Update on EC methods and mechanism of action. Emergency Contraception (EC) Historical EC (1) Historical EC (2) Current EC Options

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1 ESC Meeting 2016 Update on EC methods and mechanism of action Dr. Raymond Li MBBS, MMedSC, FRCOG, FHKAM (O&G) Cert RCOG/HKCOG (Reprod Med) Department of O&G, The University of Hong Kong The Family Planning Association of Hong Kong Emergency Contraception (EC) Despite great efforts in contraceptive development, none of the current birth control method is 100% effective EC is a back-up contraception administered to a woman after unprotected sexual intercourse or contraceptive failure so as to prevent unplanned pregnancy. Historical EC (1) Historical EC (2) Ancient times: special manoeuvres, such as sneezing, jumping and vaginal douching with various substances (eg, disinfectants, lemon juices or Coca-Cola) have been used for EC. First reported use of EC in human - early 1960s: high-dose oestrogen regimens (eg, diethylstilboestrol mg daily, ethinyl oestradiol 5 mg daily, or conjugated oestrogen 30 mg daily) were used over 5 days. Very effective, with pregnancy rates of % but were soon abandoned because of the high incidence of side effects (nausea, 54 70%; vomiting, 24 33%) and teratogenicity. (Ho PC, 2000) Current EC Options A. Hormonal methods: Yuzpe regimen Levonorgestrel (LNG) Mifepristone Ulipristal acetate B. Copper intrauterine contraceptive device Yuzpe Regimen Introduced in 1974 in Canada (Yuzpe AA et al, J Reprod Med 1974) Ethinylestradiol 100 mcg + levonorgestrel 500 mcg First dose within 72 hours of UPSI Repeated 12 h later Equivalent dose can be made up by several tablets of COC Overall failure rate: 3.2%, increase with time after UPSI Side effects: Nausea (54%), Vomiting (16%) May affect absoption and reduce efficacy Prescribed with anti-emetics 1

2 Levonorgestrel-only Regimen Levonorgestrel-only Regimen First RCT reported in 1993 (Ho PC & Kwan MSW, Hum Reprod 1993) LNG 0.75 mg, within 72 h of UPSI, repeated 12 h later Single dose LNG 1.5 mg -- same efficacy (von Hertzen et al, Lancet 2002) Current recommendati on: Single dose LNG 1.5 mg within 72 hours after UPSI. Significantly lower side effects (Ho & Kwan 1993) Lower failure rate than Yuzpe: 1.1% vs 3.2% (WHO, Lancet 1998) Efficacy decreases with time after UPSI WHO recommends up to 120 h, but use beyond 72 h is outside product licence Levonorgestrel-EC Clinical studies showed that LNG is effective as EC only when given before but not after ovulation (Novikova et al, 2007; Noe et al, 2010) Acts mainly by delaying or inhibiting follicular development before LH surge Administration after onset of LH surge does not inhibit ovulation No significant effect on sperm function, fertilisation, endometrial receptivity and implantation (Yeung et al, 2002; Lalitkumar et al, 2007; Baird 2009; Meng et al, 2009; Gemzell-Danielsson et al, 2010 Mifepristone (RU486) Anti-progestogen Use of mifepristone 600 mg within 72 h first reported in 1992 (Webb et al, 1992) Mifepristone 600 mg = 50 mg = 10 mg (WHO, Lancet 1999) Most effective among all current regimens for oral EC (Cheng L, Cochrane Database Syst Rev 2013) Low incidence of nausea & vomiting Limited by its availability: 10 or 25 mg only a/v in a few countries (eg. China, Russia, Vietnam) Mifepristone (RU486) Ulipristal acetate the new EC pill Superior efficacy may be due to broader actions Uliprital acetate (CDB-2914) Delays / inhibits ovulation Also interfere with endometrial receptivity and embryo implantation (in-vitro studies) (Lalitkumar et al, 2007; Meng et al, 2009; Gemzell-Danielsson et al, 2010) Some effect on sperm function & tubal function No significant effect on fertilisation (Wanggren et al, 2008; Baird 2009; Gemzell-Danielsson et al, 2013; Ko et al, 2014; Li ao et al, 2014) Selective progesterone receptor modulator (SPRM) Launched under the trade name ellaone 2

3 Ulipristal acetate the new EC pill Ulipristal acetate 30 mg per tablet (Creinin et al, 2006; Glasier et al, 2010) 1. UPA is more effective than LNG (Creinin et al, 2006; Glasier et al, 2010) UPA vs LNG side effects 2. Effectiveness of UPA is maintained up to 120 hours after UPSI current licenced use 3

4 UPA vs LNG side effects 3. Side effect profile similar to LNG UPA: Mechanism of action Inhibits / delays follicular development and ovulation before LH peak (even after onset of LH surge) vs LNG not effective after onset of LH surge Wider window of action (Brache et al, 2013) Post-ovulation mechanisms?? e.g. Sperm function, tubal function, implantation Effect of UPA on tubal ciliary beat frequency An overall dose-dependent suppressive effect on CBF (p<0.0001) after treatment with UPA at all concentrations Ciliary beat frequency (Hz ) * * * * * * * * * * * * p < v s * * * * (Li et al, Hum Reprod 2014) A m p litu d e (re la tiv e to c o n tro l) Effect of UPA on tubal muscular contraction * **** B asal tone (re la tiv e to c o n tro l) ** *** (Li et al, Hum Reprod 2014) Effect of UPA on tubal muscular contraction Effect of UPA on progesteroneinduced acrosome reaction 7.5 F re q u e n c y (p e r m in ) ** **** 0.0 The basal tone, amplitude and frequency of muscular contractions were significantly reduced (p<0.05) after treatment with UPA at 200 ng/ml or above (Li et al, Hum Reprod 2014) (Ko JKY et al, Andrology 2014) 4

5 Effect of UPA on progesteroneinduced sperm hyperactivation Effect of UPA on (A) residual Ca ++ influx and (B) progesterone-induced Ca ++ influx (Ko JKY et al, Andrology 2014) (Ko JKY et al, Andrology 2014) Li HWR et al, ESC meeting 2014 Li HWR et al, ESC meeting 2014 Ulipristal acetate other mechanisms of action Tube: UPA has in-vitro inhibitory effect on ciliary beating and muscular contraction in the human Fallopian tube Sperm: UPA has in-vitro inhibitory effect on progesterone-induced acrosome reaction, sperm hyperactivation and calcium influx. The clinical implication of these in-vitro findings remains to be explored. (Berger et al, Hum Reprod 2015) Endometrial attachment: UPA at pharmacological dose is unlikely to have significant effect on embryo implantation (Ko JKY et al, 2014; Li HWR et al, 2014) 5

6 UPA Clinical Study Overall failure rate 1.7% (pre-ovulatory 1.4%, postovulatory 2.1% (p>0.05) Effectiveness (percentage of pregnancies prevented): 76.3% (pre-ovulatory) vs 47.0% (post-ovulatory), i.e significantly better if used pre-ovulatory compared to postovulatory (p<0.0001) (Li et al, Hum Reprod, in press) UPA Clinical Study Conclusion: The efficacy of UPA-EC was significantly better when administered before than after ovulation. Efficacy: Cu-IUCD Insertion High effectiveness. Very few pregnancies have ever been reported; failure rates <1%. Mode of action: Act by producing endometrial changes that prevent implantation +/- effects on sperm and tubal function Timing: Cu-IUCD Insertion Can be inserted within 5 days of unprotected coitus. When the time of ovulation can be estimated, the IUCD can be inserted beyond 5 days after intercourse, as long as this is not > 5 days after ovulation. Short-term vs Long-term Use: Can have the IUCD remained as a long-term regular form of contraception. Can be taken out in the next menstrual cycle if not want to have it as a regular contraception. Not abortifacient! Ethical Concerns Pre- vs post-fertilisation mechanisms Judicial Review in UK in 2002: ruled that pregnancy starts at the time of implantation and not at fertilisation Personal view & acceptance to be respected Personalised choice of EC Concluding remarks Modern methods of EC provide a safe and effective back-up for UPSI and contraceptive failure Mifepristone is the most effective hormonal regimen for EC, but its availability at the low EC dose is limited LNG 1.5 mg single dose regimen is the recommended method in most countries UPA is a promising alternative which may be more effective with wider treatment window. Cu-IUCD insertion is another option, very effective 6

7 (Yuzpe) LNG, Concluding remarks Not relevant for EC Acknowledgements: Professor PC Ho Professor EHY Ng Professor WSB Yeung Dr. Sue Lo Dr. WS O Dr. Calvin Lee Dr. Subin Liao Dr. Shiva Li Dr. Nancy Tiantian Li Thank you 7