Mechanisms of action of levonorgest rel when used for Emergency Contraception

Mechanisms of action of Mechanisms of action of levonorgestlevonorgestrel when used forrel when used for

Emergency ContraceptionEmergency Contraception

Kristina Gemzell Danielsson Karolinska University Hospital/ Karolinska InstitutetStockholm, Sweden

Moscow, October, 2005

EC-mechanism of action, K Gemzell Danielsson

Emergency Contraception

”One of the best kept secrets in family planning”


”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


Methods for Emergency Contraception

Yuzpe:– EE (100 µg) + LNG (0.5 mg)

repeated 12h laterLNG:

– 0.75 mg repeated 12h later,– 1.5 mg

Mifepristone:– Single dose of ≥ 10 mg

IUD


Possible targets for LNG-EC

• Sperm transport and function

• Follicular development

• Ovulation

• Fertilization

• Embryo development and transport

• Endometrial receptivity and Implantation

• Corpus Luteum


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)


Levonorgestrel in vivo/ vitroLNG 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


Ovulation1

Effects on follicular development and ovulation


Effects of levonorgestrel pre- or postovulatory

• 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-glucuronideMarions et al., 2001


LNG preovulatory• LH inhibited in all subjects

• One subject early onset of next mentruationLH in levonorgestrel group

0

500

1000

1500

2000

2500

3000

3500

LH-2

LH0

LH+2

LH+4

LH+6

LH+8

LH+1

0

LH+1

2

mIU

/mm

ol C

reat

inin

e

control

preovulatory

postovulatory


Effects on follicular growth

Treatment at diameter > 15mm mean 18.1 mm

LNG (n=7)

• Arrested (3)

• Unruptured follicle (4)Marions et al., 2002


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


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


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.,


Effects on the Fallopian tube

Tubal transport

Regulated by progesterone ?

• High doses of progesterone slower ciliae beats

• Reversed by mifepristone

Mahmood et al. 1998


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


00,5

11,5

22,5

33,5

4

Control Ru486 Lev.

the

aver

age

of s

core

s fo

r im

mun

osta

inin

g

ControlRu486Lev.

**

A significant increase in PR levels was found in the Fallopian tube following treatment with mifepristone. **P<0.05



HB-EGF

IL-RtI

PGE2

PGF2a

v ß3

Glycodelin

LIF-R

LIFIL-1IL-1ßIL-1ra

ErB4

LIF-R

Endometrial Receptivity•Pinopods

•Integrins, adhesion molecules

•Secretion

•PG

•Cytokines (LIF)

•PR

•MMP



Levonorgestrel on LH+2 Effects on the Endometrium

7 21 28

P4, E2 normal plasma levels

Ovulation

1.5 mg levonorgestrel

days


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

receptivity

Expression of COX-2 affected in 2 women

No effect on 3, 4, COX-1, PR and DBAMarions et al. 2001


No effect on urinary glucuronide levels Reduced cycle length following LNG

LH/C

0500

1000150020002500

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

days

mIU

/mm

ol controlLNGMIF

P4/C

0

500

1000

1500

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

days

nmol

/mm

ol controlLNGMIF

E1/C

05

101520

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

days

nmol

/mm

ol

controlLNG MIF

Effects on the Corpus Luteum


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


Mechanism of action Cu-IUD

• Impairs fertilization

• Alters sperm motility and integrity

• Impairs implantation (embryotoxic effect by

copper)

Trussel J et al 1995


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


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

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Mechanisms of action of levonorgest rel when used for Emergency Contraception

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