1 evaluation and treatment of hypogonadism in older men alvin m. matsumoto, m.d. associate director,...

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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

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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

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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

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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

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Secondary Hypogonadism

T

Normal- LH / FSH

GnRH

T

Inhibin B DHT

T

Sperm

E2

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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%

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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?

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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

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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

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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

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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

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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)

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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