Prevalence of Age Associated Testosterone Deficiency in Males

1
Prevalence of Age Associated Testosterone
Deficiency in Males

• Bobby Jacob, Pharm.D.
• Mercer University June 29, 2010

2
Testosterone replacement therapy (TRT)
3
Do men really age?
4
Do men really age?
5
Do men really age?
6
Program Objectives

• Discuss the potential physiologic consequences of
  age associated testosterone deficiency
• Discuss current guidelines and recommendations
  regarding appropriate diagnostic criteria for age
  associated testosterone deficiency
• Discuss recent literature that has evaluated
  cross-sectional and longitudinal trends with
  respect to testosterone concentrations in males
• Discuss recent literature that has evaluated the
  prevalence of age associated testosterone
  deficiency in the general population

7
Basic anatomy and physiology
8
Male Reproductive System
Mescher AL. Junqueiras basic histology text
atlas, 12 edition. McGraw-Hill company, 2010.
9
Testes
Mescher AL. Junqueiras basic histology text
atlas, 12 edition. McGraw-Hill company, 2010.
10
Testes
Leydig or interstitial cells are the primary site
of endogenous testosterone production
(95) Testosterone is the primary androgen in
the male
Mescher AL. Junqueiras basic histology text
atlas, 12 edition. McGraw-Hill company, 2010.
11
Systemic distribution

• Regulated by protein binding in the body
• 50-70 tightly bound to sex hormone binding
  globulin (SHBG)
• 20-30 loosely bound to albumin
• 4 bound to other proteins
• Only 1-3 is free, non-protein bound
  (biologically active)

Diver MJ. Front Horm Res 20093721-31
12
HPG Axis
Hypothalamus stimulates release of GnRH
GnRH stimulates pituitary release of LH and FSH
Testosterone provides negative feedback to the HP
axis AND has a stimulatory effect on
spermatogensis
LH interacts with receptors on Leydig cells to
stimulate testosterone production
FSH acts on Sertoli cells to stimulate
spermatogenesis
Bhasin S and Jameson JL. Disorders of the testes
and male reproductive system. In Harrisons
principles of internal medicine. EdsFauci AS, et
al. McGraw-Hill Companies, 2008.
13
Definition

• Male hypogonadism
• Deficiency of both testosterone and spermatozoa
• Primary
• Secondary
• Mixed

Bhasin S, et al. JCEM 2010952536-2559
14
Pathophysiology

• Primary
• Testicular dysfunction
• Low testosterone, elevated LH/FSH
• Secondary
• Hypothalamic-pituitary dysfunction
• Low testosterone, low LH/FSH
• Mixed
• Can be observed with age associated testosterone
  deficiency

Bhasin S and Jameson JL. Disorders of the testes
and male reproductive system. In Harrisons
principles of internal medicine. EdsFauci AS, et
al. McGraw-Hill Companies, 2008.
15
Diagnostic criteria
16
Definition

• Age associated testosterone deficiency (late
  onset hypogonadism)
• A clinical and biochemical syndrome associated
  with advancing age and characterized by symptoms
  and a deficiency in serum testosterone levels
  (below the young healthy adult male reference
  range)

Wang C, et al. Int J Impotence Res 2009211-8
17
Specific symptoms

• Reduced libido and sexual activity
• Most commonly associated with hypogonadism
• Decreased spontaneous erections
• Breast discomfort
• Gynecomastia
• Loss of body hair
• Height loss
• Low trauma facture
• Low bone mineral density
• Hot flushes, sweats

Bhasin S, et al. JCEM 2010952536-2559
18
Non-specific symptoms

• Decreased energy or motivation
• Depressed mood, dysthymia
• Poor concentration or memory
• Sleep disturbances
• Mild anemia
• Reduced muscle mass and strength
• Increased body fat or body mass index
• Diminished physical or work performance

Bhasin S, et al. JCEM 2010952536-2559
19
Serum total testosterone

• Recommended measurement for diagnosis
• Normal range is variable depending on laboratory
• 280-300 ng/dL has been historically noted for
  lower limit, but we remain unclear regarding what
  is most clinically applicable
• Follow laboratory specific reference ranges
• Multiple assay types can be used
• Debatable if this is the best indicator of
  physiologic activity
• Continued difficulty in establishing standardized
  reference ranges for use across the country has
  presented challenges for clinicians
• CDC is currently working on a project to
  standardize measurement

Bhasin S, et al. JCEM 2010952536-2559
20
Serum total testosterone

• Influenced by many factors
• Circadian rhythm
• Measurement should be in the early morning
• Acute/chronic illness
• Measurement not recommended during these times
• SHBG levels
• Several chronic conditions (particularly in aging
  males) are associated with altered levels
• Certain medications
• Opioids
• Steroids

Bhasin S, et al. JCEM 2010952536-2559
21
Other laboratory measurements

• Free testosterone (FT)
• Unbound, biologically active testosterone in the
  blood
• Equilibrium dialysis is the gold standard
  however, not widely available
• Calculated using total testosterone (TT), SHBG,
  and albumin
• Lower limit of normal has been suggested between
  50-90 pg/dL
• Bioavailable testosterone (BAT)
• Free testosterone plus albumin bound testosterone
  
• Ammonium sulfate precipitation method or
  calculated using TT and SHBG

Bhasin S, et al. JCEM 2010952536-2559
22
Variability in laboratory evaluation

• Telephone survey conducted in September 2004
• Purpose was to access the state of laboratory
  diagnosis of hypogonadism
• Directors of 25 laboratories in New England were
  contacted
• 12 academic medical centers
• 12 community practice sites
• 1 national laboratory (Quest Diagnostics)
• The following information was recorded
• Types of assays used
• Manfacturer of assay
• Reference range utilized

Lazarou S, et al. J Sex Med 200631085-1089
23
Variability in laboratory evaluation

• Results regarding assays used
• Academic
• 12/12 (100) offered assay for TT
• 6/12 (50 offered assay for FT
• Community
• 8/12 (67) offered assay for TT
• 1/12 (8) offered assay for FT
• Eight different assays for TT 4 different assays
  for FT
• No laboratory performed independent validation of
  the manufacturers recommended reference range

Lazarou S, et al. J Sex Med 200631085-1089
24
Variability in lowest value for reference range
Lazarou S, et al. J Sex Med 200631085-1089
25
Endocrine Society recommendations

• Diagnosis of testosterone deficiency should be
  made ONLY in men with consistent symptoms/signs
  and unequivocally low serum testosterone levels
• Serum testosterone levels should be measured in a
  patient with clinical manifestations
• Measurement of morning serum TT by a reliable
  assay should be the initial diagnostic test
• Confirmation of the diagnosis by repeat
  measurement is recommended
• Measurement of FT or BAT is recommended in men
  near the lower limit of normal or if SHBG
  variation is suspected
• Screening of the general population is not
  recommended

Bhasin S, et al. JCEM 2010952536-2559
26
Longitudinal and Cross-sectional trends with
aging
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Massachusetts Male Aging Study (MMAS)

• Prospective, observational study on health and
  aging in men from the Massachusetts area
• Compare levels and cross-sectional trends
• Estimate within subject longitudinal trends
• 1,709 men seen at T1 (mean age 55.28.7 years)
• 1,156 men seen at T2 (mean age 62.78.3 years)
• Mean duration between T1 and T2 was 8.9 years
• TT measured by RIA FT calculated
• Height, weight, co-morbid conditions, current
  prescription and non-prescription medications,
  alcohol intake measured at each visit
• Good health defined as
• No chronic illness, no medication use, BMI lt29,
  alcohol use not gt5 drinks daily

Feldman HA, et al. JCEM 200287589-598
28
MMAS
Measure T1 () T2 ()
Married 75 76
White 95 96
Black 3 2
Good health 26 18
Diabetes 5 7
Heart disease 7 11
Hypertension 16 25
No ED 8 10
TT 520180 ng/dL 450160 ng/dL
FT 9739 pg/mL 7532 pg/mL
Feldman HA, et al. JCEM 200287589-598
29
MMAS
Good health status added 10-15 to serum
testosterone levels Did not affect longitudinal
trend significantly attenuated cross-sectional
declines in TT
Feldman HA, et al. JCEM 200287589-598
30
MMAS
Cross-sectional
Feldman HA, et al. JCEM 200287589-598
31
Baltimore Longitudinal Study on Aging (BLSA)

• Open registration study on physiology of aging,
  gt40 years duration with data collection at 2 year
  intervals
• 890 men from the Baltimore area (mean age at
  entry 53.815.8 years)
• TT measured by RIA
• During a 6 month period in 1995 samples from each
  subjects most recent visit, previous 3 visits,
  and closest to 10, 15, 20, 25, and 30 years were
  obtained

Harman SM, et al. JCEM 200186724-731
32
BLSA Longitudinal Trends
TT declines by 3.2 ng/dL per year Similar results
seen with FT Index Cross-sectional declines seen
as well
Harman SM, et al. JCEM 200186724-731
33
MMAS
From T1 to T3, there is a substantial increase in
chronic illness and polypharmacy while there is
a substantial decrease in the proportion of
smokers.
Travison TG, et al. JCEM 200792196-202
34
MMAS
Health/Lifestyle factor N Meandecline TT Mean decline FT
No illness T1 and T2 382 4.0 7.3
No illness T1 1 illness T2 162 6.3 13.1

lt6 Rx meds at T1 and T2 889 5.0 9.6
lt6 Rx meds at T1 6 at T2 49 9.9 13.4

Smoker at T1 and T2 112 1.6 (increase) 6.9
Smoker at T1 nonsmoker at T2 93 7.6 11.0

Married at T1 and T2 680 6.0 12.0
Married at T1 widowed at T2 25 16.9 21.2
Travison TG, et al. JCEM 200792549-555
35
Secular decline
Travison TG, et al. CurrOpinEndocrinol Diabetes
Obes 200916211-217
36
Secular decline - MMAS
Unadjusted Unadjusted Adjusted Adjusted
Mean decline () P value Mean decline () P value
Cross-sectional -0.4 lt0.001 -0.1 0.42
Longitudinal -1.6 lt0.001 -1.1 lt0.001
Age matched -1.2 lt0.001 -1.0 lt0.001
Adjustment for chronic illness, general health,
medication use, smoking, BMI, employment, and
marital status
Travison TG, et al. JCEM 200792196-202
37
Health in Men Study

• Prospective, cohort investigation of community
  dwelling men, 70 years in Australia
• Establish if TT and FT decline in linear fashion
  at the upper range of age or reach a plateau
• Determine appropriateness of age adjusted
  reference ranges
• 3,645 men participated (mean age 77.03.6 years)
• TT measured by immunoassay FT calculated
• Physical exam performed and questionnaire given
  on risk factors for CV disease, medical history,
  and alcohol consumption

Yeap BB, et al. Eur J Endocrinol 2007156585-594
38
Health in Men Study
Yeap BB, et al. Eur J Endocrinol 2007156585-594
39
Health in Men Study
Yeap BB, et al. Eur J Endocrinol 2007156585-594
40
Belgium study
Longitudinal study of 221 community dwelling men
over 4 years (mean age 74.0 years) Decline of
1.26 per year for TT (95 CI -2.58 to -0.01) and
2.43 (95 CI -3.78 to -1.08) for BAT
Lapauw B, et al. Eur J Endocrinol
2008159459-468
41
Prevalence Studies
42
DETECT Study

• Cross-sectional evaluation of participants in the
  DETECT study
• Diabetes Cardiovascular Risk Evaluation Targets
  and Essential Data for Commitment of Treatment
  focused on assessment of cardiovascular risk
• Estimate the prevalence of hypogonadism in
  primary care
• 2,719 men at primary care sites in Germany (men
  age 5813.4 years)
• TT measured by immunoassay
• Definition of hypogonadism
• TT lt346 ng/dL
• TT lt320 ng/dL
• TT lt300 ng/dL
• No assessment of symptoms or breakdown by age
• Physicians diagnosed co-morbid conditions based
  on pre-specified criteria

Schneider HJ, et al. ClinEndocrinol
200970446-454
43
DETECT study

• Prevalence of testosterone deficiency
• TT lt346 ng/dL 28.1
• TT lt320 ng/dL 22.3
• TT lt300 ng/dL 19.3
• Negative correlation between TT and the following
  conditions
• Diabetes, dyslipidemia, cancer, metabolic
  syndrome, depression, 4 physician diagnoses, 6
  prescription medications, acute inflammation
• No correlation with coronary artery disease,
  heart failure, or stroke
• Significantly associated with TT lt300 ng/dL
• Obesity, cancer, metabolic syndrome, 6
  prescription medications, not smoking, acute
  inflammation
• Significantly associated with TT lt100 ng/dL
• Age, cancer, and liver disease

Schneider HJ, et al. ClinEndocrinol
200970446-454
44
HIM study

• Cross-sectional evaluation (industry sponsored)
• Estimate the prevalence of hypogonadism in men
  45 years in primary care
• 2,165 men visiting primary care clinics in the
  United States (mean age 60.510.3 years)
• TT measured RIA FT measured by equilibrium
  dialysis, - hypogonadism separately defined as
• TT lt300 ng/dL
• FT lt52 pg/mL
• BAT lt95 ng/dL for ages lt70 BAT lt60 ng/dL for
  ages 70 years and older
• Current androgen therapy
• No breakdown of data by age

Mulligan T, et al. Int J ClinPract
200660(7)762-769
45
HIM study

• Prevalence rate 36.3 based on TT
• 40 based on FT
• 45 based on BAT
• Each 10 year increase in age leads to a 33
  increased risk of hypogonadism
• 67 of hypogonadal men reported at least one
  symptom

Mulligan T, et al. Int J ClinPract
200660(7)762-769
46
HIM study

• Odds ratio (95 CI) for having hypogonadism
  associated with select conditions
• Obesity 2.38 (1.93-2.93)
• Diabetes 2.09 (1.70-2.58)
• Hypertension 1.84 (1.53-2.22)
• Dyslipidemia 1.47 (1.23-1.76)
• Asthma/COPD 1.40 (1.04-1.86)
• Prostatic disease 1.29 (1.03-1.62)

Mulligan T, et al. Int J ClinPract
200660(7)762-769
47
BLSA

• Longitudinal study (40 years) with sampling at 2
  year intervals
• 890 men from Baltimore area (mean age at entry
  53.815.8 years)
• TT measured by RIA
• No assessment of symptoms
• Prevalence rate measured by age decade using two
  criteria
• TT lt325 ng/dL
• FT Index (TT/SHBG) lt0.153

Harman SM, et al. JCEM 200186724-731
48
BLSA
Harman SM, et al. JCEM 200186724-731
49
MMAS

• Observational, cohort study of men in the Boston
  area
• 1,709 men completed baseline assessment (T1)
  1,156 men completed follow-up (T2, mean interval
  for follow-up was 8.6 years)
• TT measured by RIA FT calculated
• Men screened for following symptoms
• Decreased libido, ED, depression, lethargy,
  inability to concentrate, sleep disturbance,
  irritability, depressed mood
• Criteria for androgen deficiency
• 3 symptoms AND TT lt200 ng/dL
• 3 symptoms AND TT 200-400 ng/dL AND FT lt89.1
  pg/mL

Araujo AB, et al. JCEM 2004895920-5926
50
MMAS
Araujo AB, et al. JCEM 2004895920-5926
51
MMAS

• Prevalence of testosterone deficiency
• Baseline
• Crude - 6
• 40-49 - 4.1
• 50-59 - 4.5
• 60-70 - 9.4
• Follow-up
• Crude - 12.3
• 48-59 - 7.1
• 60-69 - 11.5
• 70-79 - 22.8
• Significant increase with age across time
  (Plt0.001)

Araujo AB, et al. JCEM 2004895920-5926
52
Boston Community Area Health (BACH) Survey

• Population based, observational survey of men in
  the Boston area
• Estimate crude and age-specific prevalence rates
  of testosterone deficiency
• Examine the association between symptoms and
  testosterone deficiency
• 1,875 men (mean age 47.312.5 years)
• TT measured by immunoassay FT calculated
• Men screened for the following symptoms
• Decreased libido, ED, osteoporosis, osteoporotic
  fracture, letheray, sleep disturbance, depressed
  mood, and low physical performance
• Criteria for symptomatic testosterone deficiency
• 1 symptom AND TT lt300 ng/dL AND FT lt50 pg/mL

Araujo AB, et al. JCEM 2007924241-4247
53
BACH survey
Araujo AB, et al. JCEM 2007924241-4247
54
BACH survey
Araujo AB, et al. JCEM 2007924241-4247
55
Taiwan study

• Free health screening offered to men in Taiwan
• Evaluate the prevalence of androgen deficiency
• Identify potential risk factors
• 734 men (mean age 57.46.7 years) participated
• TT measured by immunoassay FT calculated
• Men assessed for decreased libido, ED, fatigue,
  decreased muscle strength, mood change, loss of
  height (ADAM questionnaire)
• Criteria for androgen deficiency
• TT lt300 ng/dL OR TT lt300 ng/dL AND FT lt50 pg/mL
• Criteria for symptomatic androgen deficiency
• TT lt300 ng/dL AND FT lt50 pg/mL AND positive
  symptoms from ADAM questionnaire

Liu C, et al. J Sex Med 20096936-946
56
Taiwan study
Liu C, et al. J Sex Med 20096936-946
57
Taiwan study
40-49 years 50-59 years 60-69 years ?70 years
TT lt300 ng/dL 16.5 23.0 28.9 37.2
FT lt50 pg/mL 16.5 26.9 36.7 69.0
TT lt300 ng/dL FT lt50 pg/mL 10.4 16.3 19.0 28.6
Symptomatic androgen deficiency 7.8 11.8 14.0 21.4
Liu C, et al. J Sex Med 20096936-946
58
European Male Aging Study (EMAS)

• Cross-sectional survey in 3,369 community
  dwelling men ages 40-79 years (mean age
  59.711.0) across Europe
• Single morning measurement of TT by GC-MS
• Categories of testosterone status
• Secondary hypogonadism
• Decreased TT, decreased LH
• 11.8
• Primary hypogonadism
• Decreased TT, elevated LH
• 2.0
• Compensated hypogonadism
• Normal TT, elevated LH
• 9.5

Tajar A, et al. JCEM 2010951810-1818
59
Are specific symptoms associated with specific
testosterone levels?

• Cross-sectional cohort study or symptomatic men
  50 years
• Challenge the notion that a uniform testosterone
  level can be used to explain the increase in
  testosterone deficiency related symptoms
• 434 men (mean age 57.96.6 years) participated
• Men with primary or secondary hypogonadism,
  history of androgen treatment, and those living
  alone were excluded
• Questionnaire administered regarding symptoms
• TT measured by ELISA FT calculated
• Prostate health, diabetes, obesity, LUTS, ED,
  alcohol consumption, and smoking assessed

Zitzmann M, et al. JCEM 2006914335-4343
60
Are specific symptoms associated with specific
testosterone levels?
576.4 ng/dL
432.3 ng/dL
345.8 ng/dL
288.2 ng/dL
230.5 ng/dL
Zitzmann M, et al. JCEM 2006914335-4343
61
Conclusions

• Age associated testosterone deficiency is a
  clinical syndrome associated with specific and
  non-specific symptoms occurring in a male with
  low serum total testosterone levels
• Diagnosis can be made in symptomatic older males
  based on two morning serum testosterone
  measurements however, guidelines to define low
  testosterone remain to be determined
• Longitudinal declines in the male general
  population appear to be 1-2 annually the
  influence of secular declines on testosterone
  levels remains to be fully elucidated
• Prevalence of symptomatic testosterone deficiency
  or hypogonadism in the general population appears
  to be around 5-12 - this is much lower than
  earlier studies that did not incorporate symptoms
  in the clinical diagnosis
• There does appear to be a clear association
  between increasing age and increasing prevalence
  of testosterone deficiency