L EVONORGESTREL AND ELLA “E MERGENCY C ONTRACEPTION ” How Do They Work? Kathleen M. Raviele MD AAPLOG 2015

FDA-A PPROVED E MERGENCY C ONTRACEPTIVE : P LAN B (LNG-EC) On July 28, 1999, the FDA approved the prescription progestin-only Plan B (two 750 µg levonorgestrel pills) emergency contraceptive.levonorgestrel 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.

P LAN B CONTINUED On April 30, 2013, the FDA approved (with three- year 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.Teva Pharmaceutical Industriesdriver's licensebirth certificatepassportretail clerk Genericpharmacist 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.

W EBSITE : E FFECTIVENESS OF P LAN B “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.”

W EBSITE : E XPLANATION TO W OMEN OF M ECHANISM OF A CTION “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 One- Step ® 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.”

H OW P LAN B P REVENTS P REGNANCY Direct Evidence: Interference with the ovulatory process – demonstrated in several studies Hypothetical Mechanisms: Interference with fertilization by affecting sperm migration – no direct evidence Interference with implantation – no direct evidence (Barr testimony FDA 2003)

C AN AN E MERGENCY C ONTRACEPTIVE W ORK IF IT JUST P REVENTS OVULATION AND FERTILIZATION ?

A LAN G UTT M ACHER I NSTITUTE (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.” Von Hertzen and Van Look “Readings on Emergency Contraception”

W HEN C AN A W OMAN G ET P REGNANT ?

S IX D AY F ERTILE W INDOW Probability of Conception on Specific Days Near the Day of Ovulation (Wilcox 1995) Sources: Wilcox 1995, Trussell 2003, Croxatto 2002

V ARIABILITY OF THE C YCLE

M ECHANISM OF A CTION O F LNG-EC: T IMING IS E VERYTHING ! 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?

D URAND ET AL (2001) 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:

R ESULTS : D URAND ET AL (2001) 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.

D URAND ET AL (2005) 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.

R ESULTS : D URAND ET AL (2005) “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:

P ALOMINO ET AL (2010) 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:

N OE ′ ET AL (2010) 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.

N OE ′ ET AL (2010) CONTINUED 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:

C ONCLUSION : LNG-EC IS A POOR A NOVULANT

W HAT ABOUT E FFECTS ON S PERM F UNCTION ? 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 hrs after coitus and hrs after LNG-EC administration. Contraception 66: Contraception 72:

E FFECTS ON S PERM F UNCTION CONTINUED : 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:

C ONCLUSION : M ECHANISMS OF A CTION OF LNG: 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 ) 30 MG Approved by FDA - August 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%).

E FFECTIVENESS 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.

M ECHANISMS OF A CTION When follicle measures 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

C ONCLUSION : ELLA IS MORE EFFECTIVE AT DISRUPTING OVULATION THAN LNG BUT CLEARLY HAS ABORTIFACIENT PROPERTIES