ANTICONCEPCION DE EMERGENCIA

Transcripción

1 AVANCES RECIENTES EN ANTICONCEPCION DE EMERGENCIA HORACIO CROXATTO UNIVERSIDAD DE SANTIAGO DE CHILE

2 TRATARE DOS TEMAS: COMO PREVIENE EL EMBARAZO NUEVOS COMPUESTOS

3 En varios países Latinoamericanos se ha prohibido la AE argumentando que previene la implantación y por lo tanto mata al embrión

4 March 21

5 May 21

6 July 24

7 How does emergency contraception prevent pregnancy? Por lo tanto es importante determinar si el LNG interfiere o no con la implantación

8 Demostramos en rata y en el mono cebus apella que el LNG interfiere con el proceso ovulatorio pero no interfiere con la implantación del embrión Contraception 67:415 9, 23; Human Reproduction 19, 6: , 24.

9 Postcoital treatment with levonorgestrel does not disrupt postfertilizationevents events in the rat. Muller AL, LLados CM, Croxatto HB Contraception 67:415 9, 23. Postcoital administration of levonorgestrel does not interfere with post fertilization events in the new world monkey Cebus apella. ME Ortiz, RE Ortiz, Fuentes, VH Parraguez, HB Croxatto. Human Reproduction 19, 6: , 24

10 Varios investigadores, en Estocolmo, Edimburgo, Ciudad de México y Santiago, diseñaron estudios farmacodinámicos para determinar si LNG interfiere con el proceso ovulatorio

11 Effectiveness of levonorgestrel emergency contraception given before or after ovulation a pilot study Novikova N, Weisberg E, Stanczyk FZ, Croxatto HB, Fraser IS. Contraception 75:112 8, 27

12 99 mujeres que pidieron AE dieron una muestra de sangre antes de tomar LNG para medir en ellas LH, E2 y P4. Basándose en los datos hormonales se determinó si tomaron LNG antes o después de la ovulación

13 Día del coito n=34-3 LNG n= LNG Embarazos Esperados sin LNG Novikova et al Contraception 75:112 8, 27 n=4.15 Observados con LNG n= n=3.45 n=3 8

14 Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation Noé G, Croxatto HB, Salvatierra AM, Reyes V, Villarroel C, Muñoz C, Morales G, Retamales A Contraception 81:414 2, 21.

15 QUÉ OCURRE CUANDO SE DA LNG ANTES O DESPUÉS DE LA OVULACIÓN? ADMINISTRACION CIUDAD MUJERES EN RIESGO EMBARAZOS ESPERADOS / OBSERVADOS ANTES Sidney 34 4 / Santiago / DESPUES Sidney 17 3 / 3 Santiago 35 7 / 6 Novikova et al. Contraception 75:112 8, 27 Noe et al. Contraception 81:414 2, 21

16 LA CIENCIA HA DEMOSTRADO MAS ALLA DE TODA DUDA QUE LA AE CON LNG NO PREVIENE LA IMPLANTACION Y NO MATA AL EMBRION

17 NUEVOS AE

18 Acetato de Ulipristal (UPA), un modulador selectivo del receptor de progesterona, administrado en la fase folicular media, retarda la ruptura folicular de un modo dependiente de la dosis Stratton et al. Human Reproduction 15:192 99, 2

19 Immediate pre ovulatory administration of 3 mg ulipristal acetate significantly delays follicular rupture Brache V, Cochon L, Jesam C, Maldonado R, Salvatierra AM, Levy DP, Gi Gainer E, Croxatto HB. Hum Reprod 25: , 21.

20 Percent of cycles without follicular rupture on days following UPA or placebo Proporción de folículos no rotos 1 aje Porcent Placebo UPA Días después de UPA o placebo

21 Ulipristal acetato (ellaone ; ella ) está indicado en AE Una dosis única de 3 mg hasta 12 horas postcoito previene el embarazo

22 Multiple Female Reproductive Failures in Cyclooxygenase 2 Deficient Mice Hyunjung Lim, Bibhash h C. Paria, Sanjoy K. Das, Joseph E. Dinchuk, Robert langenbach, James M. Trzaskos and Sudhansu K. Dey Cell 91: , 1997

23 La actividad de COX 2 en el folículo l es esencial para la ruptura folicular

24 Hipótesis MELOXICAM Pico de LH Fosfolipidos Fosfolipasa A 2 Acido Araquidonico + fosfolipidos COX 2 PGE 2, PF 2 α,pgi 2,TXA 2 Ruptura Folicular +36 h J Clin Pharmacol 46:925:32, 26 Hum Reprod 16; , 21 Human Reprod 22(2); 434 9, 27

25 Estudio cruzado, doble ciego y randomizado d CICLO 1 CICLO 2 11 mujeres Ciclo de descanso 11 mujeres 11 mujeres Ciclo de descanso 11 mujeres Meloxicam 15 mg/día Meloxicam 3 mg/día

26 Se administró Meloxicam 15 o 3mg/día por 5 días consecutivos, comenzando el día en que el folículo dominante alcanzó un diámetro de 18mm Se uso ecografía transvaginal para determinar si ocurrió y cuando la ruptura folicular

27 Momento de la ruptura folicular después del pico de LH % of cycles Ciclos Controles Históricos, n=11 7 Meloxicam 15 mg/día/5, n=22 Meloxicam 3 mg/día/5, n= Hours after LH peak

28 Suppression of follicular rupture with meloxicam, a cyclooxygenase 2 inhibitor: potential for Emergency Contraception Cristian Jesam, Ana Marıa Salvatierra, Jill L. Schwartz and Horacio B. Croxatto Hum Reprod 25:368 73, 21

29 Para AE recomiendo tomar Meloxicam 3 mg/día por 5 días, cuando el LNG no está disponibleibl

30 SIENTO QUE ES UN GRAN TRIUNFO PARA TODOS NOSOTROS QUE LA CIENCIA HAYA ESCLARECIDO QUE LAS MUJERES CHILENAS PUEDEN ACCEDER TRANQUILAS A LA AE

31 GRACIAS POR SU ATENCION

32 Time of follicular rupture 6 Treatment % of Follicu ular ruptur res Controles históricos, n=13 Meloxicam 15mg/día, n =22 Meloxicam 3mg/día, n = Time since the first dose of treatment (hours)

33 Currently available options for emergency contraception : Combined pills ( LNG + EE ) Progestin only: levonorgestrel (LNG 1.5 mg) SPRM: ulipristal acetate (UPA 3 mg)

34 Follicular diameter during the five days that precede rupture 25 F ollicular Diameter (mm) N=149 CYCLES Days prior to follicular rupture Croxatto, Encyclopedia of Public Health, in press

35 Eligibility Criteria Inclusion Criteria Healthy, 18 4 years of age. Regular menstrual cycles(24 35 d). Surgically sterilized Hemoglobin 11g/dL. Not breast feeding. No contraindication for the use of NSAID.

36 PROCEDURES Meloxicam E 2, LH, P 4 15 mm 18 mm DIA 1 3 TVU/WEEK BEGINNING ON DAY 7± 1 DAILY TVU SINCE FOLLICLE REACHES 18 mm 3 TVU/WEEK UNTIL FOLLICULAR RUPTURE OR NEXT MENSES

37 Time of follicular rupture after the LH peak % of cycles Ciclos Controles Históricos, n=11 7 Meloxicam 15 mg/día/5, n=22 Meloxicam 3 mg/día/5, n= Hours after LH peak

38

39 Maturation and Fertilization of Non Human Primate Oocytes are Compromised by Oral Administration of a COX 2 Inhibitor Diane M. Duffy Catherine A. VandeVoort Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA California National Primate Research Center and Department of Obstetrics and Gynecology, School of Medicine, University of California, Davis, CA, USA

40 SUPPRESSION OF FOLLICULAR RUPTURE WITH MELOXICAM, A CYCLOOXYGENASE 2 INHIBITOR: POTENTIALFOR EMERGENCYCONTRACEPTION CONTRACEPTION. Hum Reprod; 25:368 73, 21 Cristián Jesam 1, Ana María Salvatierra 1, Jill L Schwartz 2, Horacio B. Croxatto 3. Instituto Chileno de Medicina Reproductiva (ICMER), Santiago, Chile 1 CONRAD Eastern Virginia Medical School, Arlington, Virginia 2 Universidad de Santiago, Santiago, Chile 3

41 Hormone profiles after treatment: Progesterone 7 Tx after LH peak 7 Tx after LH surge 7 before peak Tx before LH surge UPA (n=8) Placebo (n=12) /L) Progestero one (nmol/ Days from treatment

42 Hormone profiles after treatment: LH levels 8 Tx before 8 Tx after LH 8 Tx after LH peak LH surge surge before peak UPA Placebo LH levels (IU/ /L) Days from treatment

43 Hormone profiles after treatment: Estradiol 7 Tx after LH peak 7 Tx after LH surge 7 Tx before LH surge before peak Estradiol le evels (pmol/l L) UPA (n=8) Placebo (n=12) Days from treatment

44 Follicular diameter after treatment Follicu ular Diamete er (mm) Tx before LH surge Tx after LH surge before peak Tx after LH peak UPA Placebo Mean days to follicular rupture UPA: 7. ±.8 Plac: 3.7 ±.8 Days from treatment UPA: 6.6 ±1.3 Plac: 3.2 ±.8 UPA: 1.5 ±.5 Plac: 1.3 ±.5

45 Efect of treatment on follicular diameter ) Follicular Diameter (mm Tx before LH surge T x a fte r L H surge before peak Tx after LH peak UPA Placebo Mean days to follicular rupture Days from treatm ent UPA: 7. ± ± ±.5 Plac: 3.7 ± ± ±.5

46 Emergency Contraception: Prevention of pregnancy after unprotected sexual intercourse has taken place

47 Primary objective of the study: Evaluate the efficacy of 3 mg UPA vs placebo in preventing follicle rupture during the 5 days after treatment administered in the advanced preovulatory phase (when the dominant follicle has reached 18mm)

48 Inhibition of follicular rupture at 5 days after treatment stratified by LH status at time of treatment 8/8 1 UPA (n=34) 8 11/14 Placebo (n=34) Percent (%) 6 4 Overall: 59% 2 1/12 /16 Tx before LH surge onset /12 /6 Tx after LH surge onset but before LH peak Tx after LH peak

49 Mean number of days from treatment to follicular l rupture Tx before Tx after LH Tx after LH LH surge surge onset but peak onset before LH peak UPA 7. ± ± 1.3 Placebo 37± 3.7 ± ± 3.2 ± ± ±.5

50 Final lead follicle outcome after treatment administration and follicle diameter at the time of rupture UPA Placebo Rupture within 5 days 14/34 34/34 of Tx (41%) (1%) Delayed rupture 15/34 /34 (within 6-1 days of Tx) (44%) (%) Luteinization prior to rupture/luf 5/34 (15%) /34 (%)

51 Cycles with no follicle rupture within 5 days after treatment (dosing at % follicular diameter 18mm) 59% n=34 15% n=48 % n=1 8% n=36 UPA 3mg LNG oral Yuzpe Placebo (2x.75mg) or 1.5 mg * Croxatto et al, Contraception 24; Massai et al, Human Reproduction 27; Croxatto et al. Contraception 22 51

52 Conclusions UPA can prevent ent pregnancy when administered late in the follicular phase, even if the LH levels have already began to rise, a time when LNG is no longer effective in preventing follicular rupture.

53 Conclusions UPA (3 mg) administered i din the advanced d follicular phase, inhibits or delays follicular rupture. This effect seems to be mediated by LH surge inhibition or delay

54 Study design: double blind, placebo controlled, cross over, randomized trial N=34 Months Study Treatment Washout Washout Treatment Post Screening Cycle 1 Cycle 2 Cycle 3 Cycle 4 Treatment Periods Randomization Placebo UPA 3mg UPA 3mg Placebo End of the Study Follow up: assessment of leading follicle by ultrasound and LH, E2 and P assays for 5 consecutive days following tx.

55 Primary efficacy: follicle rupture inhibition during 5 days following Pe ercent (%) treatment 2/34 59% UPA Placebo /34 % McNemar s test: p <.1

56 Momento de la ruptura folicular después de la primera dosis de Meloxicam cycles Number of mg/día 3 mg/día Hours