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Enhancing Endometrial Receptivity: Optimizing Luteal Support for Improved IVF Outcomes

Explore the challenges with hCG as a trigger agent in IVF, its impact on luteal phase, and the potential benefits of fine-tuned luteal support. Discover alternatives like recombinant LH trigger and GnRH agonist trigger to address unmet needs in IVF treatment.

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Enhancing Endometrial Receptivity: Optimizing Luteal Support for Improved IVF Outcomes

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  1. Addressing Unmet Needs:Endometrial receptivitycan be improved with lutealsupport fine-tuning Shahar Kol, IVF Unit, Elisha Hospital, Haifa, Israel

  2. What are the needs? • Follow physiology: • Trigger • Luteal phase

  3. Does the routine trigger meet the needs? hCG AS TRIGGER • The default, “gold starndard”, trigger agent • Works fine for most patients • Usually followed by vaginal progesterone for luteal support • Is this the best we can have?

  4. 10,000 IU hCG Natural mid-cycle LH surge GnRHa trigger-induced LH surge

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

  6. 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

  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 luteal P

  8. Levels of progesterone in the luteal phase following the natural menstrual cycle or by the use of hCG bolus trigger 10.000 IU hCG Natural mid-cycle surge PEAK P IS 5 DAYS AFTER hCG TRIGGER

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

  10. The importance of high mid-luteal progesterone in IVF Pregnancy loss in relation to the mid-luteal phase progesterone levels in women undergoing ovulation with an agonist trigger Yding Andersen & Andersen, RBMOnline, 2014; 28:552

  11. 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

  12. 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?

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

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

  15. 544 patients, long agonist protocol, hCG trigger (10,000), Endometrin 300mg, IM P 100mg Mitwally et al F&S 2010

  16. Summary so far • Although routinely used in IVF, hCG trigger does not deliver • What do we look for: • Combined LH+FSH surge • Peak luteal P in correlation with peak follicular E2 • Avoid early luteal over stimulation • Assure smooth luteal P rise to peak. • Assure peak P coincides with implantation window • Decrease patient burden • Can our dream come true?

  17. The alternatives: • Receombinant LH trigger • GnRH agonist trigger

  18. The physiology of agonist trigger LH surge1 FSH surge2

  19. Agonist trigger and the luteal phase Nevo et al, F&S 79:1123, 2003 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.

  20. A safe and OHSS-free clinical environment

  21. “The concept of an OHSS-Free Clinic has become a reality. This approach should include pituitary down-regulation using a GnRH antagonist, ovulation triggering with a GnRH agonist and vitrification of oocytes or embryos” “…luteal phase supplementation with low-dose hCG has to be fine tuned.” Hum Reprod. 2011;26:2593

  22. The mechanism of lutolysis 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.

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

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

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

  26. Very early luteal phase: Gradual P increase Plasma P levels (mean ± SEM) on 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

  27. 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

  28. Conclusions • Mean LH concentrations and LH pulse amplitude are lower than those described for a natural cycle. • The process of luteolysis starts 48 hrs after oocyte retrieval. Tannus et al, GynEndocrinol 33:741, 2017

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

  30. Thomsen et al HR 2018

  31. If we rescue the CL, do we really need to supplement with E+P? Timing is everything…just before luteolysis begins,peak P day 7, right on time!

  32. 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).

  33. Robust luteal activity post day 2 hCG 1,500 Vanetik et al GynEndocrinol 21:1, 2017

  34. 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 JUST SIX CLICKS

  35. Rules for receptive endometrium • Follow luteal P profile. • Avoid early luteal over stimulation. • 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.

  36. Very simple… Nothing…..

  37. Dream comes true? • Combined LH+FSH surge - yes • Peak luteal P in correlation with peak follicular E2 - yes • Avoid early luteal over stimulation - yes • Assure smooth luteal P rise to peak - yes • Assure peak P coincides with implantation window - yes • Decrease patient burden - yes Toda Raba

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