1. Shahar Kol, IVF Unit, Elisha Hospital, Haifa, Israel
Addressing Unmet Needs: Endometrial receptivity can be improved with luteal support 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. Natural mid-cycle LH surge
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
Promotes LH receptor formation in luteinizing granulosa cells
Promotes nuclear maturation (i.e. resumption of meiosis)
Promotes cumulus expansion
Eppig JJ. Nature 1979;281:483–484
Strickland and Beers. J Biol Chem 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

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
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
The secret is simple: quick and irreversible luteolysis
OHSS-free clinic
So we can manipulate the luteal phase to our needs.
Nevo et al, F&S 79:1123, 2003
Kol F&S 81:1,2004
Devroey et al, HR 26:2593,2011

20. A safe and OHSS-free clinical environment

21. “The concept of an OHSS-Free Clinic has become a reality
“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, Gyn Endocrinol 33:741, 2017

25. Post agonist trigger
Natural cycle
0.6
21.5
Mean LH
1.2
2-3
Pulse number
0.44
12.3
Pulse amplitude
Tannus et al, Gyn Endocrinol 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, Gyn Endocrinol 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<
Tannus et al, Gyn Endocrinol 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, Gyn Endocrinol 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 Gyn Endocrinol 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