1. Bill Lynch The St George Hospital Sydney
Epidemiological Aspects of Late Onset Hypogonadism (LOH) Does it Exist ?
Bill Lynch
The St George Hospital
Sydney

2. ????

3. Some Think So !!
TIME: 2014

4. epidemiology

5. Basics Testosterone levels peak in early 20’s Testosterone decreases
0.4% / year
Free Testosterone levels decrease
1.3% / year

6. Basics ≈ 39% men > 45 yrs have androgen deficiency (AD)
6% men yrs have symptomatic AD
symptomatic AD increases with age
4% < 50 yrs
8% > 50 yrs
Europeans – 2% men yrs have symptomatic AD

7. Summary: 4 Hypogonadism Prevalence Studies
BLSA, 2001
MMAS, 2005
HIM, 2006
BACH, 2007
Patient Number
890
1691
2165
1475
Age
22-91 yrs (mean 53.8)
40-69 yrs
≥ 45 yrs (mean 60.5)
30-79 yrs (mean 47.3)
Testosterone
Total <325ng/dl
Total <200 ng/dl x 2
Total <300 ng/dl x 1
Total <300 ng/dl AND free <5 ng/dl
Screening of
symptoms
None
ADAM questionnaire
Questions,
no questionnaire
Questions
Prevalence of
hypogonadism
Defined by T
50s = 12%
60s = 19%
70s = 28%
80s = 49%
and symptoms
Baseline = 6%
Follow up =12.3%
38.7%
Defined by T and symptoms
5.6% (18.4% in 70s)
Harman SM, Metter EJ et al. JCEM 2001; 86: Araujo AB, O’Donnell AB et al. JCEM 2004; 89: Mulligan T, Frick MF et al. Int J Clin Pract. 2006; 60:762-9.
Araujo AB, Esche GR et al. JCEM 2007; 92:

8. Gooren & Behre, 2012. Aging Male 15(1):22-7
World Data
Gooren & Behre, Aging Male 15(1):22-7

9. The Health of Australia’s Males. AIHW: 2011
Australian Data
Incidence in Males > 40 years
The Health of Australia’s Males. AIHW: 2011

10. Rhoden E & Morgentaler A: N Engl J Med 2004;350:482-492
Percentage of men with low levels of T. and bioavailable T. as a function of age
Prevalence of low levels of Total and Bioavailable Testosterone as an index of male hypogonadism according to decade of life
Figure 1. Prevalence of Low Levels of Total and Bioavailable Testosterone as an Index of Male Hypogonadism According to Decade of Life. Dark bars represent the percentage of the population with total testosterone levels under 325 ng per deciliter,1 and light bars represent the percentage of the population with bioavailable testosterone levels under 70 ng per deciliter.2 Bioavailable testosterone was not measured in some age groups.
Rhoden E & Morgentaler A: N Engl J Med 2004;350:

11. Co-Morbidities Occur More Often in Hypogonadal Men (HIM Study)
Data from 2165 men aged ≦45yrs seen in primary care practice
Percentage (%)
The HIM study found that men with hypogonadism were significantly (p<0.001) more likely to have medical co-morbidities, such as hypertension, hyperlipidaemia, diabetes and obesity, than eugonadal men.
Int J Clin Pract Jul;60(7):762-9.
Prevalence of hypogonadism in males aged at least 45 years: the HIM study.
Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C.
The Hypogonadism in Males study estimated the prevalence of hypogonadism [total testosterone (TT) < 300 ng/dl] in men aged > or = 45 years visiting primary care practices in the United States. A blood sample was obtained between 8 am and noon and assayed for TT, free testosterone (FT) and bioavailable testosterone (BAT). Common symptoms of hypogonadism, comorbid conditions, demographics and reason for visit were recorded. Of 2162 patients, 836 were hypogonadal, with 80 receiving testosterone. Crude prevalence rate of hypogonadism was 38.7%. Similar trends were observed for FT and BAT. Among men not receiving testosterone, 756 (36.3%) were hypogonadal; odds ratios for having hypogonadism were significantly higher in men with hypertension (1.84), hyperlipidaemia (1.47), diabetes (2.09), obesity (2.38), prostate disease (1.29) and asthma or chronic obstructive pulmonary disease (1.40) than in men without these conditions. The prevalence of hypogonadism was 38.7% in men aged > or = 45 years presenting to primary care offices.
Conditions
Mulligan T, Frick MF et al. Int J Clin Pract. 2006; 60:

12. Does loh exist?

13. Does it Exist ? very little direct evidence
difficult to define the “syndrome”
gradual onset
especially as compared to menopause

14. Wu F et al.: N Engl J Med 2010; 363:123-35
LOH can be defined by the presence of at last three sexual symptoms associated with a total testosterone level of less than 11 nmol/L (320 ng/dL) and a free testosterone level of less than 220 pmol/L (64 pg/mL)
Wu F et al.: N Engl J Med 2010; 363:123-35

15. Probability Symptoms vs T. Levels
Wu F et al.: NEJM 2010:363:123-35

16. Probability Symptoms vs T. Levels
Wu F et al. : NEJM 2010:363:123-35

17. Probability Symptoms vs T. Levels
Wu F et al. NEJM 2010:

18. Wu – Validation Sets

19. Wu - Validation Sets

20. Wu – Validation Sets

21. Effects on Sexual Function (3 Years)
Sexual function improved significantly and was sustained *
Sexual Desire
Sexual Activity
Sexual desire (0-7)
Sexual activity (0-7)
Satisfaction with Erection
% Without Erections
After treatment with T gel, as a group sexual desire (P = ), enjoyment without partner (P = ), enjoyment with partner (P= ), percent full erection (P = ), and self-assessment of satisfaction with erections (P= ) improved, compared with baseline, and were maintained at the same level from 6 months until the end of the treatment period. Sexual activity scores were also significantly increased and maintained at the same level from 6 months throughout the treatment period (P = ). The proportion of subjects with erections increased from a baseline of 64.8% to 81.7% at 6 months without subsequent further significant increases.
Satisfaction (0-7)
Subjects without erections (%)
Months
Months
Wang C, Cunningham G et al. J Clin Endo Metab 2004; 89:

22. Effects on Mood (3 Years)
Mood improved significantly and changes were sustained from baseline
p =
p =
Positive Moods
Negative Moods
Positive moods (0-7)
Positive mood scores improved with treatment and were sustained (P=0.0022), whereas negative mood parameters were decreased and remained significantly lower (P=0.0013) than baseline without further changes after 6 months of T gel replacement. There was overall improvement in psychosexual function in men over 60 yr, but the changes were smaller, compared with those younger than 60 yr of age (e.g. sexual activity P= in older men and P= in younger men).
Months
Months
Wang C, Cunningham G et al. J Clin Endo Metab 2004; 89:

23. Effects on Body Composition (3 Years)
Lean and fat body mass changed significantly from baseline
* p =
* p = *
Lean Body Mass Change
Fat Body Mass Change
Lean mass change (kg)
Fat mass change (kg)
Average total body mass increased by 1.2 ± 0.3 kg at 6 months (P=0.0157) and did not significantly change with continued T gel therapy.
Lean body mass increased significantly (P=0.0001) from baseline and remained increased throughout the study period. The change in lean body mass was 1.97 ± kg at 6 months and was further increased to 2.93 ± 0.32 kg at 18 months and 2.89 ± 0.41 kg at 30 months (P=0.0065). The differences in the lean body mass between the dose groups and those over and under age 60 yr were not significant.
Fat mass decreased significantly as a group with T gel replacement (P=0.0058). The decrease in fat mass was 0.8 ± 0.3 kg at 6 months and 1.57 ± 0.38 and 1.30 ± 0.51 kg at 18 and 30 months (P= when compared with 6 months), respectively, without significant differences among the different dose groups. The decreases in fat mass (P=0.032) and percent fat (P=0.0001) were observed only in the younger subjects but not in older men. The changes in body composition parameters were not related to the change in serum T concentrations during replacement therapy.
Months
Months
Wang C, Cunningham G et al. J Clin Endo Metab 2004; 89:

24. Effects on Bone Mineral Density (3 Years)
BMD showed significant gradual and progressive increase from baseline
p =
p =
Change Hip BMD
Change Spine BMD
Change in hip BMD (g/cm2)
Change in spine BMD (g/cm2)
BMD of the hip (P = ) and spine (P= ) showed a gradual and progressive increase with treatment. The increase in the BMD was more marked in the spine than the hip. Spine BMD increased by 0.031± (3.1%) and ± g/cm2 (3.8%) at 18 and 30 months of treatment, respectively, and was significantly higher than that at 6 months (P =0.0001). There were no significant differences in the improvement in BMD among the three dose groups or between the younger and older age groups. The absolute increase in BMD in the hip and spine was not related to the baseline serum T or the change in serum T levels but was significantly related to baseline BMD (P= ).
Months
Months
Wang C, Cunningham G et al. J Clin Endo Metab 2004; 89:

25. T. therapy and mortality
Conclusions: In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment.
These results should be interpreted cautiously because residual confounding may still be a source of bias. Large, randomized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels.
Shores M et al. J Clin Endocrinol Metab 2012; 97: 2050–2058.

26. potential consequences of deficiency
Testosterone:
potential consequences of deficiency
Erectile Dysfunction
Insulin receptor resistance
incl. Type 2 Diabetes
Decrease of libido
Disturbances of
Lipid metabolism
Penile Length / Volume
TOTAL
TESTOSTERONE
Abdominal adiposity
(BIOAVAILABLE)
TESTOSTERONE
DEFICIENCY
Decrease of
muscle mass (frailty)
Disturbances of
well-being and mood
Osteoporosis
Reduced
hematopoiesis
Hot flushes
Myocardial and
circulatory disturbances

27. Clinical Features of Late Onset hypogonadism (LOH)
Physical
decreased muscle mass & strength
increased body fat
decreased bone mineral density
increased osteoporosis
Psychological
decreased vitality
decreased mood
Sexual
decreased libido
erectile dysfunction
decreased early morning erections
Wu FC et al. N Engl J Med 2010; 363(2):
Wang C, Nieschlag E et al. Aging Male 2008; 1-8

28. Wu F et al.: N Engl J Med 2010; 363:123-35
LOH can be defined by the presence of at last three sexual symptoms associated with a total testosterone level of less than 11 nmol/L (320 ng/dL) and a free testosterone level of less than 220 pmol/L (64 pg/mL)
in men who have previously not experienced these symptoms and have had normal T. levels
Wu F et al.: N Engl J Med 2010; 363:123-35

29. Does LOH Exist ?
YES
Er ….
well

31. THANK YOU