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novel approach to luteal phase support

Moscow, January 2018. novel approach to luteal phase support. Shahar Kol IVF Elisha Hospital, Haifa, Israel. hCG AS TRIGGER. The default, “gold standard”, trigger agent Question of dose: to mimic the LH surge in amplitude Works fine for most patients

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novel approach to luteal phase support

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  1. Moscow, January 2018 novel approach to luteal phase support Shahar Kol IVF Elisha Hospital, Haifa, Israel

  2. hCG AS TRIGGER • The default, “gold standard”, trigger agent • Question of dose: to mimic the LH surge in amplitude • Works fine for most patients • Usually follows with vaginal Progesterone for luteal support • Can we fine-tune the trigger?

  3. hCG trigger # physiology

  4. What are the problems with hCG as trigger? • Deviations from physiology: • No FSH surge • Long half life • Early luteal over-stimulation

  5. Potential benefit of FSH surge • Eppig JJ. Nature 1979;281:483–484 • Strickland and Beers. J BiolChem 1976;251:5694–5702 • Yding Andersen C. Reprod Biomed Online 2002;5:232–239 • Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731 • Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666 • Promotes LH receptor formation in luteinizing granulosa cells • Promotes nuclear maturation (i.e. resumption of meiosis) • Promotes cumulus expansion

  6. Physiology? hCG long half life

  7. hCG trigger: price to pay • Supraphysiologic stimulation of CL in early luteal phase • Supraphysioloigc levels of E2 and P • Negative feedback at the pituitary level • Low endogenous LH secretion • Luteal phase defect • Need of luteal phase supplementation • Abnormal P production (peak P not with implantation) • Out-of-phase endometrium given high early P (?)

  8. The time gap (after r-hCG 250mcg) ? r-hCG decay hCG production by young placenta

  9. Luteal phase: special needs for P, Not hCG

  10. Importance of high mid-luteal progesterone - IVF Humaidan et al 2005, 2010, 2013

  11. Importance of mid-luteal progesterone – ovulation induction Acre et al RMBOnline 22:449,2011

  12. E+P endometrial preparation: low P low pregnancy Labarta et al HR, Oct 2017

  13. Luteal Progesterone post ovarian stimulation • If luteal P in a natural cycle is 30 nmol/L, following ovarian stimulation the needed P level is 3 times higher (>90 nmol/l). • Why? Yovich et al Aust N Z J Ob Gyn 26:59, 1986 Hull et al F&S 37:355, 1982 Yding Andersen et al RBMOnline 28:552, 2014

  14. The question of implantation potential post excessive ovarian response • “Clinical evidence for a detrimental effect on uterine receptivity of high serum oestradiol concentrations in high and normal responder patients”. Simon et al, HR 10:2432, 1995 • “Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period”. Pellicer et al, F&S 65:1190, 1996 • Is it secondary to insufficient P during implantation window?

  15. The higher late follicular E2, the higher mid-luteal P required Keep natural luteal P kinetics pattern

  16. Luteal P post hCG trigger: Day 8 « Day 3 Goldrat et al HR 9:2184, 2015

  17. Luteal P post hCG trigger: kinetics Peak hCG: 2 days after hCG injection Peak P: 7 days after hCG injection, or 5 days after OPU Beckers et al HR 15:43, 2000

  18. Agonist trigger and the luteal phase Kol F&S 81:1,2004 Devroey et al, HR 26:2593,2011 • The secret is simple: quick and irreversible luteolysis • OHSS-free clinic • So we can manipulate the luteal phase to our needs.

  19. Fatemi et al,F&S 100:742, 2013 • Four oocyte donors, each underwent 4 consecutive cycles (same protocol) • hCG trigger (10,000) + LPS (600 mg vag P+ 4 mg oral E2) • Agonist trigger (triptoreline 0.2 mg) , 1,500 hCG 35 hours later + LPS • Agonist trigger + LPS • Agonist trigger without LPS.

  20. GnRHa trigger: Complete luteolysis by day 5

  21. The mechanism of luteolysis post agonist trigger? • ….Surprise… not known…although used for many years • Hypothesis: Loss of LH pulsatility? • Study: 10 IVF hyper-responder patients, who received GnRHa as trigger, with no further support • Repeated blood sampling, every 20 minutes • Five patients on the day of oocyte retrieval • Five patients 48 hours later, on embryo transfer day.

  22. Natural cycle luteal LH Filicori et al JCI 73:1638, 1984

  23. Tannus et al, GynEndocrinol 33:741, 2017

  24. Tannus et al, GynEndocrinol 33:741, 2017

  25. Very early luteal phase: Gradual P increase Plasma P levels (mean ± SEM) in the day of oocyte retrieval. There is a significant increase in P values over time. R=0.53, P= 0.023 Tannus et al, GynEndocrinol 33:741, 2017

  26. Day 2 post OPU: peak P, and decline Plasma P throughout the study in the day of embryo transfer, 48 hrs post OPU (Mean ± SEM). There is a significant constant decline in P values over time. R= -0.94, P<0.00001 Tannus et al, GynEndocrinol 33:741, 2017

  27. Conclusions • Although pulsatile LH secretion continues, mean LH concentrations and LH pulse amplitude are lower than those described for a natural cycle. • The process of luteolysis starts 2 days after oocyte retrieval. Tannus et al, GynEndocrinol 33:741, 2017

  28. hCG-based luteal support: fixed time points? • 1,000 IU with trigger (Griffin) + E+P • 1,500 IU with OPU (Humaidan) +E+P • 1,500 IU 3 days post OPU (Haas) + E+P • What is the best timing? • Do we need exogenous E+P support? Can we avoid it?

  29. Coasting • A popular OHSS prevention strategy • So far, follicular in phase only • In OHSS high risk situation: stop gonadotropin • Follow E2 level daily • Trigger with hCG when E2 drops below a cutoff level • Mechanism: partial follicular demise

  30. Luteal coasting post agonist trigger • Suggested strategy: follow P level, when drops below a certain cutoff level, add 1,500 (?) IU of hCG • Mechanism: patient-specific, partial rescue of corpuralutea. • No need for additional P and /or E2.

  31. Luteal support strategy • Follow P levels daily from day +2. • Administer 1,500 IU of hCG when P drops below 30 nmol/l or <25% of post retrieval peak.

  32. Luteolysis kinetics (P) Kol et al, RBMOnline 31:633, 2015

  33. Luteolysis: E2 , P, LH

  34. Luteolysis: recovery • Mid luteal P=140±42 nmol/l (n=4): securing adequate P during implantation window. • In ongoing pregnancy, Day +14: P>190 nmol/l in all cases, E2=10,304±5,048 pmol/l - no need for further luteal support.

  35. If we rescue the CL, do we really need to supplement with E+P? Timing is everything…just before luteolysis begins

  36. P-free luteal support? • 44 pregnancies, GnRHa trigger followed by day 2 hCG (1,500 IU) support-only (study group). • Data from these 44 cycles were compared with the latest 44 pregnancies obtained following hCG (6,500 IU) trigger followed by progesterone luteal support (control group).

  37. Robust luteal activity post day 2 hCG 1,500 Vanetik et al GynEndocrinol 21:1, 2017 (Epub)

  38. In summary • Following GnRHa trigger, a bolus of 1,500 IU hCG 48 hours after oocyte retrieval adequately rescues the corpora lutea, without the need of any additional support • If OHSS risk: freeze all

  39. Rules for receptive endometrium • Follow luteal P profile • Maximal P to coincide with implantation window • Maximal luteal P in relation to maximal follicular E2. • If pregnancy is achieved, endogenous hCG will take over.

  40. Very simple… Nothing…..

  41. Benefits and limitation Большое спасибо • Patient friendly: cheap, simple, short. No need for daily vaginal P for a long time…. • Effective: Peak P when needed: implantation window. • No early luteal over-stimulation • Limitation: no RCT

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