Hypogonadism in the ageing male

Epidemiological aspects of LOH

Dr. Herman LeliefeldThe Netherlands

Prism IV Bruges Belgium September 25-26, 2014

Definition of Late Onset Hypogonadism(LOH)

Testosterone Deficiency Syndrome(TDS),with advancing age

• Is a clinical ánd biochemicalsyndrome associated withadvancing age and characterizedby symptoms and a deficiency in serum testosterone levels, below the young healthy adult male reference range

• This condition may result in significant detriment in the quality of life and adverselyaffect the function of multiple organ systems

ISSAM, ISA, EAU, EAA, ASA

2005, 2012

The term LOH has general consensus in guidelines

Wrong terms:

• Andropause

• Climacterium virile

• ADAM

• PADAM

Why wrong:

• Gradual over decades

• No complete loss of androgens

• “only” 20 -35% of men

• Combination of secondary andprimary hypogonadism

• Fertile in high age

Age distribution of parents in Germany and Japan

• Marlon Brando

• Pablo Picasso

• Charlie Chaplin

Nieschlag, Andrology , 2000

Life expectancy is doubled in 100 years

Nieschlag, 2000

Increase in overweight in 20 years from 30 to 60% The Netherlands ; 2009/2010

Blokstra, RIVM 2011

Serum levels of Testosterone and FT decline with age

Harman, 2001 Zitzmann, Nieschlag, 2003

From the age of 35 years:

about 1,2% fall each year

So: low Testosteron in men :

20 % in men over 60 years30 % in men over 70 years50 % in men over 80 years

The Alternative View:

The decline of T in older men is a consequence of the accumulation of comorbidities of ageing,

which can depress T unrelated to the coincidental non-specific symptoms of chronic disease, that resemble those of LOH

Alternative hypothesis :

• Decline of T in ageing male is not the cause but the consequence of comorbidities

• Is there a “prove” for this theory?

Study of Sartorius, Clinical Endocrinology, 2012, 77, 755-63

Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self‐reporting very good health: the healthy man study

Clinical EndocrinologyVolume 77, Issue 5, pages 755-763, 5 OCT 2012 DOI: 10.1111/j.1365-2265.2012.04432.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2012.04432.x/full#cen4432-fig-0001

Serum level of Testosterone is not influencedby age alone but also by:

• Hour of the day

• Level of SHBG

• Acute / chronic diseases

• Medications

• Drugs :marijuana, cocaine

• Alcohol

• Sexual intercourse

• Variation of the Androgen Receptor

• The type of immunoassay

• Environmental toxins

• Patientpopulation / healthy men

• ??

Testosteron and the Hour of the Day

Bremner, 1983 J Clin Endocrin and Met 56, 1278-1281

Deslypere, 1984 J Clin Endocrin and Met 59,955-62

Testosteron and the serum level of SHBG

Testosterone and Acute and Chronic Diseases

Acute diseases

• Operations

• Severe burns

• Multiple trauma

• Acute CVA

• Sepsis

• AIDS

Chronic diseases

• Liver cirrhosis

• Chronic renal insufficiency

• Diabetes mellitus

• Hemochromatosis

• Sickle cell anemia

• Thyroid diseases

• Malignoma

Testosterone and Sexual Intercourse

Jannini, 1999

PDE5-inhibitors can increase T

No sex: T↓;LH ↑

Fabbri,1988Carosa, 2002

Carosa,2004 Clin.Endocrinology

With sex: T ↑ ;LH ↓

What is the prevalence of LOH in the literature?

Numerous observational studies are studies on prevalence of testosterone decline alone with one single blood sample for T

• Cross-sectional studies

• Longitudinal studies

Kaufman JM and Vermeulen A Baillières Clin Endocrinol Metab 11: 289-309 (1997)

Proportion of Healthy Men Presenting

with Subnormal Testosterone Serum Levels

Pro

po

rtio

n [

%]

Total testosterone

(< 11 nmol/L)

Free testosterone

(< 0.18 nmol/L)

N=105

N=68

N=87

N=40

Age [years]

Corona G and Maggi M Nat Rev Urol 7:46-56 (2010)

Biochemical Definitions of Hypogonadism and Prevalence of

Hypogonadism (TD) in 1,922 Consecutive Patients Presenting with ED

0

4

8

12

16

20

24

28

< 7 < 8 < 10.4 < 12

Hypogonadism thresholds (nmol/l)

Pre

va

len

ce

of

pa

tie

nts

wit

h E

D

Biochemical definitions of hypogonadism

Guidelines nmol/l ng/ml ng/dl

EAA, ISA, ISSAM EAU, ASA Mild < 12 < 3.40 < 340Severe < 8 < 2.31 < 231

Endocrine Society < 10.4 < 3.00 < 300

AACE < 7 < 2.00 < 200

Prevalence of Hypogonadism in Aging Men According to

the BLSA (total T < 11.3 nmol/L, T/SHBG < 0.153)

Harman SM et al. J Clin Endocrinol Metab 86 (2): 724-731 (2001)

0

20

40

60

80

100

20-29 30-39 40-49 50-59 60-69 70-79 80+

Age Decade

Pe

rce

nta

ge

Testosterone

Free T Index

18 201279 332

350

251

94

Hypogonadism in MalesHIM Study

An Epidemiological Study to Estimate the Population Prevalence of Hypogonadism in Men Aged ≥ 45

years in the US

Mulligan T et al. Int J Clin Pract 60: 762-769 (2006)

Study Population95 sites enrolled 2,165 patients: 47 Family Practice 44 Internal Medicine3 Endocrinology1 Urology

Reasons to present to the doctors’s office:General check-up 61.6%Cardiovascualar 12.0%Respiratory 8.0%Skeletal 6.5%Other 12.1%

Mulligan T et al. Int J Clin Pract 60: 762-769 (2006)

Distribution of Total Testosterone Levels in 2,162 Men in the HIM Study

0

100

200

300

400

500

600

700

< 100 100 -

199

200 -

299

300 -

399

400 -

599

600 -

799

800 -

999

>= 1,000

Total Testosterone Levels (ng/dL)

Nu

mb

er

of

Su

bje

cts

38.7% hypogonadal

Mulligan T et al. Int J Clin Pract 60: 762-769 (2006)

Men with TDS as patients in general practice

Mulligan T et al. Int J Clin Pract 2006; 60: 762–9.

Pati

en

ts w

ith

TD

S <

10

.5 n

mo

l/L

(%

)

45–54 55–64 65–74 75–84 All≥85

n=2162

Age (years)

Prevalence Rates and Odds Ratios for Selected Co-Morbidities in Untreated Hypogonadal Patients

Medical Condition Hypogonadism Prevalence

Rate (95% C.I.)

Odds Ratio (95% C.I.)

Obesity 52.4 (47.9 – 56.9 2.38 (1.93 - 2.93)

Diabetes 50.0 (45.4 – 54.5) 2.09 (1.70 - 2.58)

Hypertension 42.4 (39.6 – 45.2) 1.84 (1.53 - 2.22)

Rheumatoid Arthritis 47.3 (34.1 – 60.5) 1.59 (0.92 - 2.72)

Hyperlipidaemia 40.4 (37.6 – 43.3) 1.47 (1.23 - 1.76)

Osteoporosis 44.4 (25.5 – 64.7) 1.41 (0.64 - 3.01)

Asthma/COPD 43.5 (36.8 – 50.3) 1.40 (1.04 - 1.86)

Prostatic Disease/Disorder 41.3 (36.4 – 46.2) 1.29 (1.03 - 1.62)

Chronic Pain 38.8 (33.7 – 44.0) 1.13 (0.89 - 1.44)

Mulligan T et al. Int J Clin Pract 60: 762-769 (2006)

Prevalence Rates and Odds Ratios for Selected Co-Morbidities in Untreated Hypogonadal Men ≥ 45 Years Visiting a Doctor’s Office

Medical Condition Hypogonadism

Prevalence Rate

(95% C.I.)

Odds Ratio

(95% C.I.)

Obesity 52.4 (47.9 – 56.9) 2.38 (1.93 - 2.93)

Diabetes 50.0 (45.4 – 54.5) 2.09 (1.70 - 2.58)

Hypertension 42.4 (39.6 – 45.2) 1.84 (1.53 - 2.22)

Mulligan T et al. Int J Clin Pract 60: 762-769 (2006)

Message 1:

Prevalence of TestosteroneDeficiency is influenced bymultiple factors and shows a broad variation

Prevalence of TestosteroneDeficiency is not the same as for LOH!!

20% over 60 years30% over 70 years50% over 80 years

Baltimore Study,2001

Prevalence of Late Onset Hypogonadism

• Population based survey

• N=1475

• Cut off point for Testosterone:10.4 nmol/l

• Overall prevalence : 5,6 %

• Endocrine Society, Bhasin 2010 : 6%

• Sharp increase with age

Araujo, 2007

Araujo et al. J Clin Endocrinol Metabolism 2007,

Age , ˂ 50 y, N=869 Age > 50 y, N=606

Message 2:Sharp increase of LOH-prevalence with

• Metabolic syndrome : 30-50%

• Diabetes mellitus Type 2 : 40 %

• COPD

• Depression

• Corticosteroid therapy

• Osteoporosis

• Sexual disfunction

Still a low awareness of the dangers of overweight

Citizens of Alabama came together to raise money for “home for lost animals”

The End