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FAT Mass Standarized Mean Differences Mario Maggi Sexual Medicine & Andrology University of Florence, [email protected] Alternative management of hypogonadism: DHEA and other Mario Maggi Sexual Medicine & Andrology University of Florence, [email protected] Alternative management of hypogonadism: DHEA and other G. Corona G. Rastrelli Alternative management of hypogonadism: DHEA at age 25 years, DHEA =0.2-0.9 μg/dL (7-31 nmol/L) DHEAS= 75-370 μg/dL (2-10 µmol/L), DHEAS= 75-370 μg/dL (2-10 µmol/L) Cholesterol 17- 17, 20 SK Pregrenolone 17-hydroxypregrenolone DHEA DHEAS 3- 3- 3- 17- 17, 20 Progesterone 17-hydroxyprogesterone Delta-4-androstenedione 17-R A Estrone Testosterone 17-R 5--R A Dihydrotestosterone Estradiol DHEA has been implicated in a broad range of age- related biological abnormalities including: -Obesity -Diabetes, insulin resistance -Osteoporosis -Sexual dysfunction -Mental disorders -Cancer -Hypertension, -Atherosclerosis -Coronary artery disease -Eating disorders DHEA Mechanism of Action ■The gamma-aminobutyric acid (GABA)-A/benzodiazepine receptor complex, via which DHEA and DHEA-S may antagonize the effects of GABA [1] ■ N-methyl-D aspartate excitatory amino acid receptors, where DHEA may potentiate the effects of glutamate [2] ■A nuclear hormone-type receptor called CAR, for which reduced metabolites of DHEA may be the natural ligands [3] ■A cell-surface receptor in vascular endothelial cells that binds DHEA (but not DHEA-S) and is functionally coupled to G-proteins and nitric oxide synthase [4] ■The sigma-1 receptor binds neurosteroids, including DHEA and DHEA-S, which have antidepressant-like effects in animal models of depression [5] 1.Sousa A, Ticku MK. Interactions of the neurosteroid dehydroepiandrosterone sulfate with the GABA(A) receptor complex reveals that it may act via the picrotoxin site. J Pharmacol Exp Ther 1997; 282:827. 2.Johansson T, Le Grevès P. The effect of dehydroepiandrosterone sulfate and allopregnanolone sulfate on the binding of [(3)H]ifenprodil to the N-methyl-d-aspartate receptor in rat frontal cortex membrane. J Steroid Biochem Mol Biol 2005; 94:263. 3.Forman BM, Tzameli I, Choi HS, et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 1998; 395:612. 4.Liu D, Dillon JS. Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to Galpha(i2,3). J Biol Chem 2002; 277:21379. 5.Takebayashi M, Hayashi T, Su TP. A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors. Pharmacopsychiatry 2004; 37 Suppl 3:S208. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006221. Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26 Study Design PUBLISHED studies UNPUBLISHED StudiesN=22 Medline searchN=220 Specific sub-population N=51 OngoingN=4 No results stratified for DHEAS=75 SpecificSub-population N=7 No RCT studies N=49 Women N=9 Children N=6 Men and women pooled results N=2 No results available N=2 Women N=8 29 Retrieved TOTAL N=29 N=0 Retrieved N=29 Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26 n=3369 Study Design • Longitudinal study – Baseline survey 2003 - 2005 – Follow-up survey 2008-2009 • Random population sample of community-dwelling men stratified by age (40-79 yr) • 8 centres in Europe, 400 subjects/country • Identical instruments, standardised methods across 8 centres for anthropometric evaluation and heel ultrasound • Questionnaires translated into local languages • Blood samples for measurement of 18 hormones and DNA polymorphisms • Lee et al. (Int J Androl. 2008; 31:1-14) EMAS Research Team Principal Investigators Expert Advisors S Boonen (Leuven) F WU (Coordinator, Manchester) M Lean, J Lara, T Han (Glasgow) and J Arnott (Manchester) D O’Connor (Leeds) G Bartfai (Szeged) N Pendleton, G McFarlane, J Adams, E Riley (Manchester) F Casanueva (Santiago de Compostela) J McKinlay (Boston) G Forti (Florence) M Maggi (Florence) A Giwercman (Malmo) Co-ordination I Huhtaniemi (Turku) J Finn, C Moseley, P Steer (Manchester) K Kula (Lodz) Data Analysis M Punab (Tartu) G Dunn M Lunt G Corona G Rastrelli D Vanderscheuren (Leuven) T O’Neill A Tajar S Pye D Lee Funding: Commission of the European Communities Fifth Framework Programme “Quality of Life and Management of Living Resources” Grant QLK6-CT-2001-00258 Relationship between circulating DHEA and DHEAS levels in European population r=0.44; p<0.0001 mol/L) DHEAS ( DHEA (nmol/L) Rastrelli, Corona et al., 2014, unpublished Does DHEA supplementation increase DHEAS levels in elderly men? DHEAS10,00 20,00 mean30,00 differences40,00 50,00 (mol/L)60,00 0,00 Source 0 10 20 30 40 50 60 Diff. in mean LL, 95% CI UL, 95% CI p Nestler et al., 1988 30,10 7,90 52,30 0,01 Flynn et al., 1999* 12,06 7,50 16,62 0,00 Flynn et al., 1999** 17,62 11,85 23,38 0,00 Baulieu et al., 2000 8,01 6,45 9,56 0,00 Arlt et al., 2001 7,70 5,83 9,57 0,00 Jedrzejuk et al., 2003 21,20 18,59 23,82 0,00 Villareal et al., 2004 8,44 7,85 9,02 0,00 Nair et al., 2006 9,00 4,78 13,22 0,00 Villareal et al., 2006 7,40 6,85 7,95 0,00 Jankowski et al., 2008 5,90 4,16 7,64 0,00 Muhlen et al., 2008 6,50 5,91 7,09 0,00 Weiss et al., 2009 8,13 7,88 8,38 0,00 Overall 9,09 8,00 10,19 0,00 Favours Placebo Favors DHEA Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26 DHEA levels variations in European population as a function of age and centres B=-0.131±0.004; P<0.0001 p=0.002 at ANOVA mol/L) mol/L) ng/dl DHEAS ( DHEAS ( Florence Lods Manchester Szeged Age (years) Leuven Malmo Santiago Tartu Rastrelli, Corona et al., 2014, unpublished DHEA levels variations in European population as a function of age and centres B=-0.131±0.004; P<0.0001 In RCT DHEA supplementation increases + DHEA DHEAS level of 9.09 [8-10.19] mol/L with mol/L) Doses ranging fro 25-100 mg/daily ng/dl DHEAS ( Age (years) Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26 Sex hormone levels according to DHEAS levels in European population Estradiol (pmol/L) SHBG (nmol/L) β r=0.05; p=0.004 17 r=-0.04; p=0.014 r= -0.09; p<0.00016 Total Testosterone (nmol/L) Testosterone Total I II III IV I II III IV I II III IV Quartiles of DHEAS Quartiles of DHEAS Quartiles of DHEAS Rastrelli, Corona et al., 2014, unpublished Sex hormone levels according to DHEAS levels in European population Estradiol (pmol/L) β DHT (nmol/L) DHT r=0.16; p<0.0001 r=0.08; p<0.0001 r=0.04; p=0.016 Free Testosterone (pmol/L) Testosterone Free Free 17 Free I II III IV I II III IV I II III IV Quartiles of DHEAS Quartiles of DHEAS Quartiles of DHEAS Rastrelli, Corona et al., 2014, unpublished Sex hormone dependent parameters according to DHEAS levels in European population + Androgenic + Estrogenic + Androgenic B= 0.121±0.053; p=0.022 PSA (ng/mL) PSA Prolactin (ng/mL) Prolactin Hemoglobin (g/dL) Hemoglobin B= 0.011±0.009; p=0.214 B= 0.033±0.040; p=0.402 I II III IV I II III IV I II III IV Quartiles of DHEAS Quartiles of DHEAS Quartiles of DHEAS Adjusted for Age/centre/n°morbidities , adjusted model Smoking/alcohol Mass derived FT, FE2, DHT Rastrelli, Corona et al., 2014, unpublished Sex hormone levels according to DHEAS levels in European population + Estrogenic + Androgenic B= 0.015±0.007; p=0.022 B= -0.292±0.098; p=0.003 Even after adjusting for confounders and major sex steroid levels, DHEAS is associated with some effects: SHBG (nmol/L) 1) Androgenic (SHBG) (ng/mL) Prolactin 2) Estrogenic (PRL) I II III IV I II III IV Quartiles of DHEAS Quartiles of DHEAS Adjusted for Age/centre/n°morbidities , adjusted model Smoking/alcohol Mass derived FT, FE2, DHT Rastrelli, Corona et al., 2014, unpublished Does DHEA supplementation increases T and 17βE2 levels in elderly men? 100,00 120,00 140,00 ‐ ‐ 40,00 20,00 E2 mean20,00 40,00 differences60,00 80,00 (pmol/L) 0,00 Source -40 -20 0 20 40 60 80 100 120 140 Diff. in mean LL, 95% CI UL, 95% CI p Morales et al., 1994 9,40 -6,60 25,40 0,25 Nestler et al., 1988 26,00 -20,46 72,46 0,273 Flynn et al., 1999** 85,81 50,32 121,30 0,000 Flynn et al., 1999** 77,94 34,86 121,02 0,000 Baulieu et al., 2000 1,67 -8,09 11,42 0,738 Arlt et al., 2001 1,00 -6,71 8,71 0,799 Jedrzejuk et al., 2003 2,57 -27,60 32,75 0,867 Villareal et al., 2004 41,18 23,65 58,70 0,000 Martina et al., 2006 16,00 3,45 28,55 0,012 Nair et al., 2006 20,00 10,62 29,38 0,000 Villareal et al., 2006 50,40 34,30 66,50 0,000 Jankowski et al., 2008 59,50 27,75 91,25 0,000 Muhlen et al., 2008 3,00 -7,58 13,58 0,578 Weiss et al., 2009 23,16 8,81 37,52 0,002 Overall 24,76 14,14 35,39 0,000 Favours Placebo Favors DHEA Corona et al., 2013 J Clin Endocrinol Metab 98:3615-26 ‐ ‐ 15,00 10,00 TT mean differences (nmol/L)10,00 15,00 ‐ 5,00 0,00 5,00 Source -15 -10 -5.0 0 5 10 15 Diff.
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