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1
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
2
Male Hypogonadism
T
LH / FSH
GnRH
T
Inhibin B DHT
Sexual Development Libido, Erections Sperm Production
Bone, Muscle, Fat Mood, Cognition
Hair, Skin
T
Sperm
E2
Fertility
Androgen Deficiency
Infertility
3
Hypogonadism in Older MenOutline
• Prevalence
• Challenges– Clinical diagnosis– Biochemical diagnosis
• Treatment considerations
• Low testosterone (T) in older men
• Low T and clinical outcomes
4
Androgen DeficiencyA 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
5
Prevalence of Low T in Aging Men (T < 2.5 Percentile of Young Men BLSA)
0102030405060708090
100
20-29 30-39 40-49 50-59 60-69 70-79 ≥ 80
Age Decade
Perc
en
tag
e
Total T <325 ng/dL
Free T Index < 0.153
SM Harman, et al, J Clin Endocrinol Metab 86:724-731, 2001
6
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
7
Androgen DeficiencyPrevalence
Biochemical^ Clinical*Prevalence 9% 50-59 yrs 12% 6%60-69 19% 11%70-79 28% 23% 80 48%
^ Total T < 345 ng/dL (BLSA)* Total T < 200 or free T < 8.9 ng/dL and ≥ 3 symptoms/signs (MMAS)
Araujo A, et al, J Clin Endocrinol Metab 89:5920-5926, 2004Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001
8
Clinical Androgen DeficiencyChallenges
• 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
9
21 year-old man with infantile genitalia, delayed growth, high-pitched voice, no axillary and pubic hair, and T 30 ng/dL
10
Prepubertal Androgen DeficiencySymptoms 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
11
56 year-old man with axillary and pubic hair, erectile dysfunction, libido,
gynecomastia, and T 100 ng/dL
12
76 year old man with severe back pain from compression fractures, muscle
wasting and weakness, and T 90 ng/dL
13
Symptoms and SignsSuggestive 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
14
Symptoms and SignsLess 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
15
Severe Androgen Deficiency in Older MenGnRH 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
16
Multiple Factors Affecting Bone Mass and Fracture Risk in Older Men
Genetics
BMD
Androgens
Estrogens
Calcium intake
Vitamin D
Medications(e.g. glucocorticoids)
GHIGF-1
ActivityImmobility
Co-morbid illness
AlcoholSmoking
Malnutrition
Fracture
FallsTrauma
Matsumoto AM, J Gerontol Med Sci 57:M76-M99, 2002
17
Biochemical Androgen DeficiencyChallenges
• Low serum total T level− Total T most common and available− Relative to normal range in young men (<280-
300 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
18
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, 20002Brambilla DJ, et al, Clin Endocrinol (Oxf) 67:853-862, 2007
19
Circulating Testosterone
SHBG-bound T (tight)
44%
Albumin-bound T (weak)54%
Free T2%
Bioavailable T
Total T
20
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
21
Common Alterations in SHBGAffect Total and Free T Analog Levels
• Estrogens• HIV
• Anabolic steroids• Acromegaly
• Anticonvulsants• Glucocorticoids/progestins
• Hyperthyroidism• Hypothyroidism
• Hepatitis, cirrhosis• Low protein (nephrotic)
• Aging• Moderate obesity
SHBG Total T
SHBG Total T
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
22
Classification of Androgen DeficiencyChallenges
• 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
23
Primary Hypogonadism
T
LH / FSH
GnRH
T
Inhibin B DHT
T
Sperm
E2
24
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
25
Secondary Hypogonadism
T
Normal- LH / FSH
GnRH
T
Inhibin B DHT
T
Sperm
E2
26
Causes of Secondary HypogonadismT 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
27
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 Normal27
28
Secondary HypogonadismImportance
• 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
29
Diagnosis of Male HypogonadismSummary
• 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
30
Male HypogonadismTreatment 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
31
T Treatment Potential Benefits and Risks
Benefits Risks• Sexual development• Erections• Libido, sexual activity• Energy, mood, vitality• Muscle strength • Physical function
• Erythrocytosis• Acne• Sperm count• Prostate biopsy• Gynecomastia• Breast cancer (rare)
• BMD • Sleep apnea (rare)• Local (pain, skin rash)
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
32
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
33
Male HypogonadismMonitoring
• 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
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
34
Longitudinal T Levels with AgeT
esto
ster
one
Tes
tost
eron
e (
nmol
/L)
(nm
ol/L
)
Age (Years)Age (Years)
1010
1212
1414
1616
1818
2020
3030 4040 5050 6060 7070 8080 9090
(177)(177)
(144)(144)(151)(151)
(158)(158)
(109)(109)
(43)(43)
Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001.Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001.
35
Age-Related Changes in Body Composition
0102030405060708090
20 30 40 50 60 70
Age (yrs)
kg
Total weight (kg)
Lean body mass (kg)
Fat mass (kg)
Forbes GB, Metabolism 14:653-663, 1970
36
Olympic Weight-Lifting Performance with Aging in Masters Athletes
0
0.2
0.4
0.6
0.8
1
1.2
30 35 49 45 50 55 60 65 70 75 80
Age (yrs)
Av
era
ge
We
igh
t L
ifti
ng
P
erf
orm
an
ce
Performance at Age 30 = 1[Corrected for Body Weight]
DE Meltzer, J Appl Physiol 80:1149-1155, 1996
37
Age-Related Increase in Incidence of Prostate Cancer
0
400
800
1200
1600
2000
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
Age Range (yrs)
Rat
e p
er 1
00,0
00
AfricanAmerican
Caucasian
1991-1995 SEER age-specific rates
38
Prevalence of Histological Prostate Cancer
0
20,000
40,000
60,000
80,000
100,000
0 20 40 60 80 100
Age (yrs)
Pre
vale
nce
/100
,000
Mal
es US
Japan
Carter HB, et al, J Urol 143:742, 1990
20-40%
39
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?
40
T Treatment of Older MenEvidence 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.
41S Page, et al, L Tenover, J Clin Endocrinol Metab 89:503-510, 2004
Effect of T Alone and T plus Finasteride on Lean Mass in Older Men
Placebo
T
T + F
0
-1.6
-3.2
-4.8
24120 36
Months
F
at M
ass
(kg)
0 12 24 36
0
3
4
1
2
5
Le
an M
ass
(kg)
Months
42
P
hysi
cal P
erfo
rman
ce (
sec)
R
ight
Han
d G
rip S
tren
gth
(kg)
-1
1
0
2
0
2
4
6
Months
0 12 24 36 120
Months
24 36
Placebo
T
T + F
Effect of T Alone and T plus Finasteride on Physical Performance and Hand Grip in Older
Men
S Page, et al, L Tenover, J Clin Endocrinol Metab 89:503-510, 2004
43
Androgen Deficiency in the Aging MaleLimitations 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, placebo-controlled trial x 1 yr in older hypogonadal men planned– Physical, sexual (cognitive?) function and vitality
44
Androgen Deficiency in the Aging MaleAssociations 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; Almeida, Arch Gen Psych 65:283, 2008; Moffat, Neurology 62:188, 2004
45
Increased Mortality/4 Yrs in 858 Older Male Veterans (Mean Age 61) with Consistently Low T
Shores MM, et al, Arch Intern Med 166:1660-1665, 2006Shores MM, et al, Arch Intern Med 166:1660-1665, 2006
46
Low Total T Levels Associated with Increased Mortality/12 Yrs in 794 Community-Dwelling Men (Mean
Age 71) in Rancho Bernardo
Laughlin GA, et al, J Clin Endocrinol Metab 93:68-75, 2008Laughlin GA, et al, J Clin Endocrinol Metab 93:68-75, 2008
370
241
288
338
422
209
266
288
507
171
Median Total T (ng/dL)
Highest decile (reference)
Lowest decile
Median~300 ng/dL
Hazards ratio1 1.5 2
47
Hypogonadism in Older MenConclusions
• Common disorder
• Nonspecific clinical findings affected by age, severity and duration of T and co-morbidities
• 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 available
48
Hypogonadism in Older MenConclusions
• 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)
49
Male HypogonadismReferences
• 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