
55- 6059 64
6569
70- 7574 79
80- 85+
84
Age Range (yrs)
1991-1995 SEER age-specific rates
37
Prevalence/100,000 Males
Prevalence of Histological Prostate
Cancer
100,000
US
Japan
80,000
60,000
40,000
20-40%
20,000
0
0
20
40
60
80
100
Age (yrs)
Carter HB, et al, J Urol 143:742, 1990
38
T Levels in the Aging Male
• Age-related alterations associated with  T
–  Muscle mass and strength, and  fat mass
–  Bone density and  fractures
–  Sexual function, energy, mood, cognitive
function
• Similar changes in young hypogonadal men
improve with T
• Does  T contribute to age-related alterations?
• Does T Rx of older men   function and clinical
outcomes, and what are the risks?
– CV and prostate disease?
39
T Treatment of Older Men
Evidence Base
• Short-term controlled trials in small #’s of
healthy older men
– Improved body composition
– In some studies,  muscle strength, BMD,
sexual function and cognition
–  Hematocrit,  lipids or prostate disease
• No long-term controlled trials to assess
clinical benefits and risks.
40
Effect of T Alone and T plus Finasteride
on Lean Mass in Older Men
5
4




0



T


T+F


Placebo




 Fat Mass (kg)
 Lean Mass (kg)
3
2
1
-1.6


-3.2










0

12
24
Months
36

0







-4.8
0
12
24
36
Months
S Page, et al, L Tenover, J Clin Endocrinol Metab 89:503-510, 2004
41

2

1
0









-1


0
12
24
Months


 Right Hand Grip Strength (kg)
 Physical Performance (sec)
Effect of T Alone and T plus Finasteride on
Physical Performance and Hand Grip in Older
Men
6


4



2

0




0
12



T


T+F


Placebo



36

24
36
Months
S Page, et al, L Tenover, J Clin Endocrinol Metab 89:503-510, 2004
42
Androgen Deficiency in the Aging Male
•
•
•
•
•
Limitations of T Treatment Trials
Men not clinically or biochemically androgen
deficiency
T treatment  T levels too high or low
Small numbers (under-powered)
Short-term evaluation of surrogate outcomes
Outcome measures not optimal
• Large multi-center, randomized, placebocontrolled trial x 1 yr in older hypogonadal
men planned
43
– Physical, sexual (cognitive?) function and vitality
Androgen Deficiency in the Aging Male
Associations with Clinical Outcomes
• In some studies, low T levels associated with
important clinical outcomes
– Metabolic syndrome and diabetes mellitus
– Cardiovascular disease and mortality
– Fractures, falls and physical performance
– Depression, Alzheimer’s disease
– Anemia
• UNKNOWN whether T treatment will improve
or prevent these outcomes
Ding EL, JAMA 295:1288, 2006; Khaw KT, Circulation 166:2694, 2007; Laughlin,
JCEM 93:68, 2008; Meier C, Arch Int Med 168:47, 2008; Levy, Urology, 2008; 44
Almeida, Arch Gen Psych 65:283, 2008; Moffat, Neurology 62:188, 2004
Increased Mortality/4 Yrs in 858 Older Male
Veterans (Mean Age 61) with Consistently Low T
45
Shores MM, et al, Arch Intern Med 166:1660-1665, 2006
Low Total T Levels Associated with Increased
Mortality/12 Yrs in 794 Community-Dwelling Men (Mean
Age 71) in Rancho Bernardo
Median Total
T (ng/dL)
507
Highest decile (reference)
422
370
338
Median~300 ng/dL
288
288
266
241
209
Lowest decile
171
1
1.5
2
Hazards ratio
Laughlin GA, et al, J Clin Endocrinol Metab 93:68-75, 2008
46
Hypogonadism in Older Men
Conclusions
• Common disorder
• Nonspecific clinical findings affected by
age, severity and duration of  T and comorbidities
• Diagnosis confirmed by repeated  T
– Accurate free T, if  SHBG suspected
– R/O reversible causes
• LH and FSH  1o vs 2o hypogonadism
• T treatment if benefits > risks
• Injectable, patch, gels, buccal T available47
Hypogonadism in Older Men
Conclusions
• Careful but not excessive monitoring
needed
• Larger short-term studies in older men are
needed
– Clinical and biochemical hypogonadism
– Physiological T replacement
– Robust and appropriate measures
• Long-term randomized trial of T in older
hypogonadal men is needed to assess role
of androgen deficiency on important clinical
outcomes (e.g. CVD, DM, fractures,
depression, dementia, prostate cancer) 48
Male Hypogonadism
References
• Bhasin S, Cunningham GR, Hayes FJ,
Matsumoto AM, Snyder PJ, Swerdloff RS, Montori
VM. Testosterone therapy in adult men with
androgen deficiency syndromes: an Endocrine
Society Clinical Practice Guideline. J Clin
Endocrinol Metab 2006;91:1995-2010.
– Available on The Endocrine Society web site:
http://www.endo-society.org
• Matsumoto AM, Vigersky R. Patient guide to
androgen deficiency syndromes in adult men.
– Available on The Hormone Foundation web site:
http://www.hormone.org
49