IL RUOLO DEL DEFICIT DI TESTOSTERONE NELLA SINDROME METABOLICA E NELLA INSUFFICIENZA RENALE NEL MASCHIO ADULTO. VA Giagulli

IL RUOLO DEL DEFICIT DI TESTOSTERONE NELLA SINDROME METABOLICA E NELLA INSUFFICIENZA RENALE NEL MASCHIO ADULTO VA Giagulli UOS di Endocrinologia e Malattie Metaboliche PT di Conversano ASL BA

Male hypogonadism - classification Hypogonadism Primary hypogonadism Secondary hypogonadism Target organ resistance (T & LH +) Age-related hypogonadism LH -/+ T - Feminisation due to androgen resistance or Late onset hypogonadism LH + T - LH - T - 5-alpha-reductase deficiency Estrogen deficit due to aromatase deficiency The role of Diseases!!! Testicular causes Hypothalamic causes Pituitary causes Klinefelter syndrome Idiopathic hypogonado- Hypopituitarism Orchitis tropic hypogonadism Congenital or acquired Kallmann syndrome Pituitary tumors anorchia Constitutional delay of Testicular maldescent growth and development Testicular tumor Jockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004 Prepubertal forms Postpubertal forms

Symptom-specific threshold testosterone levels for observed increase of prevalence in patients attending an andrology clinic Total testosterone (nmol/l) 20 15 12 10 8 0 Loss of libido P<0.001 Loss of vigour P<0.001 Obesity P<0.001 Feeling depressed P=0.001 Disturbed sleep P=0.004 Lacking concentration P=0.002 Diabetes mellitus type 2 P<0.001 Hot flushes P<0.001 Erectile dysfunction P=0.003 Patients (n) 74 69 84 65 67 75 Increasing prevalence of symptoms with decreasing testosterone concentrations Zitzmann et al. JCEM 2006;91:4335

Identification of late onset hypogonadism (EMAS) Wu et al NEJM 363:123-35; 2010 Prevalence: 0.1% 40-49y 0.6% 50-59y 3.2% 60-69y 5.1% 70-79y 4

Serum testosterone and SHBG vs age Kaufman &Vermeulen Endocr Rev 2005 according to Vermeulen et al JCEM,1996 5

FAT DISTRUBUTION AND DEPOSITION ACROSS THE LIVE IN MEN (E2 = 30 pg/ml) Lean ass cft= 2 ng/dl cft= 12 ng/dl Obese man T< 300 ng/dl SHBG = <30 nm/l cft=< 6 ng/dl cft= 4,5 ng/dl Fat mass PUBERTY T = < 200 ng/dl SHBG = 80 nm/l ADULT T = 600 ng/dl SHBG = 35 nm/l AGEING T = < 300 ng/dl SHBG = 55 nm/l Giagulli VA & Vermeulen A,1994 e 1996

Three Ways to Review Effects of Testosterone in Men 1. Evidence from Epidemiology and Observation 2. Evidence from Testosterone Deprivation 3. Evidence from Testosterone Treatment

JCEM,2012

Cross-sectional survey on 3200 community - dwelling men aged 40-79 yr from a prospective cohort study in 8 European countries Wu et al., J Clin Endocrinol Metab. 2008;93:2737

Random-Effects Pooled Mean Difference of Serum T Between Type 2 Diabetes Cases and Controls in Men (Ding EL et al JAMA,2006) 2,66nMol/= 77 ng/dl

Changes in Body Composition in 32 Men after Androgen Deprivation Therapy for Prostate Cancer for 48 weeks 90 80 70 p=0.005 Baseline Basal 48 weeks 60 50 p<0.001 40 30 p=0.005 p<0.001 20 Weight (kg) BMI (kg/m2) Fat mass (%) (DEXA) Lean mass (%) (DEXA) Smith MR et al. J Clin Endocrinol Metab 87(2): 599-603 (2002)

GnRH Agonists are Associated with Significant Excess Risk of Diabetes, Coronary Heart Disease, Myocardial Infarction, and Sudden Cardiac Death Adjusted Hazard Ratios Excess Risk p value Diabetes 44 % <0.001 Coronary heart disease 16 % <0.001 Myocardial infarction 11 % 0.03 Sudden cardiac death 16 % 0.04 0. 1. 1. Better Worse Saylor PJ and Smith MR J Urol 181: 1998-2008 (2009)

Effects of Testosterone Therapy on Total Body Fat: a Meta-Analysis Baseline T < 10 nmol/l Morley et al. (1993) Sih et al. (1997) Boyanov et al. (2003) Steidle 1 et al. (2003) Steidle 2 et al. (2003) Page et al. (2005) Subtotal Baseline T > 10 nmol/l Marin et al. (1992) Snyder A et al. (1999) Kenny et al. (2001) Ly et al. (2001) Blackman et al. (2002) Wittert et al. (2003) Liu et al. (2003) Casaburi et al. (2004) Subtotal Glucocorticoid Treated Reid et al. (1996) Crawford et al. (2003) Overall Mean Difference (95%Cl) 1.86 (-5.09, 8.80) -4.67 (-9.24, 0.10) -1.40 (-9.25, 6.45) -0.90 (-3.99, 2.19) -0.9 (-3.13, 1.33) -4.80 (-10.97, 1.37) -1.46 (-3.01, 0.09) 1.60 (-6.21, 3.01) -2.00 (-4.66, 0.66) -1.40 (-4.47, 1.67) -2.30 (-6.81, 2.21) -1.10 (-5.37, 3.17) -0.95 (-5.27, 3.37) -1.30 (-3.54, 0.94) -0.93 (-7.68, 5.82) -1.50 (-2.72, 0.28) -2.90 (-7.48, 1.68) -3.00 (-12.30, 6.30) -1.56 (-2.49, 0.63) -10-8 -6-4 -2 0 2 4 6 8 10 Total Fat Mass (kg) Isidori AM et al. Clin Endocrinol 63: 280-293 (2005)

Effects of Testosterone Therapy on Total Fat Free Mass: a Meta-Analysis Baseline T < 10 nmol/l Boyanov et al. (2003) Steidle 1 et al. (2003) Steidle 2 et al. (2003) Page et al. (2005) Subtotal Baseline T > 10 nmol/l Marin et al. (1992) Tenover (1992) Clague et al. (1999) Snyder A et al. (1999) Ly et al. (2001) Kenny B et al. (2001) Blakman et al. (2002) Ferrando et al. (2003) Wittert et al. (2003) Liu et al. (2003) Casaburi et al. (2004) Subtotal Glucocorticoid Treated Reid et al. (1996) Crawford et al. (2003) Overall Mean Difference (95%Cl) - 0.50 (-5.00, 4.00) 0.80 (-2.10, 3.70) 0.90 (-1.73, 3.53) 3.98 (-0.21, 8.17) 1.16 (-0.49, 2.80) 0.40 (-5.98, 6.78) 1.90 (-2.35, 6.15) -0.80 (-8.62, 7.02) 2.40 (0.153, 4.65) 1.20 (-3.19, 5.59) 0.80 (-2.48, 4.08) 1.50 (-2.20, 5.20) 6.20 (-2.83, 15.23) 1.65 (-2.30, 5.60) 2.90 (-1.86, 7.66) 2.09 (-3.99, 8.17) 1.80 (0.57, 3.03) 2.30 (-2.85, 7.45) 2.30 (-4.39, 8.99) 1.61 (0.65, 2.57) -10-8 -6-4 -2 0 2 4 6 8 10 Total Fat Free Mass (kg) Isidori AM et al. Clin Endocrinol 63: 280-293 (2005)

What is the possible mechanism causing hypogonadism in man affected by metabolic diseases and renal failure?

Normal physiology Preoptic area Leptin + Glicaemia

ANDROGENS AND INSULIN PLASMA LEVELS IN NONOBESE HEATHY MEN AND OBESE MEN (Giagulli VA et al, 1994) c= p <0.01 vs nonobese d= p< 0.05 vs nonobese Functional Hypogonadism (?)

INFLUENCE OF THE DEGREE OF OBESITY ON SERUM LH AND MEAN OF PULSE AND SUM OF PULSE AMPLITUDE (Giagulli et al 1994) c= p <0.01 vs nonobese d= p< 0.05 vs nonobese

Serum T, E, LH, FSH after Letrozolo 2,5mg/d in Hypogonadic Obese men (de Boer et al, 2005)

Inter.J End. 2014

Testis damage in chronic renal diseases (Clinical aspects)

Fertility in male with chronic kidney disease Xu HM et al, 2012

Testosterone Replacement Therapy

Current Testosterone Formulations on Market Giagulli et al Curr.Pharm.Design,2011

TESTOSTERONE THERAPY AND END-STAGE RENAL DISEASE TU os (240 mg/die x 3 mesi): < PRL e LH (Van Coevorden et al,1986) Differenti Tuttavia studi hanno i dati (RCTs) documentato in lettaratura che la terapia sono con T sulla DE è efficace veramente solo scarsi in caso e pertanto di ipogonadismo non franco (Canguven possono O et al essere 2010) considerati definitivi La somminstrazione di T migliora l eritropeotina e l anemia nei pazienti I distubi con biochinici insufficienza e quelli renale cronica di fase avanzata clinici dell ipogonadismo (Gaughan WJ 1997). nel paziente con stadio finale della insufficienza renale MIGLIORANO con il trapianto Iglesias P et al J Nephrol, 2012

PREVALENCE of HYPOGONADISM IN T2 DM References n Age(years) % Criteria used Barrett-Connor et al. (US-1990) 985 40-79 21 TT< 12nM Tan et al. (US-2002) 71 mean 73 64 TT < 10.4 nm Dhindsa et al., (US-2004) 103 55.4±1.9 33 FT<146 pm Corona et al., (ITA-2004) 155 58.0± 8.9 34 TT < 12 nm Corona et al., (ITA-2006) 199 58.9± 8.2 24.5 TT < 10.4 nm Kapoor et al., (UK- 2007) 355 58.1±0.5 20 TT< 8 nm Kapoor et al., (UK- 2007) 355 58.1±0.5 31 TT< 12 nm Kapoor et al., (UK- 2007) 355 58.1±0.5 50 FT< 255 pm Grossman et al (AU- 2008) 580 65 ± 1 43 TT < 10 nm

Corona et al., J Sex Med. 2014;11:1577 The effects of testosterone supplementation (TS) on male sexual functions in ED subjects are still more controversial. Another controversial issue is the effect of TS on PDE5i outcomes The aim of present study is to meta-analyse available data evaluating the effect TS on male sexual function and its therapeutic synergism with the combined use of PDE5i.

PUBLISHED studies Medline search N=1703 Review or Editorial N=4 No testosterone use included=649 No RCT studies N=755 Women N=5 Review n N=3 No data on sexual function N=245 UNPUBLISHED Studies N=31 Ongoing N=5 No testosterone use included=3 No data on sexual function N=9 No results available N=13 Case report N=1 40 Retrieved TOTAL N=41 N=1 Retrieved TS vs. placebo N=28 TS+PDE5ì vs. nothing or placebo + PED5ì N=12 TS vs. placebo N=1 Eugonadal N=5 Mixed N=5 Hypogonadal N=18 hypogonadal N=0 Mixed N=3 Eugonadal N=9 Hypogonadal N=1

Male sexual response cycle Motivation (libido) Arousal (erection) Orgasm (ejaculation)

Effect size (with 95%CI) of testosterone supplementation (TS) versus placebo on libido component Source Libido component standardized mean differences - 0,50 0,00 0,50 1,00 1,50 2,00 2,50 3,00-0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 Diff. in mean LL, 95% CI UL, 95% CI p Overall eugonadal Overall mixed Overall hypogonadal Overall hypogonadal (TT <12 nm) Overall hypogonadal (TT < 8 nm) Overall pharmaceutical industry supported Overall pharmaceutical industry not supported 0,25-0,24 0,74 0,320 0,64 0,14 1,13 0,012 1,00 0,47 1,53 0,012 0,97 0,22 1,71 0,271 0,98 0,42 1,53 0,012 0,43 0,26 0,60 0,000 1,34 0,29 2,39 0,000 Overall 0.81 0,81 0.47 0,47 1.17 1,17 0.001 0,000 Placebo TS Corona et al., 2013 submitted

Conclusions T supplementation is able to improve libido but only in hypogonadal men (TT < 12 nm)

Effect size (with 95%CI) of testosterone supplementation (TS) versus placebo on overall erectile function component (including sexual and spontaneous erections) Source Overall erectile function component standardized mean -0.5 0 0.5 differences 1.0 1.5 2.0 2.5 Diff. in mean LL, 95% CI UL, 95% CI p - 0,50 0,00 0,50 1,00 1,50 2,00 2,50 Overall eugonadal Overall mixed Overall hypogonadal Overall hypogonadal (TT <12 nm) Overall hypogonadal (TT < 8 nm) Overall pharmaceutical industry supported 0,19-0,19 0,58 0,323 0,18-0,13 0,48 0,261 1,23 0,74 1,72 0,002 1,25 0,51 1,99 0,001 1,23 0,56 1,90 0,000 1,36 0,55 2,16 0,001 Overall pharmaceutical industry not supported 0,33 0,13 0,54 0,001 Overall Overall 0.82 0,82 0.47 0,47 1.17 1,17 0.001 0,001 Placebo TS

Conclusions T supplementation is able to improve libido but only in hypogonadal men (TT < 12 nm) T supplementation is able to improve erectile function but only in hypogonadal men (TT < 12 nm)

Effect size (with 95%CI) of testosterone supplementation (TS) versus placebo on erectile function component (including only sexual-related erections) Source Erectile function component standardized mean -0.5 0 0.5 1.0 1.5 differences 2.0 2.5 3.0 3.5 4.0 Diff. in mean LL, 95% CI UL, 95% CI p - 0,50 0,00 0,50 1,00 1,50 2,00 2,50 3,00 3,50 4,00 Overall oral formulations 1,77-0,19 3,73 0,076 Overall transdermal formulations 0,31 0,04 0,59 0,026 Overall parental formulations 0,46 0,18 0,74 0,001 Overall 0,75 0,37 1,12 0,000 Placebo TS

Conclusions T supplementation is able to improve libido but only in hypogonadal men (TT < 12 nm) T supplementation is able to improve erectile function but only in hypogonadal men (TT < 12 nm). No differences between transdermal and parental formulations

Effect size (with 95%CI) of testosterone supplementation (TS) versus placebo on orgasm component Source Orgasm component standardized mean -5.0-4.0-3.0-2.0-1.0 differences 0 1.0 2.0 3.0 4.0 5.0 Diff. in mean LL, 95% CI UL, 95% CI p - 5,00-4,00-3,00-2,00-1,00 0,00 1,00 2,00 3,00 4,00 5,00 Skakkebaek et al., 1981 1,46 0,52 2,40 0,00 Davidson et al., 1979 1,06-0,26 2,39 0,12 Kwan et al., 1983 1,58-0,26 3,41 0,09 Gluud et al., 1988 0,11-0,27 0,49 0,58 Carani et al., 1990 0,79-0,38 1,97 0,19 Schiavi et al., 1997 1,62 0,30 2,94 0,02 Cavallini et al., 2004 1,00 0,54 1,46 0,00 Chaing et al., 2009 0,97 0,31 1,62 0,00 Jones et al., 2011 0,05-0,24 0,34 0,74 Hackett et al., 2013 0,42 0,13 0,72 0,00 Overall 0.68 0.34 1.02 0.001 0,68 0,34 1,02 0,00 Placebo TS

Recommendation 11: Combination therapy with T and PDE5- Is (EBMl1b). Evidence is emerging suggesting a therapeutic synergism with the combined use of Tth and PDE5-Is in men with ED and low T. These observations are preliminary and need additional studies. However, combination therapy can be considered in TD men who have not improved with T alone. In addition it is recommended to measure T in case of PDE5-Is failure if not previously done. Data suggests that the threshold level of T for optimal response to PDE5-Is is 3 ng/ml for TT and 52 pg/ml (180 pmol/l) for cft. J Sex Med. 2013;10:245.

Source Standardized mean differences - 2,00 0,00 2,00 4,00 6,00 8,00 10,00 12,00-2.0 0 2 4 6 8 10 12 Diff. in mean LL, 95% CI UL, 95% CI p Kalinchenko et al., 2003 Foresta eta la., 2004 Shamloul et al., 2005 Roschira et al 2006 Hwang et al., 2006 Garcia et al., 2009 Kim et al., 2013 Overall non placebo controlled 7,71 6,57 8,84 0,00 1,57 0,56 2,58 0,00 1,02 0,09 1,95 0,03 0,96 0,36 1,56 0,00 0,74 0,18 1,31 0,01 8,86 7,17 10,55 0,00 0,69 0,23 1,15 0,00 2,96 1,28 4,64 0,00 Aversa et al., 2003 4,98 3,21 6,76 0,00 Shabshig et al., 2004 Favours PDE5is Favours PDE5is + TS - 0,33-0,80 0,14 0,17 Buvat et al., 2009 0,20-0,10 0,50 0,20 Spitzer et al., 2012 0,17-0,19 0,53 0,36 HackeH et al., 2013 0,17-0,57 0,91 0,65 Overall placebo controlled 0,49-0,16 1,15 0,14

Source Standardized mean differences - 2,00 0,00 2,00 4,00 6,00 8,00 10,00 12,00-2.0 0 2 4 6 8 10 12 Diff. in mean LL, 95% CI UL, 95% CI p Kalinchenko et al., 2003 Foresta eta la., 2004 Shamloul et al., 2005 Roschira et al 2006 Hwang et al., 2006 Garcia et al., 2009 Kim et al., 2013 Overall non placebo controlled Aversa et al., 2003 Shabshig et al., 2004 Buvat et al., 2009 Spitzer et al., 2012 HackeH et al., 2013 Overall placebo controlled 7,71 6,57 8,84 0,00 1,57 0,56 2,58 0,00 1,02 0,09 1,95 0,03 0,96 0,36 1,56 0,00 0,74 0,18 1,31 0,01 8,86 7,17 10,55 0,00 0,69 0,23 1,15 0,00 2,96 1,28 4,64 0,00 4,98 3,21 6,76 0,00-0,33-0,80 0,14 0,17 0,20-0,10 0,50 0,20 0,17-0,19 0,53 0,36 0,17-0,57 0,91 0,65 0,49-0,16 1,15 0,14 Favours PDE5is Favours PDE5is + TS

Favours PDE5is Favours PDE5is + TS Source Standardized mean differences - 2,00 0,00 2,00 4,00 6,00 8,00 10,00 12,00-2.0 0 2 4 6 8 10 12 Diff. in mean LL, 95% CI UL, 95% CI p Kalinchenko et al., 2003 Foresta eta la., 2004 Shamloul et al., 2005 Roschira et al 2006 Hwang et al., 2006 Garcia et al., 2009 Kim et al., 2013 Overall non placebo controlled Aversa et al., 2003 7,71 6,57 8,84 0,00 1,57 0,56 2,58 0,00 1,02 0,09 1,95 0,03 0,96 0,36 1,56 0,00 0,74 0,18 1,31 0,01 8,86 7,17 10,55 0,00 0,69 0,23 1,15 0,00 2,96 1,28 4,64 0,00 4,98 3,21 6,76 0,00 Shabshig et al., 2004 Buvat et al., 2009 Spitzer et al., 2012 HackeH et al., 2013 Mixed eugonadal/hypogonadal subjects - 0,33-0,80 0,14 0,17 0,20-0,10 0,50 0,20 0,17-0,19 0,53 0,36 0,17-0,57 0,91 0,65 Overall placebo controlled 0,49-0,16 1,15 0,14

Change in IIEF scores with sildenafil alone or in combination with testosterone or placebo. Spitzer et al., Ann Int Med. 2012;157:681

Conclusions T supplementation is able to improve libido but only in hypogonadal men (TT < 12 nm) T supplementation is able to improve erectile function but only in hypogonadal men (TT < 12 nm). No differences between transdermal and parental formulations T supplementation is able to improve orgasm function particularly in subjects with low T levels More studies comparing PDE5i+T in hypogonadal subjects are advisable

Trial Flow Diagram Records identified through different sources n = 2747 Records removed: No clinical trials n = 2287 No human species n = 2 No english language n = 13 No male subsjects n = 145 Full-text articles assessed for eligibility n = 300 Full-text articles excluded: Women n = 4 No T use included n = 45 No RCT n = 21 No placebo (or p-only) arm n = 108 No T-only arm n = 4 Study duplicates n = 18 UNPUBLISHED Studies n = 649 Ongoing n = 202 No results available n = 372 No placebo n = 26 Women n = 21 No T arm n = 27 Study assessed for eligibility n = 1 Studies included in qualitative synthesis n = 101 RCT: Randomized clinical trials; T: Testosterone. Studies excluded (see table 6) n = 26 Studies included in quantitative synthesis (meta-analysis) n = 75 Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

Odds Ratio for Major Adverse Cardiovascular Events (MACE) in Subjects Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure Odds ratio for MACE TRT Placebo Source MH - OR LL UL p 0.01 0.1 1 10 100 #Events # Patients #Events # Patients Copenhagen SG, 1986 (31) 1,97 0,08 48,82 0,68 Hall et al., 1996 (34) 0,32 0,01 8,23 0,49 Sih et al., 1997 (36) 0,88 0,05 15,33 0,93 Snyder et al., 1999 (40) 2,04 0,18 23,17 0,57 English et al., 2000 (42) 3,12 0,12 80,39 0,49 Seidman et al., 2001 (47) 0,41 0,02 10,83 0,59 Steidle et al., 2003 (52) 2,83 0,11 70,27 0,53 Armory et al., 2004 (54) 3,13 0,12 80,68 0,49 Kenn et al., 2004 (56) 0,23 0,01 7,05 0,40 Svartberg et al., 2004 (60) 0,29 0,01 7,74 0,46 Brockenbrough et al., 2006 (63) 3,75 0,36 39,59 0,27 Malkin et al., 2006 (69) 2,17 0,19 25,01 0,53 Nair et al., 2006 (72) 5,70 0,26 123,78 0,27 Svartberg et al., 2008 (81) 3,16 0,12 82,64 0,49 Chapman et al., 2009 (84) 1,00 0,05 20,83 1,00 Legros et al., 2009 (85) 1,01 0,04 25,01 1,00 Aversa et al., 2010 (89) 0,08 0,00 2,07 0,13 Aversa et al., 2010 (90) 0,07 0,00 1,97 0,12 Basaria et al., 2010 (11) 13,39 0,74 240,78 0,08 Kalinchenko et al., 2010 (92) 0,21 0,01 5,15 0,34 Srinivas- Shankar et al., 2010 (93) 1,01 0,14 7,31 0,99 Ho et al., 2011 (95) 1,00 0,06 16,37 1,00 Jones et al., 2011 (96) 0,51 0,05 5,75 0,59 Kaufman et al. 2011 (97) 0,87 0,04 18,48 0,93 Behre et al. 2012 (99) 2,95 0,12 72,91 0,51 Hildreth et al. 2013 (100) 0,15 0,02 1,53 0,11 Overall 1,01 0,57 1,77 0,96 LL: Lower limit; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit Placebo TS 1 134 0 87 0 35 1 35 1 17 1 15 2 54 1 54 1 25 0 25 0 13 1 17 1 106 0 99 1 24 0 24 0 6 1 5 0 15 1 14 3 19 1 21 2 37 1 39 2 30 0 32 1 19 0 19 1 6 1 6 1 237 0 79 0 40 1 10 0 42 1 10 6 106 0 103 0 113 1 71 2 136 2 138 1 60 1 60 1 108 2 112 2 234 0 40 1 183 0 179 1 96 3 47 31 1895 20 1341 Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

Odds Ratio for Acute Myocardial Infarction (AMI), Acute Coronary Syndrome, Stroke, Heart Failure, and Cardiovascular (CV) Mortality in Subjects Treated with Testosterone or Placebo Source # Trials Odds ratio for MH-OR LL UL p 0.01 MACE 0.1 1 10 100 TRT Placebo #Events # Patients #Events # Patients AMI 14 0,68 0,30 1,52 0,34 11 1086 11 747 Acute coronary syndrome 15 0,92 0,43 1,97 0,83 18 1093 11 738 Stroke 5 0,82 0,24 2,83 0,76 3 244 4 242 New heart failure 3 1,64 0,25 10,63 0,60 3 387 0 193 CV mortality 13 1,14 0,49 2,66 0,76 11 1173 8 928 Placebo TS LL: Lower limit; MACE: Major adverse cardiovascular events; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

Odds Ratio for Major Adverse Cardiovascular Events (MACE) According to Baseline Characteristics in Subjects Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure Source # Trials MH-OR LL UL p Odds ratio for TRT Placebo 0.01 MACE 0.1 1 1 10 10100 100 #Events # Patients #Events # Patients Associated diseases Elderly men 10 1,22 0,49 3,03 0,67 Men with CVD 2 2,48 0,35 17,45 0,36 Frail men 5 2,25 0,72 7,08 0,17 Men with metabolic diseases 4 0,19 0,04 0,85 0,03 13 954 6 549 3 62 1 64 13 401 4 355 1 303 5 203 Hypogonadism status Mixed population 14 1,26 0,58 2,73 0,56 TT < 12 nm 12 0,84 0,32 2,23 0,73 15 1066 11 865 16 829 9 476 Type of support Drug company not supported 12 0,94 0,39 2,24 0,88 Drug company supported 14 1,07 0,51 2,24 0,86 10 437 8 332 21 1458 12 1009 Trial duration 12 weeks 4 1,02 0,20 5,29 0,98 >12 weeks 22 1,01 0,55 1,84 0,98 2 147 2 145 29 1746 18 1196 CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper limit; MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone Placebo TS Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

TRT and Prostatic Cancer Until now there has been no data showing a direct correlation between TRT and Prostatic Carcer (Morgantaler, 2006) However, to have a definitive evidence, Some meta-analysis there would be almost studies 6000 did hypogonadal not present men a significant difference who in have prostatic been treating carcer with between T for 5 yrs patients least. treated with TRT or (Cunningham placebo GR (Calof & Toma OM SM, et JCEM, al et 2010) al 2005, Fernadez-Barsells MM et al, 2010). Similar results were found by another Authors: Krieg et al 1993 Slater et al 2000 Heikkila et al 1999 Hsing et al 2001 Zitzmann et all, 2013

Hypogonadism, Metabolic diseases Chronic renal diseases and CVD CVD Obesity Metabolic Syndrome Chronic renal Diseases Diabetes Aging Male INSULIN RESISTANCE Hypotestosteronemia

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