Avances in Oral contraception

Transcription

1 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 Motpellier, Frace

2 Overview Pharmacology of Progestis Risks ad beefits of curret Progestis Prospects for research Coclusios

3 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)

4 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)

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6 Adrogeic Potecy Progesteroe Icrease Prostate Growth (%) Testosteroe LNG DSG Nestoroe NOMAc NETA MPA Dieogest Trimegestoe Drospireoe

7 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

8 Effect of EE o hepatic markers whe give with o-adrogeic Progestis SHBG HDL Agiotesioge Modificatio of some clottig factors

9 so Effects of OC with 30µgEE ad Drospireoe or LNG Weight KG DBP mm SHBG HDL % DRSP LNG Oelkers W et al., JCEM 1995

10 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

11 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

12 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

13 Overview Pharmacology of Progestis Risks ad beefits of curret Progestis Prospects for research Coclusios

14 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

15 Coroary artery atherosclerosis i mokeys Clarkso T.B., Athoy M.S. et al 1996 Plaque area (mm2) Cotrol Estradiol Estradiol + Progesteroe

16 Coroary Artery Diameter i atherosclerotic mokeys 15 OVX % chage from cotrol E2 E + NMA * * ACH -7 ACH -6 ACH NTG Adapted from: Williams JK, Clie JM, Hoore EK, Delasore R, Paris J. Am J Obstet Gyecol 1998; 179: ACH=acetylcholie NTG=itroglyceri E2=Estradiol NMA=Nomegestrol Acetate

17 Atimieralocorticoid effect of DRSP E2 or EE Liver impact Agiotesioge AI A II Block MR DROSPIRENONE Aldosteroe Na & Water Retetio Na & Water Excretio

18 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

19 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)

20 MCF 7 cells grow without E2 DNA (μg/well) Estradiol Gestodee Norgestrel MPAc Catherio, Jeg ad Jorda; 1993, Br J. Cacer,

21 Overview Pharmacology of Progestis Risks ad beefits of curret Progestis Prospects for research Coclusios

22 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

23 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