Giorgio Arnaldi

1. Case forandrogens Giorgio Arnaldi ClinicadiEndocrinologia AOU OspedaliRiunitiAncona Ancona gioarnaldi@gmail.com

2. Adrenalandrogens and bone Agenda • Physiologyofadrenalandrogens , i.e. DHEA • Effectsofadrenalandrogens on bone • DHEA treatment in post-menopausal women • DHEA treatment and boneeffects in Addison

3. 10 000 Man DHEAS nmol l-1 Woman 0 10 20 30 40 50 60 70 Fetal Period Age (years) DHEA and DHEAS are the mostabundantsteroids in humans Adult 6-month oldinfant Birth At 50-60 yr, DHEA hasalreadydecreasedby 70% The individualvariabilityacrossadulthoodissubstantial and the normalrangeofserum DHEA(S) isthereforevery wide at each decade of life

4. DHEA exertsitsprimaryeffectsthroughitsestrogenic and androgenicmetabolites Labrie 2007

5. A specific DHEA receptorhasnotbeencharacterized Although DHEA maybeconvertedto DHEAS by SULT2A1, no relevantamountsof DHEA resultfromconversionof DHEAS. Therefore, DHEAS levels, which are measured in the routine clinicalpractice, maynotalwaysreflect the amountofavailable DHEA. In women, exogenous DHEA ismainlyconvertedtoandrogens. An increase in serumandrogensisobservedonly in menwith low androgenlevels Lang et al BP&R ClinEndocrinolMetab 2015

6. Adrenalandrogens and bone Agenda • Physiologyofadrenalandrogens , i.e. DHEA • Effectsofadrenalandrogens on bone • DHEA treatment in post-menopausal women • DHEA treatment and boneeffects in Addison

8. A specificbone DHEA receptor ?

9. “Thesefindingssuggestthat the hyperandrogenismobserved in Premature Adrenarchemaydirectly or indirectlyaffectbonemineralmass….”

10. DHEA and itsmetabolites are independentdeterminantsofcortical density, particularlybefore the activationofpubertal sex hormones • Remer, Tet al. Adrenarche and bonemodeling and remodeling at the proximalradius: weakandrogensmakestrongercorticalbone in healthychildren. Journal ofBone and MineralResearch, 18, 1539–1546. 2003 • DHEAS correlatesnegativelywithbone turnover beforepeak mass • Walsh, J.S.et al Hormonaldeterminantsofbone turnover before and afterattainmentofpeakbone mass. ClinicalEndocrinology (Oxf), 72, 320–327. 2010 • DHEAS, androstenedione and estrone were positive predictorsofboneage (….buttheywerenotassociatedwithbone density) • VandewalleSet al. Relation ofadrenal-derivedsteroidswithbonematuration, mineral density andgeometry in healthyprepubertal and earlypubertalboys. Bone. 69:39-46. 2014

11. Eighty CAH adults (47 classic, 33 nonclassic) low DHEAS maybeassociatedwithweakcorticalboneindependentofglucocorticoidexposure. • DHEAS was the onlyindependentsignificantpredictorof BMD at the forearm and spine • In a multivariate analysisafteradjustingforage, gender, height standard deviation, phenotype and cumulative glucocorticoidexposure, higher DHEAS wasindependentlyassociatedwithhigher BMD at the spine, radius and whole body.

13. Adrenalandrogens and bone Agenda • Physiologyofadrenalandrogens , i.e. DHEA • Effectsofadrenalandrogens on bone • DHEA treatment in post-menopausal women • DHEA treatment and boneeffects in Addison

14. Exogenous DHEA treatment • Whenadministeredtopostmenopausal women, DHEA ismainlytransformedtoandrogensratherthanestrogens. • Usingliquidchromatographycombinedwith tandem mass spectrometry, anoral dose of DHEA 50 mg dailyfor 12 monthsincreases: • estrone 34% and estradiol 57% • total testosterone about 100%, • DHT relativelyunchanged Davis et al JClinEndocrinolMetab, 2011, 96(6):1642–1653

15. DHEA wasadministeredpercutaneously once daily in the morningas a 10% cream 14 women (60 to 70 yr) Total hip +2% at 12 months Labrieet al JClinEndocrinolMetab, 82:3498–3512, 1997

16. Effectsof DHEA on bone in postmenopausal women in placebo-controlledtrials The effectissmall in relation toother treatment No fractures data are available Over 26 weeks 640 women Davis et al JClinEndocrinolMetab, 2011, 96(6):1642–1653

17. Adrenalandrogens and bone Agenda • Physiologyofadrenalandrogens , i.e. DHEA • Effectsofadrenalandrogens on bone • DHEA treatment in post-menopausal women • DHEA treatment and boneeffects in Addison

18. Adrenalinsufficiency • Replacementtherapy • Glucocorticoid • Mineralocorticoid • (Addisononly) • DHEAS (?) In bothprimary and secondaryadrenalinsufficiency, DHEA secretionisclearlydecreased and oftenevenabsent. In women, itresults in significantandrogendeficiencywhereastesticular testosterone ispreserved in men.

19. Gurnellet al Double-blind trial, randomized 106 subjects (44 males, 62 females) withAddison’sdiseasetoreceiveeither 50 mg dailyofmicronized DHEA or placebo orallyfor 12 months DHEA reversedongoing loss ofbonemineral density at the femoralneck (P 0.05) butnot at othersites. The improvementwasmodestcomparingother treatment

20. 10 femalepatients (medianage 38.5 years, range 28–52) withadrenalfailureweretreatedwith DHEA 50 mg for6months in a double-blind, randomized, placebo-controlled, and crossover study

21. No effects on muscle, fat, and bonetissue and on fuelmetabolism Frequentadverseeffects 10 femalepatients (medianage 38.5 years, range 28–52) withadrenalfailureweretreatedwith DHEA 50 mg for6months in a double-blind, randomized, placebo-controlled, and crossover study

23. JInternMed. 2014;275:104-15.