il ruolo del deficit di testosterone nella … · pt di conversano asl ba . jockenhövel f: male...

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

Jockenhövel F: Male hypogonadism. UNI_MED Verlag Bremen 2004

Male hypogonadism - classification

Hypogonadism

Primary

hypogonadism

Secondary

hypogonadism

Target organ

resistance (T & LH +)

•  Feminisation due to androgen resistance or 5-alpha-reductase deficiency •  Estrogen deficit due to aromatase deficiency

Age-related

hypogonadism

•  Late onset hypogonadism

Testicular causes

•  Klinefelter syndrome •  Orchitis

•  Congenital or acquired anorchia

•  Testicular maldescent •  Testicular tumor

Hypothalamic causes

•  Idiopathic hypogonado- tropic hypogonadism

•  Kallmann syndrome •  Constitutional delay of

growth and development

Pituitary causes

•  Hypopituitarism

•  Pituitary tumors

Prepubertal forms

Postpubertal forms

LH + T -

LH - T -

LH -/+ T -

The role of Diseases !!!

Zitzmann et al. JCEM 2006;91:4335

20

12

10

8

0

Hot flushes P<0.001 Erectile dysfunction P=0.003

Feeling depressed P=0.001 Disturbed sleep P=0.004 Lacking concentration P=0.002 Diabetes mellitus type 2 P<0.001

Obesity P<0.001

Loss of libido P<0.001 Loss of vigour P<0.001

15

Total testosterone (nmol/L)

74

69

84 65

67

75

Patients (n)

Increasing prevalence of symptoms with decreasing testosterone concentrations

Symptom-specific threshold testosterone levels for observed increase of prevalence in patients attending an andrology clinic

4

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

5

Serum testosterone and SHBG vs age

Kaufman &Vermeulen Endocr Rev 2005 according to Vermeulen et al JCEM,1996

FAT DISTRUBUTION AND DEPOSITION ACROSS THE LIVE IN MEN

(E2 = 30 pg/ml)

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

cFT= 2 ng/dl

cFT= 12 ng/dl

cFT= 4,5 ng/dl

Fat mass

Obese man T< 300 ng/dl

SHBG = <30 nM/L cFT=< 6 ng/dl

Lean mass

Giagulli VA & Vermeulen A,1994 e 1996

1.  Evidence from Epidemiology and

Observation

2.  Evidence from Testosterone Deprivation

3.  Evidence from Testosterone Treatment

Three Ways to Review Effects of Testosterone in Men

JCEM,2012

Wu et al., J Clin Endocrinol Metab. 2008;93:2737

Cross-sectional survey on 3200 community - dwelling men aged 40 - 79 yr from a prospective cohort study in

8 European countries

2,66nMol/= 77 ng/dl

Random-Effects Pooled Mean Difference of Serum T Between Type 2 Diabetes Cases and Controls in Men

(Ding EL et al JAMA,2006)

Changes in Body Composition in 32 Men after Androgen Deprivation Therapy for Prostate Cancer for 48 weeks

Smith MR et al. J Clin Endocrinol Metab 87(2): 599-603 (2002)

20

30

40

50

60

70

80

90

Weight (kg) BMI (kg/m2) Fat mass (%)(DEXA)

Lean mass (%)(DEXA)

Baseline 48 weeksp=

0.00

5

p<0.

001

p<0.

001

p=0.

005

Basal 48 weeks

Saylor PJ and Smith MR J Urol 181: 1998-2008 (2009)

GnRH Agonists are Associated with Significant Excess Risk of Diabetes, Coronary Heart Disease, Myocardial Infarction,

and Sudden Cardiac Death

Better Worse

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.

-10 -8 -6 -4 -2 0 2 4 6 8 10Total Fat Mass (kg)

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)

Isidori AM et al. Clin Endocrinol 63: 280-293 (2005)

Effects of Testosterone Therapy on Total Body Fat: a Meta-Analysis

Isidori AM et al. Clin Endocrinol 63: 280-293 (2005)

Effects of Testosterone Therapy on Total Fat Free Mass: a Meta-Analysis

-10 -8 -6 -4 -2 0 2 4 6 8 10Total Fat Free Mass (kg)

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)

What is the possible mechanism causing hypogonadism in man affected by metabolic

diseases and renal failure?

Normal physiology

Preoptic area

Leptin

+

Glicaemia

c= p <0.01 vs nonobese d= p< 0.05 vs nonobese

ANDROGENS AND INSULIN PLASMA LEVELS IN NONOBESE HEATHY MEN AND OBESE MEN

(Giagulli VA et al, 1994)

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

Giagulli et al Curr.Pharm.Design,2011

Current Testosterone Formulations on Market

TESTOSTERONE THERAPY AND END-STAGE RENAL DISEASE

•  TU os (240 mg/die x 3 mesi): < PRL e LH (Van Coevorden et al,1986)

•  Differenti studi hanno documentato che la terapia con T

sulla DE è efficace solo in caso di ipogonadismo franco (Canguven O et al 2010)

•  La somminstrazione di T migliora l’eritropeotina e l’anemia nei pazienti con insufficienza renale cronica di fase avanzata (Gaughan WJ 1997).

Tuttavia i dati (RCTs) in lettaratura sono veramente scarsi e pertanto non

possono essere considerati definitivi

I distubi biochinici e quelli clinici dell’ipogonadismo nel paziente con

stadio finale della insufficienza renale MIGLIORANO con il trapianto

Iglesias P et al J Nephrol, 2012

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

PREVALENCE of HYPOGONADISM IN T2 DM

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 studiesMedline search N=1703

40 Retrieved

UNPUBLISHED Studies N=31

Ongoing N=5

N=1 Retrieved

Review or Editorial N=4

No testosterone use included=649

No RCT studies N=755

Case report N=1

No data on sexual function N=245

Review n N=3

TS vs. placebo N=28

TOTAL N=41

No results available N=13

Women N=5

No testosterone use included=3

No data on sexual function N=9

EugonadalN=5

MixedN=5

HypogonadalN=18

TS+PDE5ì vs. nothing or placebo + PED5ì N=12

hypogonadalN=0

MixedN=3

EugonadalN=9

TS vs. placebo N=1

HypogonadalN=1

Motivation (libido)

Arousal (erection)

Orgasm (ejaculation)

Male sexual response cycle

-‐0,50

0,00

0,50

1,00

1,50

2,00

2,50

3,00Source

Libido component standardized mean differences -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

Placebo TS

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

Overall

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

0,81 0,47 1,17 0,000

Effect size (with 95%CI) of testosterone supplementation (TS) versus placebo on libido component

Overall 0.81 0.47 1.17 0.001

Corona et al., 2013 submitted

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

-‐0,50

0,00

0,50

1,00

1,50

2,00

2,50Source

Overall erectile function component standardized mean differences -0.5 0 0.5 1.0 1.5 2.0 2.5 Diff. in mean LL, 95% CI UL, 95% CI p

Placebo TS

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

Overall

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

0,33 0,13 0,54 0,001

0,82 0,47 1,17 0,001

Effect size (with 95%CI) of testosterone supplementation (TS) versus placebo on overall erectile function component (including sexual and spontaneous erections)

Overall 0.82 0.47 1.17 0.001

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)

Overall oral formulations

Overall transdermal formulations

Overall parental formulations

Overall

-‐0,50

0,00

0,50

1,00

1,50

2,00

2,50

3,00

3,50

4,00Source

Erectile function component standardized mean differences -0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Diff. in mean LL, 95% CI UL, 95% CI p

Placebo TS

1,77 -0,19 3,73 0,076

0,31 0,04 0,59 0,026

0,46 0,18 0,74 0,001

0,75 0,37 1,12 0,000

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

Skakkebaek et al., 1981

Davidson et al., 1979

Kwan et al., 1983

Gluud et al., 1988

Carani et al., 1990

Schiavi et al., 1997

Cavallini et al., 2004

Chaing et al., 2009

Jones et al., 2011

Hackett et al., 2013

Overall

1,46 0,52 2,40 0,00

1,06 -0,26 2,39 0,12

1,58 -0,26 3,41 0,09

0,11 -0,27 0,49 0,58

0,79 -0,38 1,97 0,19

1,62 0,30 2,94 0,02

1,00 0,54 1,46 0,00

0,97 0,31 1,62 0,00

0,05 -0,24 0,34 0,74

0,42 0,13 0,72 0,00

0,68 0,34 1,02 0,00

-‐5,00

-‐4,00

-‐3,00

-‐2,00

-‐1,00

0,00

1,00

2,00

3,00

4,00

5,00Source

Orgasm component standardized mean differences-5.0 -4.0 -3.0 -2.0 -1.0 0 1.0 2.0 3.0 4.0 5.0 Diff. in mean LL, 95% CI UL, 95% CI p

Placebo TS

Effect size (with 95%CI) of testosterone supplementation (TS) versus placebo on orgasm component

Overall 0.68 0.34 1.02 0.001

J Sex Med. 2013;10:245.

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.

-‐2,00

0,00

2,00

4,00

6,00

8,00

10,00

12,00Source

Standardized mean differences -2.0 0 2 4 6 8 10 12

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

Diff. in mean LL, 95% CI UL, 95% CI p

Favours PDE5is Favours PDE5is + TS

-‐2,00

0,00

2,00

4,00

6,00

8,00

10,00

12,00Source

Standardized mean differences -2.0 0 2 4 6 8 10 12

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

Diff. in mean LL, 95% CI UL, 95% CI p

Favours PDE5is Favours PDE5is + TS

Mixed eugonadal/hypogonadal subjects

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

Studies included in qualitative synthesis n = 101

Studies included in quantitative synthesis (meta-analysis) n = 75

Studies excluded (see table 6) n = 26

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

RCT: Randomized clinical trials; T: Testosterone.

Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

LL: Lower limit; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit

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


TRT Placebo Source MH - OR LL #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

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

UL p 0.01 0.1 1 10 100 Odds ratio for MACE

Placebo TS

LL: Lower limit; MACE: Major adverse cardiovascular events; MH-OR: Mantel-Haenszel odds ratio; UL: Upper limit

Odds Ratio for Acute Myocardial Infarction (AMI), Acute Coronary Syndrome, Stroke, Heart Failure, and Cardiovascular (CV) Mortality

in Subjects Treated with Testosterone or Placebo


Odds ratio for MACE Source # Trials

TRT Placebo #Events # Patients #Events # Patients

Placebo TS

AMI 14 0,68 0,30 1,52 0,34

Acute coronary syndrome 15 0,92 0,43 1,97 0,83

Stroke 5 0,82 0,24 2,83 0,76

New heart failure 3 1,64 0,25 10,63 0,60

CV mortality 13 1,14 0,49 2,66 0,76

11 1086 11 747

18 1093 11 738

3 244 4 242

3 387 0 193

11 1173 8 928

p LL UL 0.01 0.1 1 10 100 MH-OR

CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper limit; MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone


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 p TRT Placebo #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

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

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

Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12

2 147 2 145

29 1746 18 1196

UL

1009

100 Odds ratio for MACE

Placebo TS

0.01 0.1 1 10 0.01 0.1 1 10 100

•  Until now there has been no data showing a direct correlation between TRT and Prostatic Carcer (Morgantaler, 2006)

•  Some meta-analysis studies did not present a significant difference in prostatic carcer between patients treated with TRT or placebo (Calof OM et al et 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

TRT and Prostatic Cancer

However, to have a definitive evidence, there would be almost 6000 hypogonadal men who have been treating with T for 5 yrs at least.

(Cunningham GR & Toma SM, JCEM, 2010)

Hypogonadism, Metabolic diseases Chronic renal diseases and CVD

Obesity Metabolic Syndrome Diabetes

Aging Male

Hypotestosteronemia

INSULIN RESISTANCE

CVD

Chronic renal Diseases

Thanks for bearing with me

il ruolo del deficit di testosterone nella … · pt di conversano asl ba . jockenhövel f: male...

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