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Hypogonadism in the ageing male
Epidemiological aspects of LOH
Dr. Herman LeliefeldThe Netherlands
Prism IV Bruges Belgium September 25-26, 2014
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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
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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
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Age distribution of parents in Germany and Japan
• Marlon Brando
• Pablo Picasso
• Charlie Chaplin
Nieschlag, Andrology , 2000
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Life expectancy is doubled in 100 years
Nieschlag, 2000
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Increase in overweight in 20 years from 30 to 60% The Netherlands ; 2009/2010
Blokstra, RIVM 2011
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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
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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
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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
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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
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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
• ??
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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
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Testosteron and the serum level of SHBG
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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
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Testosterone and Sexual Intercourse
Jannini, 1999
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PDE5-inhibitors can increase T
No sex: T↓;LH ↑
Fabbri,1988Carosa, 2002
Carosa,2004 Clin.Endocrinology
With sex: T ↑ ;LH ↓
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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
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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]
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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
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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
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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)
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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)
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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)
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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)
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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)
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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)
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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
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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
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Araujo et al. J Clin Endocrinol Metabolism 2007,
Age , ˂ 50 y, N=869 Age > 50 y, N=606
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Message 2:Sharp increase of LOH-prevalence with
• Metabolic syndrome : 30-50%
• Diabetes mellitus Type 2 : 40 %
• COPD
• Depression
• Corticosteroid therapy
• Osteoporosis
• Sexual disfunction
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Still a low awareness of the dangers of overweight
Citizens of Alabama came together to raise money for “home for lost animals”
The End