Art agonist freezing


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Art agonist freezing

  1. 1. In high responders: Antagonist protocol, triggering with agonist and freezing all Aboubakr Elnashar Benha university Hospital
  2. 2. 1. High responders 1.1 Definitions 1.2 Hazards 1.3 Management 2. Antagonist protocol 3. Triggering with agonist 4. Freezing all
  3. 3. 1. High responders
  4. 4. 1.1 Definition: Prior to an IVF cycle Young age (22 y), lean (BMI, 19 kg/m2), PCOS History of: High response during a previous COS Cycle cancellation related to high response Development of moderate or severe OHSS (Golan et al., 1989; Ragni et al, 2005; Griesinger et al, 2007; Imbar et al, 2012) Basal investigations Total AFC > 16 AMH>25.0 pmol/l FSH<4 IU/l (NICE, 2013) -Follicles of 2–10 mm measured by transvaginal ultrasound on day 3 of cycle: high response was ≥15 oocytes or ≥20 oocytes =3.50ng/ml
  5. 5. During IVF: One of the following Peak E2 > 3000-4000 pg/mL, 20 follicles at least 10 mm, in addition to the leading follicles on the day of hCG Retrieval of >15 oocytes (Golan et al., 1989; Ragni et al, 2005; Griesinger et al, 2007; Imbar et al, 2012) For GnRH-antagonist-based stimulation: 18 follicles 11 mm on the day of hCG: 83% specificity in predicting severe OHSS (Papanikolaou et al.,2006)
  6. 6. 1.2 Hazards  Poor pregnancy outcome. {Elevated E2 level may affect the endometrium at implantation high - or excessive- number of oocytes retrieved may have a higher proportion of immatures}  OHSS. {acute volume shift from the intravascular to the extravascular space}: hemoconcentration, ascites, pleural effusion, renal failure, venothromboembolic, respiratory failure, and very rarely death
  7. 7. 1.3 Reported strategies for the high-responders  Dual suppression with OCP and GnRHa  Minimal stimulation protocols (CC/gonadotropins/antagonist)  In vitro maturation of human oocytes  GnRH antagonists instead of GnRH-agonists  GnRH-agonists as a substitute for hCG in antagonist cycles  Coasting  Withholding hCG and cycle cancellation  Reducing the hCG dose  Cryopreservation of all embryos
  8. 8. 2. Use of GnRH antagonists in stimulation protocols
  9. 9. GnRH antagonist protocol is associated with a lower pregnancy rate compared with GnRHa long protocol but with a significant reduction in severe OHSS (Al-Inany et al, Cochrane Database Syst Rev. 2006). Difference in PR: did not remain significant when a sub group analysis for ‘low response women’ was performed. (NICE, 2013)
  10. 10. 3. GnRH-agonist as a substitute for hCG in antagonist cycles in high-responders to prevent OHSS
  11. 11. Two different methods of ovulatory triggers: 1. Exogenous hCG: long half life (30 H) with serum hCG detectable up to 14 days after the injection. :prolonged luteotrophic effect: multiple corpora lutea and supraphysiologic levels of VEGF (McClure et al., 1994). development of OHSS via the enhancement of capillary leak (Lesterhuis et al., 2009). 2. GnRHa in antagonist cycles : pituitary endogenous LH surge which is enough to cause a trigger but does not last enough to result in OHSS.
  12. 12. Itskovitz-Eldor et al., 2000 8 patients: an increased risk for OHSS (>20 follicles 11 mm and/or E2 3000 pg/ml). 0.2 mg triptorelin (Decapeptyl) to trigger ovulation None of the patients developed OHSS. Four clinical pregnancies have been achieved from the embryos obtained during these cycles A new treatment option reducing risk of developing OHSS in high responders cycle cancellation.
  13. 13. Several studies Confirmed (Gonen et al., 1990; Itskovitz et al., 1991; Itskovitz-Eldor et al., 2000; Kol and Itskovitz-Eldor, 2000 Fauser et al., 2002; Orvieto et al., 2006; Bodri et al., 2009; Humaidan et al., 2011). Recently pregnancy outcome using GnRHa triggering for final oocyte maturation is superior to that of coasting in patients at high risk for OHSS (DiLuigi et al., 2010). GnRHa triggering is a valid alternative to hCG, resulting in the prevention of OHSS (Humaidan et al., 2011).
  14. 14. Other trials Beneficial effect of the GnRHa triggering approach that virtually eliminated OHSS in high-risk patients at the cost of reduced pregnancy rates (Humaidan et al., 2005; Orvieto et al. 2006) GnRHa triggering was associated with comparable numbers of retrieved oocytes but lower ongoing pregnancy rates, compared with hCG (Griesinger et al., 2006).
  15. 15. Recent Cochrane review a significant reduction in the OHSS rate when using the GnRHa to trigger ovulation, the live birth and ongoing pregnancy rates were lower compared with protocols using hCG as the ovulation trigger (Youssef et al., 2010).
  16. 16. The cause of lower pregnancy after GnRH- agonist triggering and fresh embryo transfer observed in previous RCTs (Humaidan et al., 2005; Kolibianakis et al., 2005) 1. In general patient population is unknown {Defective luteal phase} (Fauser et al., 2002; Nevo et al., 2003; Humaidan et al., 2005; Yding Andersen and Humaidan, 2005; Griesinger et al., 2007), despite luteal phase support with vaginal progesterone and oral estradiol (E2).
  17. 17. 2. In patients at risk of OHSS A disturbed luteal phase after agonist triggering and fresh ET will also impair pregnancy, despite a good prognosis in this patient group (young age, good ovarian response). late-onset OHSS in a GnRH-agonist-triggered cycle as a result of hCG exposure from an implanting embryo cannot be excluded (Chun, 2005).
  18. 18. Engmann et al., 2005 luteal phase support following GnRHa triggering should consist of IM progesterone combined with transdermal E2 An optimal protocol has not been established (Griesinger et al., 2006).
  19. 19. 4. Freezing all of the embryos and refraining from fresh embryo transfer
  20. 20. The unfavorable outcome of f-ET with this approach had led clinicians to favor cryopreservation of all the embryos and frozen– thawed ET (ft-ET) in a future cycle (Griesinger et al., 2007a,b; Griesinger et al., 2011). ET in an artificial cycle that is unaffected from ovarian stimulation might be of benefit to patients, who have a severely altered endocrine situation in the follicular phase, e.g. excessive steroid production
  21. 21. N % Monitored cycles 193 Survival 175 90.67 Pregnant/Started cycles 85 44 Implantaion rate 18.18 Clinical preg./Started cycles 69 35.8 Clinical preg./ET 69 39.6 Results of blastocyst vitrification and warming in Agial Hospital : from June 2012 till February 2013 (Hisham Saleh)
  22. 22. Kol and Muchtar (2005) 6 patients considered at OHSS risk were triggered with 0.2 mg triptorelin s.c. and received luteal phase support with daily 600 mg micronized vaginal progesterone and 4 mg vaginal E2; one patient conceived.
  23. 23. Babayof et al. (2006) 15 PCOS patients were agonist triggered and received luteal phase support with daily 50 mg IM progesterone and 4 mg oral E2; one patient conceived.
  24. 24. Imbar et al, 2012  f-ET group (n=70). intensive luteal phase supplementation 50 mg i.m. progesterone in oil and 6 mg of oral 17ß estradiol initiated on oocyte retrieval day ft-ET group (n=40) embryos were cryopreserved and transferred in the next cycle. The live birth rate per f-ET was 27.1 Vs 20% in the ft-ET group The implantation, pregnancy and spontaneous abortion rates were comparable in both groups. None of the patients developed OHSS.
  25. 25. Acceptable clinical pregnancy and live birth rates can be achieved by either ft-ET after cryopreservation of all embryos, or f-ET after GnRHa trigger, provided that adequate luteal phase support is administered. Confirmation of these findings by RCTs is now required
  26. 26. Conclusion GnRH-agonist triggering of final oocyte maturation with cryopreservation of all embryos offers patients at increased risk of OHSS a good chance of pregnancy while reducing the risk of OHSS. Although recent study indicated preliminary promising results on fresh ET with use of intensive luteal phase support, further RCT are needed to confirm
  27. 27. Thank you