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

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

EC-mechanism of action, K Gemzell Danielsson ” 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 A.D

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

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

EC-mechanism of action, K Gemzell Danielsson 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 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 Effects of LNG on ovulation LNG-EC interrupts development of the dominant follicle if given before 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 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 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 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 ** 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

HB-EGF IL-RtI PGE 2 PGF 2a  v ß3ß3 Glycodelin LIF-R LIF IL-1  IL-1ß IL-1ra ErB4 LIF-R Endometrial Receptivity Pinopods Integrins, adhesion molecules Secretion PG Cytokines (LIF) PR MMP

EC-mechanism of action, K Gemzell Danielsson

Levonorgestrel on LH+2 Effects on the Endometrium P4, E2 normal plasma levels Ovulation 1.5 mg levonorgestrel days

EC-mechanism of action, K Gemzell Danielsson LNG postovulatory Effects on the endometrium Cycle length unchanged Hormonal levels unchanged Endometrial development: No effect on endometrial histology No signoificant effect on markers of endometrial receptivity Expression of COX-2 affected in 2 women No effect on  3,  4, COX-1, PR and DBA Marions et al. 2001

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

EC-mechanism of action, K Gemzell Danielsson Conclusions Mechanism 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 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 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 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