L` evoluzione dell`estroprogestinico

Transcription

1 1 1

2 L` evoluzione dell`estroprogestinico dosaggio estrogeno e progestinici Contraccezione con solo progestinico Sintesi e/o impiego di progestinici a minor impatto androgenico o selettivi Nuove vie di somministrazione Nuovi regimi di somministrazione Introduzione di estrogeni naturali 2

3 1957 Enovidcon 150 mcg di mestranolo 9,85 mg di noretinodrel 2001 EP con EE 15 mcg+ Gestodene 60 mcg Estrogeni naturali 1973 Microgynon 50 mcg di EE+Lng 150mcg 2009: Klaira, E 2 V/DNG In regime quadrifasico : Schering sviluppa Etinilestradiolo 1961: Anovlar EE 50 mcg + NETA 4mg 2000:OC con drospirenone Yasmin 2006: YAZ drospirenone 3mg /EE 20 mcg 24/4 regimen Sintesi Clorrmadinone ac. 3

4 Riduzione della dose di EE 50 mcgee 30 mcg EE 20 mcg EE 15 mcg EE rischio cardiovascolare effetti collaterali estrogeno correlati ( peso, nausea, tensione mammaria, cefalea ) stimolo sintesi sistema renina angiotensina stimolo sintesi epatica trigliceridi e VLDL Limite per deficit estrogenico Rischio di TVE e dosaggio EE nelle OC users Osteopenia, bleeding attività secretiva mucose produzione HDL colesterolo 4

5 Adverse events associated with EE : WHY? effects on liver metabolism higher exposure due to greater bioavailability extended half-life. 5

6 17β -E2 vs ethinylestradiol: Different metabolisms (1) 17α-Ethinyl Estradiol OH C CH HO H H H Endogenous and synthetic exogenous estradiol are extensively biotransformed to estrogen conjugates Limitation of EE conjugation Limitation of EE metabolism 6

7 L impatto metabolico di EE ed E2 è lo stesso? Etinilestradiolo Importante impatto su markers epatici SHBG Angiotensinogeno Markers Coagulazione HDL-colesterolo NO HDL E2 Potenza relativa di estrogeni diversi(%) SHBG Angiotensinogeno E EE Markers coagulazione SHBG HDL colesterolo 7

8 E2- based pills: Why only now? Historically, the development of E2- containing pills was stopped due to bleeding irregularities when administered as monophasic or biphasic regimens The first E2 pill with an acceptable bleeding profile was introduced in several markets in 2009: It combines estradiol valerate with dienogest administered in a quadriphasic, 26-day pill regimen ( dynamic dosing regimen ) 8

9 E2- based pills: Seeking the ideal progestin The challenge remains to combine a progestin that: Offers good cycle control Leads to an easy-to-use regimen (monophasic regimen) 9

10 10

11 Classification of Progestins Related to Progesterone Related to Testosterone Dydrogesterone Medrogestone 17-OH Progesterone (Pregnanes( Medroxyprogesterone Ac CyproteroneAc ChlormadinoneAc MegestrolAc 19-nor progesterone Nestorone Pregnanes) Nomegestrolacetate (NOMAC) Trimegestone Estranes Norethisterone Estranes Estranes\Pregnanes Dienogest 13-ethyl Gonanes Levonorgestrel Desogestrel (etonogestrel) Gestodene Norgestimate (norelgestromin) Spirolactone Drospirenone 11

12 Nomegestrolo acetato + E2 Dienogest + E2 Valerato

13 Biological activities of progestins + effective; - not effective; +/- weakly effective Progestins Antiestrogenic Estrogenic Androgenic Anti-androgenic Glucocorticoid Anti-mineralocorticoid Chlormadinone acetate Cyproterone acetate Dienogest +/- +/ Drospirenone Etonogestrel (3-ketodesogestrel) Gestodene Levonorgestrel Medroxyprogesterone acetate + - +/ Nomegestrol acetate /- - - Noresthisterone Norgestimate Progesterone /

14 Nomegestrolo acetato + E2 Why not 19-Norprogesterone? 14

15 Why progestins related to Progesterone To avoid the androgenic effects To prevent/preserve estrogen- dependent effects To improve the safety profile Metabolic safety Cardiovascular safety 15

16 Biological activities of progestins + effective; - not effective; +/- weakly effective Progestins Antiestrogenic Estrogenic Androgenic Anti-androgenic Glucocorticoid Anti-mineralocorticoid Chlormadinone acetate Cyproterone acetate Dienogest +/- +/ Drospirenone Etonogestrel (3-ketodesogestrel) Gestodene Levonorgestrel Medroxyprogesterone acetate + - +/ Nomegestrol acetate /- - - Noresthisterone Norgestimate Progesterone /

17 Nomegestrol acetate s ID High affinity for progesterone receptor High selective antigonadotropic activity Mild antiandrogenic activity No estrogenic, androgenic, and mineralo-glucocorticoid effects To preserve 17β- estradiol benefits, it is preferable to use a progestin devoid of glucocorticoid, androgenic and estrogenic effects 17

18 Progestins in COCs with various half-lifelife Half-life of various progestins Half-life can be given in a range of values for a few progestins 55 E2-based pills EE-based pills Half-life of nomegestrol acetate is as long as 46h 18

19 NOMAC Pharmacodynamic Endometrial effect of EE and estrogen withdrawal bleeding Progestogens induce the conversion of E2 in to E1 in the endometrial cells via stimulation of 17β-estradiol dehydrogenase type 2 This mechanism occurs only with combinations of progestogens (as NOMAC) with E2, as ethinylestradiol is not a substrate for this enzyme Endometrial proliferation breaks down Silent menstruations 19

20 Incidence of unscheduled bleeding or spotting episodes per evaluable cycle (B) The incidence of absence of scheduled bleeding episodes per cycle (B) 20

21 Cycle control analysis Absence of withdrawal bleeding Absence of withdrawal bleeding ranged over the cycles 1-12 from 18% to 32% of cycles in the Zoely group Early absence of withdrawal bleeding, occurring during the first months of Zoely use, is predictive of a persistent absence of bleeding with time: 21

22 Bleeding profile: Potential users of Zoely should be counseled regarding the absence of withdrawal bleeding, which is not a sign of reduced contraceptive efficacy* 22

23 Zoely Easy-to-use Contraceptive reliability (primary health benefit) Comfort Safety Breast 23

24 NOMAC and breast NOMAC could reduce the amount of estradiol in the normal breast and in breast cancer cells 24

25 Le nuove associazioni con estrogeni naturali Maggior neutralità metabolica Minor impatto procoagulativo 25

26 Ciproterone acetato Levonorgestrel Gestodene Desogestrel Etonogestrel Norelgestromina Clormadinone ac. Drospirenone Etinil-estradiolo Dienogest Nomegestrolo ac. Estradiolo valerato Estrogeni nelle associazioni EP Estradiolo Progestinici nelle associazioni EP 26

27 Easy-to-use Contraceptive reliability (primary health benefit) Comfort Safety Metabolic and haemostatic markers 27

28 Metabolismo glicidico Associazione E2 /Nomegestrolo acetato Zoely does not induce changes in carbohydrate metabolism Associazione E2 Valerato/Dienogest Confronto con EE/ Lng ParkeetAl 2008 Zoely does not induce changes in lipid metabolism No modificazioni significative sensibilità Insulina Agren U.M JungeetAl

29 Hormonal contraception and thrombotic risk Conflicting results Biases prescription BMI and other risk factors Lack androgenicity or anti-androgenic properties of progestins SHBG as a marker of predominant effect of potent estrogen in COCs and not as a marker of thrombotic risk 29

30 Relative potency of estrogens Estrogen FSH SHBG CBG Angiotensinogen 17β-E EE Le OC users vanno ± incontro a resistenza all effetto anticoagulante della Proteina C 30

31 Sistema emostatico Associazione E2 /Nomegestrolo acetato The low impact on haemostasis parameters may be explained by the lower potency of E2 compared with EE Nomac/E2 Lng/EE 20 F nM AT III + 0.3% -4.4% APCR Di Dimero Plasminogeno + 6% +30% PAI ng/ml Gaussem et Al 2011 Associazione E2 Valerato/Dienogest Confronto con EE/ Lng E2/V EE/Lng trifasica Fibrinogeno 7.9 % 28.1 % Fattore VII 13% 24.4 % Prot.S 1.8% 11.7% Parke et Al 2008 D-dimero in EE/Lng Fibrinogeno in EE/Lng Fattore VII in EE/Lng Proteina S in EE/Lng Junge et Al

32 Conclusions : Zoely and Klaira Contraceptive reliability Comfort Safety Both Bleeding pattern: Good tolerability Metabolic profile Haemostatic profile No changes in BMD 32

33 Conclusions : Zoely and Klaira Easy-to-use (?) Contraceptive reliability Comfort Safety Monophasic 24/4 Quadriphasic Both Bleeding pattern: Good tolerability Metabolic profile Haemostatic profile No changes in BMD 33

34 MONOPHASIC CONTINOUS OR EXTENDED 34

35 35

36 36

37 37