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Mechanisms of action of levonorgest rel when used for Emergency Contraception

Moscow, October, 2005. Mechanisms of action of levonorgest rel when used for Emergency Contraception. Kristina Gemzell Danielsson Karolinska University Hospital/ Karolinska Institutet Stockholm, Sweden. Emergency Contraception. ” One of the best kept secrets in family planning”.

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Mechanisms of action of levonorgest rel when used for Emergency Contraception

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  1. Moscow, October, 2005 Mechanisms of action of levonorgestrel when used forEmergency Contraception Kristina Gemzell Danielsson Karolinska University Hospital/ Karolinska Institutet Stockholm, Sweden

  2. Emergency Contraception • ”One of the best kept secrets in • family planning” EC-mechanism of action, K Gemzell Danielsson

  3. ”the woman ought, in the moment during coitus when the man ejaculates his sperm, to hold her breath, draw her body back a little so that the semen cannot penetrate into the os uteri, then immediately get up and sit down with bent knees, and in this position, provoke sneezes. She should then wipe out the vagina carefully or drink cold water in addition” Soranos of Ephesus 98-138 A.D EC-mechanism of action, K Gemzell Danielsson

  4. Methods for Emergency Contraception Yuzpe: • EE (100 µg) + LNG (0.5 mg) repeated 12h later LNG: • 0.75 mg repeated 12h later, • 1.5 mg Mifepristone: • Single dose of ≥ 10 mg IUD EC-mechanism of action, K Gemzell Danielsson

  5. Possible targets for LNG-EC • Sperm transport and function • Follicular development • Ovulation • Fertilization • Embryo development and transport • Endometrial receptivity and Implantation • Corpus Luteum EC-mechanism of action, K Gemzell Danielsson

  6. Effects on the spermatozoa • 90 sek endocervix • 5 min Fallopian tube Progesterone • Triggers acrosome reaction of capacitated human spermatozoa in vitro (Fukui et al 2000) EC-mechanism of action, K Gemzell Danielsson

  7. Levonorgestrel in vivo/ vitro LNG 3 to 10 h postcoital: • Reduced no of sperms in uterine cavity (3h) • Immobilisation of sperms (9h) • Increased viscosity of cervical mucus (9h) • Composition of the uterine fluid (10h) Kesserü et al., 1974 Effect in vitro: • Conflicting data • No effect of doses relevant for EC Yeung et al., 2002, Bahamondes et al., 2003 EC-mechanism of action, K Gemzell Danielsson

  8. Effects on follicular development and ovulation 1 Ovulation EC-mechanism of action, K Gemzell Danielsson

  9. Effects of levonorgestrel pre- or post- ovulatory • 18 fertile women • Levonorgestrel 1.5 mg • Pre- or post-ovulatory • Control and treatment cycles • Endometrial biopsy LH+6 to LH+8 • LH, estron- pregnanediol-glucuronide Marions et al., 2001 EC-mechanism of action, K Gemzell Danielsson

  10. LNG preovulatory • LH inhibited in all subjects • One subject early onset of next mentruation EC-mechanism of action, K Gemzell Danielsson

  11. Effects on follicular growth Treatment at diameter > 15mm mean 18.1 mm LNG (n=7) • Arrested (3) • Unruptured follicle (4) Marions et al., 2002 EC-mechanism of action, K Gemzell Danielsson

  12. Preovulatory levonorgestrel • LNG 0.75 mg repeated after 12 h (n=12) • Treatment on, or before, the LH rise in urine • Various effects: • Anovulation (n=1) • Delayed LH peak (n=4) • No effect on ovulation • Reduced LH and cycle length Hapangama et al 2001 • Closer to ovulation the effect declines in rats Müller et al., 2003 EC-mechanism of action, K Gemzell Danielsson

  13. Effects of LNG on ovulation • LNG-EC interruptsdevelopment of the dominant follicle if givenbefore the onset of the LH peak • Variable effects on follicular growth: • Delayed development • Inhibited growth • Unruptured follicle • Closer to ovulation the effect declines EC-mechanism of action, K Gemzell Danielsson

  14. Effects on embryo development and pregnancy • No direct effect on monkey embryos • No effect of human pregnancies in vivo or the pregnancy outcome • Cheng et al., EC-mechanism of action, K Gemzell Danielsson

  15. Effects on the Fallopian tube Tubal transport Regulated by progesterone ? • High doses of progesterone  slower ciliae beats • Reversed by mifepristone Mahmood et al. 1998 EC-mechanism of action, K Gemzell Danielsson

  16. Steroid receptor expression in the Fallopian tube • Treatment on day LH+2: • LNG 0.75 mg repeated 12h later (n=8) • Controls, no treatment (n=8) • Daily urine samples for LH, estrone- and pregnanediol- glucuronide • Surgery on day LH+ 3 to 6 • Biopsies from ampullar and isthmic part EC-mechanism of action, K Gemzell Danielsson

  17. ** A significant increase in PR levels was found in the Fallopian tube following treatment with mifepristone. **P<0.05 EC-mechanism of action, K Gemzell Danielsson

  18. EC-mechanism of action, K Gemzell Danielsson

  19. IL-1 IL-1ß IL-1ra PGE2 PGF2a LIF • Endometrial Receptivity • Pinopods • Integrins, adhesion molecules • Secretion • PG • Cytokines (LIF) • PR • MMP ErB4 LIF-R HB-EGF Glycodelin ß3  v IL-RtI LIF-R EC-mechanism of action, K Gemzell Danielsson

  20. EC-mechanism of action, K Gemzell Danielsson

  21. Levonorgestrel on LH+2 Effects on the Endometrium P4, E2 normal plasma levels Ovulation 21 28 7 days 1.5 mg levonorgestrel EC-mechanism of action, K Gemzell Danielsson

  22. LNG postovulatoryEffects on the endometrium • Cycle length unchanged • Hormonal levels unchanged • Endometrial development: No effect on endometrial histology • No signoificant effect on markers of endometrial receptivityExpression of COX-2 affected in 2 women No effect on b3, a4, COX-1, PR and DBA Marions et al. 2001 EC-mechanism of action, K Gemzell Danielsson

  23. Effects on the Corpus Luteum No effect on urinary glucuronide levels Reduced cycle length following LNG EC-mechanism of action, K Gemzell Danielsson

  24. ConclusionsMechanism of action of LNG-EC • The contraceptive effect of levonorgestrel used for EC is mainly due to impaired ovarian function • If the effect of EC is mainly to block the LH surge or to interfere with other processes involved in ovulation is not clear and needs to be further studied • Levonorgestrel in the doses used for EC has no effect on the endometrium • Levonorgestrel used for EC is no abortifacients and does not adversely affect an on-going pregnancy EC-mechanism of action, K Gemzell Danielsson

  25. Mechanism of action Cu-IUD • Impairs fertilization • Alters sperm motility and integrity • Impairs implantation (embryotoxic effect by copper) Trussel J et al 1995 EC-mechanism of action, K Gemzell Danielsson

  26. Recommendations • EC with 1.5 mg LNG, as a single dose should be offered during the entire menstrual cycle • Treatment should be started as soon as possible after intercourse (higher effecacy the earlier ECP are taken) up to 120h • No contraindications for EC pills • ECP do neither prevent nor promote STD and does not increase the risk of ectopic pregnancies • Regular contraceptives can be started immediately • Copper IUD is the most effective EC EC-mechanism of action, K Gemzell Danielsson

  27. WHO Collaborating Centre for Research in Human Reproduction Karolinska Hospital/ Institutet • Kristina Gemzell Danielsson • Lena Marions • Marc Bygdeman • Alexander Christow • Xiaoxi Sun • Xiayan Qui • Annette Aronsson • Angelos Sioutas • Marja-Liisa Swahn • Sten Cekan • Lena Elffors Söderlund • Margareta Hellborg • Berit Ståbi • Hongzhen Li • Anneli Stavreus-Evers EC-mechanism of action, K Gemzell Danielsson

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