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

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Some Think So !! TIME: 2014

epidemiology

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

Basics ≈ 39% men > 45 yrs have androgen deficiency (AD) 6% men 40-70 yrs have symptomatic AD symptomatic AD increases with age 4% < 50 yrs 8% > 50 yrs Europeans – 2% men 40-79 yrs have symptomatic AD

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: 724-731. Araujo AB, O’Donnell AB et al. JCEM 2004; 89: 5920-5926. Mulligan T, Frick MF et al. Int J Clin Pract. 2006; 60:762-9. Araujo AB, Esche GR et al. JCEM 2007; 92: 4241-4247.

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

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

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;350:482-492

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. 2006 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; 60:762-769.

Does loh exist?

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

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

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

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

Probability Symptoms vs T. Levels Wu F et al. NEJM 2010:10.1056

Wu – Validation Sets

Wu - Validation Sets

Wu – Validation Sets

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 = 0.0001), enjoyment without partner (P = 0.0001), enjoyment with partner (P= 0.0022), percent full erection (P = 0.0001), and self-assessment of satisfaction with erections (P= 0.0001) 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 = 0.0001). 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; 89:2085-98.

Effects on Mood (3 Years) Mood improved significantly and changes were sustained from baseline p = 0.0022 p = 0.0013 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=0.0129 in older men and P= 0.0001in younger men). Months Months Wang C, Cunningham G et al. J Clin Endo Metab 2004; 89:2085-98.

Effects on Body Composition (3 Years) Lean and fat body mass changed significantly from baseline * p = 0.0001 * p = 0.0058 * 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 ± 0.24 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= 0.088 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; 89:2085-98.

Effects on Bone Mineral Density (3 Years) BMD showed significant gradual and progressive increase from baseline p = 0.0004 p = 0.0001 Change Hip BMD Change Spine BMD Change in hip BMD (g/cm2) Change in spine BMD (g/cm2) BMD of the hip (P = 0.0004) and spine (P= 0.0001) 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± 0.006 (3.1%) and 0.037 ± 0.006 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= 0.0001). Months Months Wang C, Cunningham G et al. J Clin Endo Metab 2004; 89:2085-98.

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.

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

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): 123-135 Wang C, Nieschlag E et al. Aging Male 2008; 1-8

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

Does LOH Exist ? YES Er …. well ...........

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