Avaces i Oral cotraceptio The Progestis: All similar? Regie Sitruk-Ware, MD Populatio Coucil & Rockefeller Uiversity, New York, USA World Cogress Pediatric & Adolescet Gyecology May 22-25 Motpellier, Frace
Overview Pharmacology of Progestis Risks ad beefits of curret Progestis Prospects for research Coclusios
Classificatio of Progestis Related to Progesteroe Related to Testosteroe Dydrogesteroe Medrogestoe Estraes Norethisteroe 17-OH Progesteroe (Pregaes) Medroxyprogesteroe Ac Cyproteroe Ac Chlormadioe Ac Megestrol Ac 19-or progesteroe Nestoroe Nomegestrol ac Trimegestoe Spirolactoe Drospireoe Dieogest (o-ethyl) 13-ethyl Goaes Levoorgestrel Desogestrel (etoogestrel) Gestodee Norgestimate (orelgestromi)
Progestis Mechaism of Actio GR MR AR DNA P4 PR A B A B P4 PR Receptor associated proteis & trascriptio factors Cytoplasm SRC1 COa Nucleus SMRT COr Progesti Respose Elemet (PRE)
Adrogeic Potecy Progesteroe Icrease Prostate Growth (%) Testosteroe LNG DSG Nestoroe NOMAc 100 10 0 NETA MPA Dieogest Trimegestoe Drospireoe
Progesti adrogeicity i hormoal cotraceptio with EE EE give orally or via o-oral route has similar impact o the liver EE-related SHBG icrease is opposed by a adrogeic progesti No-adrogeic progestis should be preferably combied with atural estradiol E2
Effect of EE o hepatic markers whe give with o-adrogeic Progestis SHBG HDL Agiotesioge Modificatio of some clottig factors
so Effects of OC with 30µgEE ad Drospireoe or LNG 25 20 15 10 5 0-5 -10-15 Weight KG DBP mm SHBG HDL % DRSP LNG Oelkers W et al., JCEM 1995
NEW PROGESTINS FOR CONTRACEPTION Predomiet effects Drospireoe (DRSP) = atimieralocorticoid Dieogest (DNG) = atiadrogeic Nestoroe (NES) = highest atiovulatory effect (o-oral) Nomegestrol (NOM Ac) = highly atigoadotropic Trimegestoe (TMG)= highly progestatioal Noe is adrogeic or estrogeic
Nomegestrol Acetate (NOMAc) for oral cotraceptio High atigoadotropic actio No adrogeic effect Low atiadrogeic effect No estrogeic effect No glucocorticoid actio Makig it highly suitable for oral cotraceptive use
Nestoroe i o-oral cotraceptives Highest atiovulatory potecy high progestatioal potecy ot active orally ot boud to SHBG o adrogeic or estrogeic effect o glucocorticoid activity at cotraceptive doses Makig it highly suitable for o-oral delivery
Overview Pharmacology of Progestis Risks ad beefits of curret Progestis Prospects for research Coclusios
Cliical Beefits of Progestis without adrogeic activity o weight gai o ace o adverse effect o Lipids miimal impact o Glucose ad Isuli Should have less impact o the vessels ad vasomotio
Coroary artery atherosclerosis i mokeys Clarkso T.B., Athoy M.S. et al 1996 Plaque area (mm2) 0.23 0.10 0.10 Cotrol Estradiol Estradiol + Progesteroe
Coroary Artery Diameter i atherosclerotic mokeys 15 OVX % chage from cotrol E2 E + NMA 2-150 * * -15-8 ACH -7 ACH -6 ACH NTG Adapted from: Williams JK, Clie JM, Hoore EK, Delasore R, Paris J. Am J Obstet Gyecol 1998; 179: 1288-94. ACH=acetylcholie NTG=itroglyceri E2=Estradiol NMA=Nomegestrol Acetate
Atimieralocorticoid effect of DRSP E2 or EE Liver impact Agiotesioge AI A II Block MR DROSPIRENONE Aldosteroe Na & Water Retetio Na & Water Excretio
Effect of Progestis o hemostasis No chages i clottig factors whe Progesti are give without estroge, however: Progestis with glucocorticoid actio potetiate the vascular procoagulat effects of thrombi (Herkert O 2001) No icreased risk with CMA give aloe (Plu- Bureau G, 2004) Estrogeicity of COCs reflected by the icrease of SHBG levels potetiate the risk of VTE
Progesteroe ad progesti actio o breast cells differ All progestis do ot stimulate breast tissue growth the same way (Wood CE, 2007 ) Progesteroe either oral or vagial stimulate less tha MPA (Wood C, 2007) Observatioal studies: o icrease i BC risk with progesteroe RCT-WHI : No previous users of HRT, 5 years i the trial with CEE +MPA RR = 1.06 ( = 12,504)
MCF 7 cells grow without E2 DNA (μg/well) 35 30 25 20 15 10 5 0-14 -13-12 -11-10 -9-8 -7-6 -5 Estradiol Gestodee Norgestrel MPAc Catherio, Jeg ad Jorda; 1993, Br J. Cacer, 67.945-952
Overview Pharmacology of Progestis Risks ad beefits of curret Progestis Prospects for research Coclusios
Beeficial Role of P & some progestis i the euroal tissue Icrease euroal survival Icrease sythesis of myeli specific proteis by oligodedrocytes P & 19-or P icrease Bcl-2 expressio prevetig cell death Nilse & Brito, Edocriology 2002, Nilse et al Gyecol Edocriol 2006, Ibaez C et al Neuropathol Appl Neurobiol 2004; 30: 80-9
Coclusios Differet progestis have various iteractios with the steroid receptors, hece differet side-effects New Progestis are o-adrogeic ad should preferably be used with E2 Adrogeic Progestis ca be combied with EE Most Progestis whe give aloe do ot modify hemostasis Potetial beefits of P ad some progestis o europrotectio ad myeli regeeratio deserve further developmet