The reality of LOH-symptoms PRISM IV Bruges, Belgium September 25-26, 2014 Dr. Herman Leliefeld Androsmannenkliniek The Netherlands
The reality of LOH symptoms
male external & internal genitalia Testosterone Corona et al., J Sex Med 2011;8:3869.
Age, < 50 y, N=869 Age >50 y, N=606 Araujo et al. J Clin Endocrinol Metabolism 2007,
The reality of LOH symptoms
Three less specific symptoms of LOH Osteoporosis Overweight Depression and: Mortality!
T is metabolized to 5alfaDHT and 17betaEstradiol
Low trauma fracture, low bone mineral Density 1.Osteoporosis in men 10 years later than in women 2.More hipfractures in men with low testosteron High costs because of hip- and lumbar spine fractures Meier C, Arch Int Med 2008;168;
Three less specific symptoms of LOH Osteoporosis Overweight Depression and: Mortality!
European Male Aging Study (EMAS) Relation between Age, BMI and Testosterone 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
The risks of a high BMI: 30kg/m 2 = Obese Cohort study :6502 men born in 1955 in Denmark Follow up :33 years Normal weight: 5407 men =83% Underweight : 353 men =5% Overweight : 639 men=10% Obese : 97 men=1,5% Schmidt M, BMJ Open 2013:3(4)
Results Danisch Study, Schmidt, BMJ Open 2013 % of DM-2, hypertension, myocardial infarction, venous tromboembolism or death before the age of 55 years Normal weight : 20 % Overweight : 31 % Obese men : 48%
Results Danisch Study, Schmidt, BMJ Open 2013 Event Rate : DM-2 RR MI Tromboemb. Death Normal weight : 1 1 1 1 1 Overweight : 3,1 2 1,1 0,9 0,9 Obese men : 8,2 2,0 2,5 4,7 2,1 Absolute risk increase of 30% in obese men
Association Mortality with Overweight and Obesity Meta-analysis by K. Flegal, JAMA, 2013, 309, 71-82. PubMed and EMBASE search -7034 articles, - 97 elegible : combining a sample size of: - 2,88 million individuals - 270.000 deaths
Association Mortality with Overweight and Obesity Flegal, K, JAMA 2013
Lower mortality in overweight and grade 1 obese men/women Possible explanations: -Earlier presentation of heavier patients -Greater likelihood of receiving optimal medical treatment -Benefits of higher metabolic reserves Flegal K, JAMA 2013 ; 309
Low Testosterone as a risk factor for CV-Mortality Meta-analysis by Corona G, Eur J of Endocr, 2011, 165, 687-701 Medline search 1969-2011 - 1178 articles, - 70 elegible
Lower T as a risk factor for (cardiovascular)mortality Corona G, 2011
LOH and all-cause mortality in men with DM-2 Muraleedharan V, T Hugh Jones, Nottinghamshire, UK -6-year follow up -n=581 men with type 2 diabetes -Mortality rates compared between: TT 10,4 nmol/l : n=343: 9% TT 10,4 nmol/l : n=238: 17,2% Eur J Endocrin, 2013 169 725-33
Figure 1 Multivariate-adjusted survival curves using Cox regression model for all-cause mortality based on total testosterone (TT). Hazard Ratio: 2.02 9% 17,2% Muraleedharan V et al. Eur J Endocrinol 2013;169:725-733 2013 European Society of Endocrinology
Figure 3 Multivariate-adjusted survival curves using Cox regression model for treated and untreated groups compared with those with normal testosterone. 64 with TRT: 9,3% Effect of TRT on mortality in 238 men with low T Mean duration of TRT: 41 months Hazard ratio:2,3 for decreased survival 340 normal TT: 9,1% 174 without TRT: 20,1% Muraleedharan V et al. Eur J Endocrinol 2013;169:725-733 2013 European Society of Endocrinology
TRT increases the risk of a cardiovascular mortality 4 studies: 1.Basaria, NEJM 2010;363; 109-122 2.Xu, BMC Medicine 2013; 11: 108 3.Vigen, JAMA 2013; 310: 1829-1836 4.Finkle, PLoS ONE 2014;9(1); e85805 Generated considerable concern regarding safety of TRT among global medical community and lay public
Death by Testosterone? We Think Not! The Journal of Sexual Medicine Volume 11, Issue 3, pages 624-629, 4 MAR 2014 DOI: 10.1111/jsm.12464 http://onlinelibrary.wiley.com/doi/10.1111/jsm.12464/full#jsm12464-fig-0002
Overview of the literature by Traish J Sex Med 2014
Three less specific symptoms of LOH Osteoporosis Overweight Depression and: Mortality!
2-year incidence diagnosis depression ICD-9-CM Increased incidence of depression in hypogonadism Shores et al Arch Gen Psychiat 2004 N = 278 men > 45 years initially without depression Total T nmol / L 5 7 9 11 13
Symptomprävalenz % Depression Zitzmann et al. JCEM 2006 30 25 20 15 Overall Somer s d: p < 0.001 10 5 0 T<8 T:8-10 T:10-12 T:12-15 T:15-20 T 20 Sextile Total T (nmol/l) 75 67 65 84 69 74 n (patients) (Total n = 434)
The reality of LOH-symptoms Symptoms not very specific, but Symptoms necessary for the Diagnosis LOH Symptoms are relatively mild, insidious and difficult to recognize but Often bothersome, and frustrating because of an overall decrease of the quality of life (until death!)
Are symptom questionnaires of any help? ADAM questionnaire 2000 Good sensitivity AMS-questionnaire 2004 Low specificity NERI Hypogonadism screener 2011 ANDROTEST 2006 70/70%
AMS questionnaire 17 questions 5 points each In total 85 points
Frequency distribution of complaints by AMS in a normal population vs patients before and after 12 weeks of TRT 50 40 30 20 no/little mild moderate severe 10 0 standard population before therapy after therapy Moore C et al, Eur Urol 46:80-87(2004)
New Definition of LOH: EMAS, Wu,NEJM 2010 Syndromic association between Triad of sexual symptoms and Biochemical condition -Low libido -Reduced spontaneous erections -Reduced sex-related erections -Morning Total T < 11 nmol/l (<3.1ng/ml) -Free T < 222,2 pmol/l (<64 pg/ml)
So, are the symptoms real?? Answer: Yes, they are Are the symptoms specific for LOH? No, only for a triad of three sexual symptoms
Is this the End? Pieter Brueghel de Oude 1525-1569
Or like this? Mick Jagger, 70 years The End
Gender as a risk factor for cardiovascular mortality In General in Europe: before 65 years before 75 years Men 1 in 8 1 in 4 Women 1 in 20 1 in 6 Atlas of Health in Europe, WHO 2008