1. Patient scheduling & Luteal phase support Konstantin Y. Boyarsky MD, PhD IVF Clinics “GENESIS” Department of Obstetrics and Gynecology, State Pediatric Medical Academy, St.- Petersburg, Russia

2. 2 If GnRH Antagonist IVF Is More Patient-Friendly and Safer, Why Are We Not Using it More?

3. 3 Cycle scheduling Less predictable day of cycle commencement Peaks and troughs in workload Week end working Scheduling with OC Pros and Cons Other options? What type of luteal support Which is the best protocol? Concerns that doctors report when considering moving over to the use of GnRH antagonists

4. 4 IVF Cycle Programming  Concerns regarding the ability to program GnRH antagonist cycles in order to avoid weekend oocyte retrievals (ORs) is the final barrier to general uptake of GnRH antagonist IVF therapy  We can equip doctors with 3 different tools to avoid weekend ORs –Scheduling With the OCP –Avoiding Weekend OR by Adjusting the Start Day for IVF Stimulation –Avoidance of Weekend OR by Simple Advancement or Delay of OR by 1 Day From Ideal

5. 5 IVF Cycle Programming –Scheduling With the COCP –Avoiding Weekend OR by Adjusting the Start Day for IVF Stimulation or hCG Administration –Avoidance of Weekend OR by Simple Advancement or Delay of OR by 1 Day From Ideal

6. 6  The following protocol using OCP cycle programming has been suggested: –The OCP should be started with menses (day 1-5) –The OCP must be taken for at least for14 days –Withdrawal bleeding can be expected within 48-72 h of ceasing the OCP –rFSH stimulation can be started on day 2-5 following withdrawal of the OCP 1 1. Huirne et al. Hum Reprod. 2006;21:1408; 1. Scheduling With the OCP

7. 7 1 Griesinger et al. Fertil Steril. 2010. 2. Huirne et al. Reprod Biomed Online. 2006;13:235-245 Drawbacks of Scheduling With OCP Pretreatment Disadvantages of OCP pretreatment include:  Longer duration of FSH stimulation (1 day) with the need for 1 additional injection and increased cost of gonadotrophins. 1  Infertile patients often do not like the concept of taking “contraceptive” medication. 1  Possible reduction in pregnancy rates 1  Altered endocrinology and follicle growth rates have been described after OCP 2

8. 8 OCP Pretreatment Rate difference in ongoing pregnancy per woman: -5% (95% CI: -10 to -1), P=0.02 Does the Efficacy of GnRH Antagonists Change With Contraceptive Pill Pretreatment? Griesinger et al. Fertil Steril. 2010.

9. 9 Is OCP cycle programming recommended?  It thus appears that OCP pretreatment negatively affects ongoing pregnancy rates, and should not be routinely used. OCP pretreatment is also associated with increased recFSH usage and a longer duration of recFSH stimulation (Huirne et al. 2006; Griesinger et al. 2010).  Lastly, from the patient’s perspective, OCP pretreatment increases the perceived length of treatment, and thus negates one of the major advantages of GnRH antagonists over agonists: the reduction in treatment duration (Devroey et al. 2009).  The benefits (cycle scheduling, synchronizing follicular cohort) must be weighed against the drawbacks (higher FSH consumption, longer stimulation, reduced pregnancy likelihood) Devroey et al. Hum Reprod 2009;24:764–74. Griesinger et al. Fertil Steril 2010;94:2382–4. Huirne et al. Reprod Biomed Online 2006;13:235–45. Tavmergen et al. Hum Reprod 2009;24(Suppl 1):O-211.

10. 10 Do we have other options than the OCs for cycle programming?

11. 11 Luteal Estradiol Pre-treatment Coordinates Follicular Growth During COS with GnRH Antagonist Luteal E2 group Control Group P # follicles >10mm (day 8) 16.416.8NS Mean follicle size (day 8) 9.911.1<0.001 Day of GnRH antagonist 9.18.5<0.01 Day of hCG11.910.8<0.001 # follicles ≥16mm day of hCG 9.97.9<0.01 # available embryos 6.44.6<0.01 Clinical pregnancy rate per cycle 34%25%NS Fanchin R et al. Hum Reprod 2003;18:2698-2703

12. 12 An RCT: E 2 V programming in IVF with GnRH antagonists compared with classical long agonist protocol A Guivarc’h-Levêque et al Gynecol Obstet Fertil 2010; 38:18-22 GnRH antagonist protocol with oestradiol valerate: 4 mg from day 25 until wanted start of stimulation day; ie, Thursday to Sunday Antagonist + E 2 VLong agonist protocol P Ongoing pregnancy rate 29%28% NS

13. 13 IVF Cycle Programming –Scheduling With the COCP –Avoiding Weekend OR by Adjusting the Start Day for IVF Stimulation or hCG Administration –Avoidance of Weekend OR by Simple Advancement or Delay of OR by 1 Day From Ideal

14. 14 2. Avoiding Weekend OR by Adjusting the Start Day for IVF Stimulation or hCG administration There is some flexibility in scheduling the start day of ovarian stimulation.  Pregnancy rates do not appear to be compromised when altering the start day of recFSH to day 2, 3, or 4 of menses 1,2  Moving the day of hCG administration by one day is a common practice. Pregnancy rates do not appear to be compromised with 1-day delay of hCG administration 2 1 Huirne et al. Hum Reprod 2007;22:2805–13. 2 T. Hillensjo et al. Human reproduction 2011 – ESHRE P-468

15. 15 IVF Cycle Programming –Scheduling With the COCP –Avoiding Weekend OR by Adjusting the Start Day for IVF Stimulation or hCG Administration –Avoidance of Weekend OR by Simple Advancement or Delay of OR by 1 Day From Ideal

16. 16 3. Avoidance of Weekend OR by Simple Advancement or Delay of OR by 1 Day From Ideal  It is common practice to administer the hCG trigger as soon as at least 3 follicles are ≥17 mm –Kolibianakis and colleagues suggest that waiting 2 days after this ‘ideal’ time is deleterious 1 –Administering hCG as soon as at least 3 follicles were ≥17 mm resulted in an ongoing pregnancy rate of 35.6%, compared with a rate of 25% when hCG was given 2 days later  Is it possible to avoid “ideal” Sunday OPUs by delaying them until Monday (1day delay)? Will this compromise IVF outcomes?  Could you avoid “ideal” Saturday OPUs by advancing the OPU by one day to Friday (1day advancement)? Does this compromise pregnancy rate? 1. Kolibianakis et al. Fertil Steril. 2004;82:102-107;

17. 17 Kelton Tremellen et al., Human Reproduction 2010;25:1219–1224. IVF outcomes for ORs conducted on the ideal day of scheduling compared with those advanced or delayed by 1 day from ideal Avoidance of weekend OPU during GnRH antagonist treatment by simple advancement or delay of hCG administration does not adversely affect IVF live birth outcomes 3. Avoidance of Weekend OR by Simple Advancement or Delay of OR by 1 Day From Ideal

18. 18 Scheduling Overview  While the COCP can be used to program start dates for rFSH stimulation to help avoid weekend OPUs, this makes the IVF cycle longer and may reduce pregnancy rates— NOT IDEAL. EV2 FUTURE OPTION?  Treatment flexibility at the start or completion of ovarian stimulation does not affect clinical outcome.  Simple advancement or delay of OPUs by 1 day from “ideal” is sufficient to totally avoid weekend OPUs, without compromising pregnancy rates.  Fear of an inability to “program” GnRH antagonist cycles should now be resolved!

19. 19 Luteal Phase Support

20. 20  All stimulated IVF/ICSI cycles have abnormal LP vs 8.1% natural cycles  Main reason is the inhibition of LH secretion due to supraphysiological steroid levels –multifollicular development –long half life of hCG Shorter duration of LH secretion = luteolysis Edwards, 1980; Fatemi, 2007 Tavaniotou, 2001; Fauser and Devroey, 2003 Luteal phase

21. 21 intensivesteroidsupport Engmann et al 2008 hCGrLHaGnRH Humaidan et al 2010 Castillo et al 2010 Papanikolau et al 2010 Kyrou et al 2011 How to rescue the luteal phase

22. 22 The Use of Progesterone in IVF Nosarka et al. 2005.

23. 23 Progesterone in LPS IM P Oral PVaginal P LPS = Luteal Phase Support

24. 24 IM Progesterone  Effective  Physiological serum levels  Painful (long, thick needles)  Occasional sterile abscess  Occasional allergic reaction (oil vehicle)  Needs to be administered by nurse, husband  Acute eosinophilic pneumonia associated with IM administration of progesterone as luteal phase support after IVF: 5 case reports

25. 25 IM vs Vaginal Progesterone Zarutskie et al. Fertil Steril. 2009;92:163. Study IM Progesterone n/N Vaginal Progesterone n/N Odds Ratio (Fixed) 95% CI With GnRHa Smitz 199225/13140/1311.86(1.05, 3.30) Abate 199915/526/520.32(0.11, 0.91) Saucedo 200011/4011/371.12(0.41, 3.00) Propst 200139/9925/1020.50(0.27, 0.91) Saucedo 20037/5015/502.63(0.97, 7.17) Dal Prato 200838/13832/1370.80(0.47, 1.38) Total (therapeutic doses)135/510129/5090.94(0.71, 1.26) Intramuscular vs vaginal P administration: ongoing pregnancy per ET Test for homogeneity chi-square = 18.8 df = 5 P=0.002 Test for overall P=0.676.

26. 26 Oral Progesterone Ineffective?  Progesterone administered orally  Degradation to its 5α- and 5β-reduced metabolites (Penzias, 2002)  Bourgain (1990) and Devroey (1988) reported absence of any secretory transformation of the endometrium in patients treated with oral micronized progesterone compared to IM or vaginal micronized progesterone  DG, a retroprogesterone with good oral bioavailability, has an antiestrogenic effect on the endometrium, causing a secretory transformation (Whitehead, 1980)  Chakravarty et al (2005) in a prospective, randomized study compared the efficacy of vaginal micronized progesterone with oral DG as luteal phase support after IVF  Both DG and micronized progesterone were associated with similar rates of successful pregnancies (24.1% vs 22.8%, respectively; P=0.81) DG = dydrogesterone.

27. 27 Estrogen + progesterone for luteal support Rate difference for live birth Kolibianakis et al, Hum Reprod 2008 (2008) (2006)

28. 28 Is hCG in the Luteal Phase Superior to Progesterone?  hCG does not provide better results than progesterone and is associated with a greater risk of OHSS Daya and Gunby. Cochrane Database Syst Rev. 2008;CD004830.

29. 29 GnRH agonist trigger and Luteal Phase Support  In fresh-autologous cycles, GnRH agonist triggering was less effective than hCG in live birth rate (OR 0.44, P=0.04)  Lower pregnancy rate may be due to luteal phase defect with GnRH agonist trigger, resulting from the short half-life of the LH surge Youssef et al. Cochrane Database Syst Rev. 2010 Nov 10; 11:CD008046.

30. 30 What Is the Best Length of Luteal Support?  Prolongation of progesterone supplementation in early pregnancy has no influence on the miscarriage rate, and thus no effect on the ongoing pregnancy rate  Progesterone supplementation can safely be withdrawn at the time of a positive hCG test in antagonist protocols patients Kyrou et al, 2011

31. 31 St.-Petersburg experience in the luteal support 200 mg vaginal progesterone three times daily during 14 days from the day of transfer until the day of a positive HCG in three groups of patients during first IVF attempt. Modified natural protocol, antagonist + FSH from 7 day of cycle (n=27 patients), IR= 35,3% Mild stimulation, antagonist + FSH from 5 day of cycle (n=25 patients), IR=27,8% Conventional ovarian stimulation, antagonist + FSH from 3 day of cycle (n=29), IR=37,9% Short luteal support can provide high implantation rate in antagonist protocols with different days of FSH administration

32. 32 Scheduling with GnRH antagonist protocols is possible to help avoiding weekend OPUs -COCP (E2?) to program start dates gonodotropin stimulation. -Adjusting the Start Day for IVF Stimulation or hCG Administration. - Advancement or Delay of OR by 1 Day From Ideal. Conclusions

33. 33 Adequate luteal support is necessary in GnRH antagonist cycles Vaginal progesterone is effective and is the most popular form of luteal support Duration of luteal support required may be shorter than current practice Conclusions

34. 34 THANK YOU! IVF CLINICS “GENESIS”, ST.-PETERSBURG, RUSSIA: IUI,IVF/ICSI/IMSI, OOCYTE DONATION, SURROGACY WWW.MCGENESIS.RU BOYARSKY@POCHTA.RU WWW.MCGENESIS.RU