Prevalence of Age Associated Testosterone Deficiency in Males

Prevalence of Age Associated Testosterone Deficiency in Males

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

Testosterone replacement therapy (TRT)

Do men really age?

Do men really age?

Do men really age?

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

Basic anatomy and physiology

Male Reproductive System

Mescher AL. Junqueira’s basic histology text & atlas, 12 edition. McGraw-Hill company, 2010.

Testes


Testes

Leydig or interstitial cells are the primary site of endogenous testosterone production (~95%)

Testosterone is the primary androgen in the male


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 2009;37:21-31

HPG Axis

Hypothalamus stimulates release of GnRH GnRH stimulates

pituitary release of LH and FSH

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: Harrison’s principles of internal medicine. EdsFauci AS, et al. McGraw-Hill Companies, 2008.

Testosterone provides negative feedback to the HP axis AND has a stimulatory effect on spermatogensis

Definition Male hypogonadism

Deficiency of both testosterone and spermatozoa Primary Secondary Mixed

Bhasin S, et al. JCEM 2010;95:2536-2559

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: Harrison’s principles of internal medicine. EdsFauci AS, et al. McGraw-Hill Companies, 2008.

Diagnostic criteria

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 2009;21:1-8

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


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


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


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


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 SHBGBhasin S, et al. JCEM 2010;95:2536-2559

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 2006;3:1085-1089

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 manufacturer’s recommended reference range


Variability in lowest value for reference range


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


Longitudinal and Cross-sectional trends with aging

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 55.2±8.7 years) 1,156 men seen at T2 (mean age 62.7±8.3 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 <29, alcohol

use not >5 drinks daily

Feldman HA, et al. JCEM 2002;87:589-598

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 520±180 ng/dL 450±160 ng/dL

FT 97±39 pg/mL 75±32 pg/mL


MMAS

“Good health” status added 10-15% to serum testosterone levels Did not affect longitudinal trend; significantly attenuated cross-sectional declines in TT


MMAS

-3

-2.5

-2

-1.5

-1

-0.5

0

Baseline Follow-up Longitudinal

TT

FT


Cross-sectional

Baltimore Longitudinal Study on Aging (BLSA) Open registration study on physiology of

aging, >40 years duration with data collection at 2 year intervals

890 men from the Baltimore area (mean age at entry 53.8±15.8 years)

TT measured by RIA During a 6 month period in 1995 samples

from each subject’s most recent visit, previous 3 visits, and closest to 10, 15, 20, 25, and 30 years were obtained

Harman SM, et al. JCEM 2001;86:724-731

BLSA – Longitudinal Trends

TT declines by 3.2 ng/dL per year

Similar results seen with FT Index

Cross-sectional declines seen as wellHarman SM, et al. JCEM 2001;86:724-731

MMAS

Travison TG, et al. JCEM 2007;92:196-202

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.

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%

<6 Rx meds at T1 and T2 889 5.0% 9.6%

<6 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 2007;92:549-555

Secular decline

Travison TG, et al. CurrOpinEndocrinol Diabetes Obes 2009;16:211-217

Secular decline - MMAS

Unadjusted Adjusted

Mean decline (%)

P value Mean decline (%)

P value

Cross-sectional

-0.4 <0.001 -0.1 0.42

Longitudinal -1.6 <0.001 -1.1 <0.001

Age matched

-1.2 <0.001 -1.0 <0.001

Adjustment for chronic illness, general health, medication use, smoking, BMI, employment, and marital status

Travison TG, et al. JCEM 2007;92:196-202

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 77.0±3.6

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 2007;156:585-594

Health in Men Study


Health in Men Study


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 2008;159:459-468

Prevalence Studies

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

58±13.4 years) TT measured by immunoassay

Definition of “hypogonadism” TT <346 ng/dL TT <320 ng/dL TT <300 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 2009;70:446-454

DETECT study Prevalence of testosterone deficiency

TT <346 ng/dL – 28.1% TT <320 ng/dL – 22.3% TT <300 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 <300 ng/dL Obesity, cancer, metabolic syndrome, ≥6 prescription

medications, not smoking, acute inflammation Significantly associated with TT <100 ng/dL

Age, cancer, and liver diseaseSchneider HJ, et al. ClinEndocrinol 2009;70:446-454

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 60.5±10.3 years)

TT measured RIA; FT measured by equilibrium dialysis, - hypogonadism separately defined as: TT <300 ng/dL FT <52 pg/mL BAT <95 ng/dL for ages <70; BAT <60 ng/dL for ages

70 years and older Current androgen therapy

No breakdown of data by age

Mulligan T, et al. Int J ClinPract 2006;60(7):762-769

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


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)


BLSA Longitudinal study (40 years) with sampling at

2 year intervals 890 men from Baltimore area (mean age at

entry 53.8±15.8 years) TT measured by RIA No assessment of symptoms Prevalence rate measured by age decade

using two criteria TT <325 ng/dL FT Index (TT/SHBG) <0.153


BLSA


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 <200 ng/dL ≥3 symptoms AND TT 200-400 ng/dL AND FT <89.1 pg/mL

Araujo AB, et al. JCEM 2004;89:5920-5926

MMAS


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 (P<0.001)


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 47.3±12.5 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 <300 ng/dL AND FT <50 pg/mL


BACH survey


BACH survey


Taiwan study Free health screening offered to men in Taiwan

Evaluate the prevalence of androgen deficiency Identify potential risk factors

734 men (mean age 57.4±6.7 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 <300 ng/dL OR TT <300 ng/dL AND FT <50 pg/mL

Criteria for symptomatic androgen deficiency TT <300 ng/dL AND FT <50 pg/mL AND positive

symptoms from ADAM questionnaire

Liu C, et al. J Sex Med 2009;6:936-946

Taiwan study


Taiwan study

40-49 years

50-59 years

60-69 years

70 years

TT <300 ng/dL 16.5% 23.0% 28.9% 37.2%

FT <50 pg/mL 16.5% 26.9% 36.7% 69.0%

TT <300 ng/dL + FT <50 pg/mL

10.4% 16.3% 19.0% 28.6%

Symptomatic androgen deficiency

7.8% 11.8% 14.0% 21.4%


European Male Aging Study (EMAS) Cross-sectional survey in 3,369 community

dwelling men ages 40-79 years (mean age 59.7±11.0) 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 2010;95:1810-1818

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 57.9±6.6 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 2006;91:4335-4343

Are specific symptoms associated with specific testosterone levels?

Zitzmann M, et al. JCEM 2006;91:4335-4343

576.4 ng/dL

432.3 ng/dL

345.8 ng/dL

288.2 ng/dL

230.5 ng/dL

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

Documents

Prevalence of Age Associated Testosterone Deficiency in Males