Testosterone and obesity. Referent Prof. Dr. Michael Zitzmann

Transcription

1 Testosterone and obesity Referent Prof. Dr. Michael Zitzmann

2 Transparenzinformation arztcme Die Bundesärztekammer und die Landesärztekammer Hessen fordern zur Schaffung von mehr Transparenz beim Sponsoring in der ärztlichen Fortbildung auf. Fortbildungsveranstalter sind gehalten, potenzielle Teilnehmer von Fortbildungen bereits im Vorfeld der Veranstaltung u ber Umfang und Bedingungen der Unterstu tzung der Arzneimittelindustrie zu informieren. Dieser Verpflichtung kommen wir nach und werden Sie hier u ber die Höhe des Sponsorings() der beteiligten Arzneimittelfirma sowie u ber mögliche Interessenkonflikte der Autoren informieren. Diese Fortbildung wurde fu r den aktuellen Zertifizierungszeitraum von 12 Monaten mit 9.875,- EUR durch die Jenapharm GmbH & Co. Co. KG unterstu tzt. Mögliche Interessenkonflikte Prof. Dr. Michael Zitzmann erklärt: Bei der Erstellung dieses Beitrags fu r eine durch die Landesärztekammer Hessen anzuerkennende Fortbildung bestanden keine Interessenkonflikte im Sinne der Empfehlungen des International Committee ofmedical Journal Editors ( Die Produktneutralität dieser Fortbildung wurde durch ein Review mit zwei Gutachtern gepru ft. Diese Fortbildung ist auf online verfu gbar. Die Transparenzinformationen sind fu r den Arzt dort einsehbar. () Die Sponsoringbeiträge können je nach Art und Umfang der Fortbildung unterschiedlich sein.

3 Testosterone and obesity Prof. Dr. Michael Zitzmann Andrologist, Endocrinologist, Diabetologist Sexual Medicine (FECSM) Clinical Andrology / Centre for Reproductive Medicine and Andrology, University Clinics Muenster Germany WHO Collaborating Centre for Research in Human Reproduction Training Centre of the European Academy of Andrology

4 Testosterone levels in men related to age (n=10098) Kelsey et al. PLoS one 2014

5 Problem: Obesity

6 New EAU guideline 2015 Markers of Hypogonadism and Indications for Substitution Therapy in case of low total T (<12.1 nmol/l) or free T (<243 pmol/l) Loss of Libido Depressive Mood Metabolic Disorders

7 European Male Aging Study (EMAS) relation between age and testosterone (40-79) Wu FCW et al. J Clin Endocrin Metab 93(7): (2008)

8 European Male Aging Study (EMAS) relation between age and testosterone (40-79), n= Wu FCW et al. J Clin Endocrin Metab 93(7): (2008)

9 Prevalence of Hypogonadism (%) Prevalence of Hypogonadism in 1687 Men Presenting to an Outpatient Andrology Unit 40 BMI < 25 kg/m 2 BMI kg/m 2 BMI 30 kg/m NS p< for trend p< for trend Age quintiles (years) Corona G et al. J Sex Med 8: (2011)

10 PREVALENCE OF TYPE 2 DIABETES MELLITUS, 2025 Source: IDF diabetes atlas

11 LH (U/L) Corona et al., J. Sex. Med., 2014 Jul;11(7): Hypogonadal status in 4173 ED subjects studied at the University of Florence Testosterone (nmol/l)

12 LH (U/L) Testosterone 10.4 nmol/l Corona et al., J. Sex. Med., 2014 Jul;11(7): Primary hypogonadism (2.5%) Compensated hypogonadism (4.1%) Hypogonadal status in 4173 ED subjects LH = 9.4 U/L Secondary hypogonadism (17.3%) Testosterone (nmol/l) Eugonadism (76.1%)

13 Prevalence of hypogonadism in patients seeking medical care for ED, n= % 49.6% 3.2% 69.2% 17.4% 89.1% 10.9% Eugonadism Primary Secondary Unknown Specific medical conditions Corona & Maggi, 2015 JSM

14 Specific medical conditions associated with secondary hypogonadism 1,1 1,7 1,1 89.1% 10.9% 3,4 1,1 2,4 0,1 Unknown Genetic Empty sella Drugs Specific medical conditions Surgery/CT PRL-adenomas Radio-T Trauma Corona & Maggi, 2015 JSM

15 Specific medical conditions associated with secondary hypogonadism 71,8 28,2 89.1% 10.9% Concomitant metabolic disease Obesity, T2DM or MetS Unknown Specific medical conditions Unknown Corona & Maggi, 2015 JSM

16 Men with TDS as patients in general practice Complaints related to testosterone levels Risk factor Hypogonadism prevalence rate (95% CI) Odds ratio (95% CI) Obesity 52.4 ( ) 2.38 ( ) Diabetes mellitus 50.0 ( ) 2.09 ( ) Hypertension 42.4 ( ) 1.84 ( ) Hyperlipidemia 40.4 ( ) 1.47 ( ) CI, confidence interval Mulligan T et al. Int J Clin Pract 2006; 60:

17 Total testosterone (nmol/l) Testosterone levels and symptoms men (age years) n= Loss of libido Loss of vigour 84 More and more problems 10 8 Overweight Depression Sleeping disorders Heat flushes Erectile Dysfunction Lacking concentration Typ 2-Diabetes mellitus Zitzmann et al. J Clin Endocrinol Metab 2006; 91(11):

18 Hormone constellations in male hypogonadism Testicular damage T LH Functional hypogonadism Possibly reversible Hypothalamic / pituitary disorder

19 New Criteria for the Definition of the Metabolic Syndrome 1. Waist Circumference > cm 2. Triglycerides > 150 mg/dl or treatment 3. HDL-Cholesterol < 40 mg/dl or treatment 4. Arterial Blood Pressure > 130 mmhg systolic and/or > 85 mmhg diastolic or treatment 5. Fasting glucose > 100 mg/dl or known Type 2 Diabetes mellitus 3 of 5 Criteria have to be met (Consensus IDF & NCEP ATP III) Alberti et al Circulation

20 Prevalence of hypogonadism Total T levels decrease with increasing number of metabolic syndrome components TT <8 nmol/l TT <10.4 nmol/l TT <12 nmol/l n=1491 p<0.001 for trend in all subgroups Number of metabolic syndrome components Corona G et al. Int J Androl 2009

21 BMI and BMI are not the same... the role of visceral fat tissue 189 cm, 93 kg = BMI cm, 94 kg = BMI 26 Waist circumference Testosterone > < Waist circumference Testosterone

22 Total testosterone (nmol/l) Testosterone levels decrease with increasing waist circumference Men aged years (n=1584) p<0.001 for trend Limit of lower normal Waist circumference (cm): n= < Svartberg J et al. Eur J Epidemiol 2004; 19: (The Tromsø-Study).

23 Visceral Fat Insulin Leptin IL-6 Testosterone With agreement of Rob McLachlan und Carolyn Allan, Monash University, Melbourne, Australia Zitzmann et al , Walsh et al. 2005, Mulligan et al. 2006

24 MHCII + Area/field (μm 2 x 10 3 ) Fat cells/field Testosterone induces Myogenesis in pluripotent Stem Cells 150 Myogenic Cells 40 Fat Cells T (nm) T (nm) MHC + Myogene Zellen 0 nm 3 nm 30 nm 100 nm 300 nm Testosterone Concentration Singh et al. Endocrinology 2003; 144(11): Myogenic Cells: p< 0,01; p< 0,001 Fat Cells: p = 0,02; p< 0,004; p< 0,001

25 Testosterone changes pathways for stem cells Mesenchymal Stem Cells Testosterone Fat Cells Smooth Muscle Cells Singh et al. Endocrinology 2003; 144(11):

26 Visceral fat tissue + Metabolic Syndrome Insulin Resistence Arterial hypertension Adiposity + + Consequences Type 2 Diabetes mellitus Cardiovaskular Diseases Erectile Dysfunction Visceral Fat + + Insulin Hypogonadism Depression Other psychotropic effects Osteoporosis Anemia Leptin Cytokines - + Hypothalamic-Pituitary-Gonadal Axis / GPR54-Kisspeptin-System Leydig Cell Function Estradiol Zitzmann M. Nat Rev Endocrinol 2009; 5:

27 The interplay of fat tissue, insulin resistance, testosterone deficiency and VASCULAR INTEGRITY Zitzmann Nature Endo Rev 2009

28

29

30 Effects of Weight Loss on Testosterone Levels Meta-Analysis Bariatric Surgery Diet / Exercise Grossmann M et al. J Clin Endocrinol Metab 96(8): (2011)

31 8 Changes Testosterone related to weight change longitudinal results European Male Ageing Study (n=2395) 6 5, ,96 0,28 p<0.05 p<0.05 p< Δ p<0.05 (nmol/l) p<0.01-0, ,2-1, ,35-6 lost > 15% lost 10-15% lost 5-10% within 5% gained 5-10% gained 10-15% Camacho EM et al. Eur J Endocrinol 168: (2013) gained > 15%

32 Rastrelli et al JCEM June 2015

33 Rastrelli et al JCEM June 2015

34 Rastrelli et al JCEM June 2015

35 Time-depent and symptom-specific onset of effects of testosterone substitution Months Libido Vigor Depression Red blood count Obesity Insulin sensitivity Erectile function Bone density Saad, Zitzmann et al. EJE 2011

36 Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial Fui MNT et al. BMC Med 14:153 (2016) Design: 56-week, randomised, double-blind, parallel, placebocontrolled study conducted at a tertiary referral centre Subjects: 100 obese adult men (BMI 30 kg/m 2 ) with a repeated total testosterone level <12 nmol/l and median age 53 years receiving 10 weeks of a VLED followed by 46 weeks of weight maintenance Treatment: randomisation to 56 weeks of 1000 mg intramuscular testosterone undecanoate (n=49) or matching placebo (n=51) Key outcome measures (pre-specified): differences in fat and lean mass by DXA scan, and visceral fat area by CT scan

37 Change from Baseline in Outcome Change from Baseline in Body Composition After 10 Weeks of a VLED and Treatment with Intramuscular Testosterone Undecanoate or Placebo Placebo (n=51) Testosterone (n=49) p=ns p=ns p=ns p<0.05 versus baseline within group; data are mean + 95% confidence interval NS, not significant; VLED, very low energy diet Fui MNT et al. BMC Med 14(1):153 (2016)

38 Change from Baseline in Outcome Change from Baseline in Body Composition After 56 Weeks of Treatment with Intramuscular Testosterone Undecanoate or Placebo Placebo (n=51) Testosterone (n=49) p=0.003 p=0.002 p=0.04 p<0.05 versus baseline within group; data are mean + 95% confidence interval NS, not significant Fui MNT et al. BMC Med 14(1):153 (2016)

39 Change from Baseline in VAT Area (mm 2 ) Change from Baseline in Body Composition After 10 and 56 Weeks of Treatment with Intramuscular Testosterone Undecanoate or Placebo Placebo (n=51) Testosterone (n=49) p=ns p=0.04 p<0.05 versus baseline within group; data are mean + 95% confidence interval NS, not significant; VAT, visceral abdominal tissue; VLED, very low energy diet Fui MNT et al. BMC Med 14(1):153 (2016)

40 Change in Total testosterone (nmol/l) Effects of 5 years Treatment with Testosterone on Δ Total Testosterone (nmol/l) in 40 Hypogonadal Men (T<11 nmol/l) with Metabolic Syndrome (IDF criteria) Testosterone (n=20) Control (n=20) baseline 12 months 24 months 36 months 48 months 60 months Francomano D et al. Urol 2013

41 Change in Waist circumference (cm) Effects of 5 years Treatment with Testosterone on Δ Waist Circumference (cm) in 40 Hypogonadal Men (T<11 nmol/l) with Metabolic Syndrome (IDF) Testosterone (n=20) Control (n=20) baseline 12 months 24 months 36 months 48 months 60 months Francomano D et al. Urol 2013

42 Change in Weight (kg) Effects of 5 years Treatment with Testosterone on Δ Body Weight (kg) in 40 Hypogonadal Men (T<11 nmol/l) with Metabolic Syndrome (IDF) 2 Testosterone (n=20) Control (n=20) 0-2 baseline 12 months 24 months 36 months 48 months 60 months Francomano D et al. Urol 2013

43 Waist Circumference (cm) # # # p= p= p=ns p=ns # # # # p=ns p= # # # # # p= p=ns p= Reduction of Waist Circumference (mean ± S.E.s) in 411 Hypogonadal Men in Obesity Classes I, II, and III Receiving Long-Term Testosterone Treatment Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Class I Class II Class III p< vs. baseline; # p< vs. previous year; all other p values indicate comparison to previouss yr. Saad F et al. Int J Obes 40(1): (2016)

44 Weight (kg) # # p= # # # p= # # # p= p= # # # # p= p= # # # Reduction of Body Weight (mean ± S.E.s) in 411 Hypogonadal Men in Obesity Classes I, II, and III Receiving Long-Term Testosterone Treatment Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Class I Class II Class III p< vs. baseline; # p< vs. previous year; all other p values indicate comparison to previous yr. Saad F et al. Int J Obes 40(1): (2016)

45 Baseline Characteristics, Comorbidities and Concomitant Medication in Total and Propensity-Matched Groups Traish A et al. J Cardiovasc Pharmacol Therapeut 22, published online Feb 09, 2017

46 Changes in Waist Circumference in Total Testosterone-Treated and Untreated Groups Yellow bars show the estimated mean difference between groups, adjusted for baseline age, weight, waist circumference, fasting glucose, lipids, blood pressure, and quality of life (measured by AMS) Traish A et al. J Cardiovasc Pharmacol Therapeut 22, published online Feb 09, 2017

47 Longterm treatment of hypogonadal men: results from a 9-year-registry Zitzmann et al AUA patients with hypogonadism 266 with primary forms (age 34±12 y) including 149 Klinefelter patients 196 with secondary origin (age 32±12 y) 188 with non-classical ( functional ) hypogonadism (age 42±11 y) receiving intramuscular of T undecanoate (1000 mg) for max 9 y 110,0 108,0 106,0 104,0 102,0 100,0 98,0 Waist Circumference (cm) ANOVA p< Baseline and follow-up years 100,0 98,0 96,0 94,0 92,0 90,0 Body weight (kg) ANOVA p< Baseline and follow-up years 96,0 88,0

48 Longterm treatment of hypogonadal men: results from a 9-year-registry Zitzmann et al AUA 2017

49 Longterm treatment of hypogonadal men: results from a 9-year-registry Zitzmann et al AUA 2017

50 Corona, Maggi, Zitzmann et al EJE 2016; 174(3):R99-R116 Meta-Analysis of 59 randomized controlled trials of T substitution in hypogonadism 3029 men (treated) vs 2049 (controls)

51

52

53

54 A pathway to endothelial dysfunction and vascular morbidity Other interventions Lifestyle Lack of physical activity Overnutrition Smoking Stress MetS TDS Endothelial dysfunction Type 2 diabetes Modified after Makhsida et al. J Urol 2005; 174: