IL RUOLO DEL DEFICIT DI TESTOSTERONE NELLA … · PT di Conversano ASL BA . Jockenhövel F: Male...
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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 hypo- gonadism
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
-‐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
Corona G et al. Expert Opin Drug Saf, published online August 19, 2014
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
Corona G et al. Expert Opin Drug Saf, published online August 19, 2014
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
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 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