THE EFFECTIVENESS OF THE MIRENA COIL (LEVONORGESTREL ...€¦ ·
Mechanisms of action of levonorgestrel when used for Emergency Contraception Kristina Gemzell...
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Transcript of Mechanisms of action of levonorgestrel when used for Emergency Contraception Kristina Gemzell...
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 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 98-138 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
Ovulation1
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-glucuronideMarions et al., 2001
EC-mechanism of action, K Gemzell Danielsson
LNG preovulatory
• LH inhibited in all subjects
• One subject early onset of next mentruation
LH in levonorgestrel group
0
500
1000
1500
2000
2500
3000
3500
LH
-2
LH
0
LH
+2
LH
+4
LH
+6
LH
+8
LH
+10
LH
+12
mIU
/mm
ol
Cre
ati
nin
e
control
preovulatory
postovulatory
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
0
0,5
1
1,5
2
2,5
3
3,5
4
Control Ru486 Lev.
the
aver
age
of
sco
res
for
imm
un
ost
ain
ing
Control
Ru486
Lev.
**
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
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
EC-mechanism of action, K Gemzell Danielsson
Levonorgestrel on LH+2 Effects on the Endometrium
7 21 28
P4, E2 normal
plasma levelsOvulation
1.5 mg levonorgestrel
days
EC-mechanism of action, K Gemzell Danielsson
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 DBA
Marions et al. 2001
EC-mechanism of action, K Gemzell Danielsson
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
control
LNG
MIF
P4/C
0
500
1000
1500
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12
days
nm
ol/
mm
ol
control
LNG
MIF
E1/C
0
5
10
15
20
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12
days
nm
ol/
mm
ol
control
LNG
MIF
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