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LEVONORGESTREL AND ELLA
“EMERGENCY CONTRACEPTION”
How Do They Work?
Kathleen M. Raviele MD AAPLOG 2015
FDA-APPROVED EMERGENCY
CONTRACEPTIVE: PLAN B (LNG-EC)
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On July 28, 1999, the FDA approved the prescription
progestin-only Plan B (two 750 µg levonorgestrel
pills) emergency contraceptive.
On August 24, 2006, the FDA approved
nonprescription behind-the-counter access to Plan B
from pharmacies staffed by a licensed pharmacist
for women 18 or older; a prescription-only form of
Plan B was made available for younger females aged
17 and younger.
On March 23, 2009, a US judge ordered the FDA to
allow 17-year-olds to acquire Plan B without a
prescription. This changed the August 24, 2006
ruling with Plan B now available "behind the
counter" for men and women. A doctor’s Rx required
for girls under 17.
PLAN B CONTINUED
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On April 30, 2013, the FDA approved (with threeyear marketing exclusivity) Teva Pharmaceutical
Industries Plan B One-Step for sale without a
prescription to anyone age 15 or over who can show
proof of age such as a driver's license, birth
certificate, or passport to a drug store retail clerk.
Generic one-pill levonorgestrel emergency
contraceptives and all two-pill levonorgestrel
emergency contraceptives will remain restricted to
sale from a pharmacist—without a prescription to
anyone age 17 or over who can show proof of age.
On June 10, 2013, the Obama administration ceased
trying to block the over-the-counter availability of
the pill for all women and girls. With this reversal it
means that any woman or girl will be able to
purchase the Plan B One-Step without a
prescription.
WEBSITE : EFFECTIVENESS OF PLAN B
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“If Plan B One-Step® is taken as directed, it
can significantly decrease the chance that
you will get pregnant. About 7 out of every
8 women who would have gotten pregnant
will not become pregnant.”
WEBSITE : EXPLANATION TO WOMEN OF
MECHANISM OF ACTION
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“Plan B One-Step® is one tablet with
levonorgestrel, a hormone that has been used in
many birth control pills for several decades.
Plan B One-Step® contains a higher dose of
levonorgestrel than birth control pills, but
works in a similar way to prevent pregnancy. It
works mainly by stopping the release of an egg
from the ovary. It is possible that Plan B OneStep® may also work by preventing fertilization
of an egg (the uniting of sperm with the egg) or
by preventing attachment (implantation) to the
uterus (womb). It should not be used as regular
birth control, as it is not as effective.”
HOW PLAN B PREVENTS PREGNANCY
Direct Evidence:
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Interference with the ovulatory process –
demonstrated in several studies
Hypothetical Mechanisms:
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Interference with fertilization by affecting
sperm migration – no direct evidence
Interference with implantation – no direct
evidence
(Barr testimony FDA 2003)
CAN AN EMERGENCY
CONTRACEPTIVE WORK IF IT JUST
PREVENTS OVULATION AND
FERTILIZATION?
ALAN GUTTMACHER INSTITUTE (1996)
“to achieve the highest possible efficacy, the
ideal emergency contraceptive drug needs
to act interceptively; that is, it should be
capable of interfering with a physiological
event that occurs after fertilization – during
the period of early embryonic development
prior to implantation.”
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Von Hertzen and Van Look
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“Readings on Emergency
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Contraception”
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WHEN CAN A WOMAN GET
PREGNANT?
SIX DAY FERTILE WINDOW
Probability of Conception
Probability of Conception on Specific Days Near the Day
of Ovulation
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-6
-5
-4
-3
-2
Cycle Day
Sources: Wilcox 1995, Trussell 2003, Croxatto 2002
-1
0
(Wilcox
1995)
1
VARIABILITY OF THE CYCLE
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
30 31 32 33 34
MECHANISM OF ACTION OF LNG-EC:
TIMING IS EVERYTHING!
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Was the woman in the fertile window when
she took the drug?
Did the drug prevent or delay ovulation?
Did the drug incapacitate sperm by a
cervical effect or sperm motility effect?
What effect did the drug have on embryo
survival and successful implantation?
DURAND ET AL (2001)
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Studied 45 women who had been sterilized.
First cycle control cycle.
Women tested daily urinary LH, then serum
+ daily ultrasounds once detected.
Daily serum estradiol and progesterone
levels until period began.
LNG-EC given day 10 of cycle.
Contraception 64: 227-234.
RESULTS: DURAND ET AL (2001)
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LNG-EC suppressed ovulation 80% of the
time when given day -5 or earlier.
All ovulated when LNG-EC given days -4 to 2. Deficient progesterone levels and luteal
phase deficiencies in those who ovulated.
All ovulated when given the drug -1 to +1
with no effect on luteal phase.
No effect on endometrial histology.
DURAND ET AL (2005)
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Looked at 3 groups: Group 1 given drug
days -4 or -3, Group 2 given drug day -1 (LH
surge), Group 3 given drug day +1 (day after
ovulation).
Looked at long-term effects of premature
rise in progesterone on luteal progesterone
and glycodelin levels.
Glycodelin-A is at low levels except in the
late luteal phase and prevents maternal
rejection of the blastocyst.
RESULTS: DURAND ET AL (2005)
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“Levonorgestrel taken for emergency
contraception prior to the LH surge alters
the luteal phase secretory pattern of
glycodelin in serum and endometrium.”
Levels of glycodelin-A were low at the time
of implantation, preventing the suppression
of mother’s natural killer cells.
Contraception 71: 451-457.
PALOMINO ET AL (2010)
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LNG-EC given the day of the LH surge only
Results: no effect on progesterone or factors
necessary for implantation when given the
day of the LH surge.
Concluded LNG-EC had no postfertilization
effect but that was only for that day of
administration! Timing is everything.
Fertility and Sterility 94: 1589-1594.
NOE′ ET AL (2010)
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Studied 337 women seeking EC: LMP, time
of intercourse and drew blood tests on day
of LNG-EC administration.
Measured daily serum LH, estradiol,
progesterone and daily U/S’s to measure the
follicle.
63.7% received the drug in the infertile
time.
62 women were on days -5 to -1 and 86%
ovulated with no pregnancies.
NOE′ ET AL (2010) CONTINUED
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35 women took the drug the day of
ovulation or after and all ovulated and
there were the usual number of
pregnancies.
Their conclusion: “ this suggests that other
mechanisms than suppression of ovulation
prevents pregnancy in these women.”
Contraception: 81: 414-420.
CONCLUSION: LNG-EC IS A
POOR ANOVULANT
WHAT ABOUT EFFECTS ON SPERM
FUNCTION?
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Yeung et al (2002) - LNG-EC affects sperm
function only at high concentrations in
vivo.
Brito et al (2005) – no effect on the
acrosomal reaction in sperm in the uterus
36-60 hrs after coitus and 24-48 hrs after
LNG-EC administration.
Contraception 66: 453-457.
Contraception 72: 225-228.
EFFECTS ON SPERM FUNCTION
CONTINUED:
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do Nascimento et al (2007)- no effect on
sperm function or cervical penetration
when tested uterine washings 36 to 60
hours after intercourse and 24 to 48 hours
after giving LNG-EC.
Human Reproduction 22: 2190-2195.
CONCLUSION: MECHANISMS OF ACTION OF
LNG:
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LNG-EC does not consistently prevent
ovulation unless given on the first day of
the fertile window.
LNG-EC appears to have no effect on sperm
function or thickening of cervical muscus.
LNG-EC’s effectiveness depends on other
effects on the normal survival of the
embryo prior to implantation.
ELLA (ULIPRISTAL ACETATE)
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30 MG
Approved by FDA - August 2010.
Selective progesterone modulator which
binds to the progesterone receptor but
prevents the effects of progesterone on the
target organ similar to mifepristone.
Side effects – headaches (18%), nausea
(12%), pain(12%), dizziness (5%).
EFFECTIVENESS
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Reduces pregnancy rate from single act
intercourse from 5.5% to 2.2%
Used up to 120 hours but most effective first
48 hrs.
More effective than LNG.
Can be given close to ovulation and still
disrupt it.
MECHANISMS OF ACTION
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When follicle measures 18-20 mm and
ovulation will occur next 48 hrs (-2), ella
prevents ovulation in 60% of cycles
Has an effect on histology and
histochemistry of endometrium at high or
repeated doses
Not studied in pregnant women but causes
abortion in pregnant animals
CONCLUSION: ELLA IS MORE
EFFECTIVE AT DISRUPTING
OVULATION THAN LNG BUT
CLEARLY HAS ABORTIFACIENT
PROPERTIES