1. Reducing implantation failure: novel approach to luteal phase support
Frankfurt, Germany,
Reducing implantation failure: novel approach to luteal phase support
Shahar Kol
IVF Elisha Hospital, Haifa, Israel

2. I declare to receive honoraria from Merck, MSD and Ferring

3. 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?

4. hCG trigger # physiology

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. Physiology?
hCG long half life

8. 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 (?)

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

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

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

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

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

14. 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

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. 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?

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.
Kol F&S 81:1,2004
Devroey et al, HR 26:2593,2011

20. Voting system: Do you use GnRH agonist as trigger?
Never
In all my IVF patients
In about 30%-50% of my patients
Only in OHSS-high risk cases

21. hCG trigger (10,000) + LPS (600 mg vag P+ 4 mg oral E2)
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.
Fatemi et al,F&S 100:742, 2013

22. GnRHa trigger: Complete luteolysis by day 5

23. 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.

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

26. Tannus et al, Gyn Endocrinol 33:741, 2017

27. 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

28. 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, Gyn Endocrinol 33:741, 2017

29. 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

30. 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, Gyn Endocrinol 33:741, 2017

31. 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?

32. Voting system: Post GnRHa trigger I use:
Always freeze all
Intensive E2+P support
1,500 IU hCG on day of OPU +E2+P
1,000 IUI hCG with trigger+ E2+P
other

33. 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

34. 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 corpura lutea.
No need for additional P and /or E2.

35. 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.

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

37. Luteolysis: E2 , P, LH LH (IU/l) E2 (pmol/l) P (nmol/l) 1.56±0.9
3,794±1,770
63.2±31
Day +2
2.38±1.3
3,738±2,454
38.9±36
Day +3

38. 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.

39. Voting system: following hCG trigger: when do you stop luteal support?
Immediately, if pregnancy test is positive
Four weeks after ET, if fetal heart +
Gestation week 9
Gestation week ≥ 12

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

41. 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).

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

43. 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
Luteal P kinetics mimics physiology, with maximal P to coincides with implantation window
If OHSS risk: freeze all

44. Very simple…
Nothing…..

45. Take-home messages
Receptive endometrium requires physiological P exposure
Need to mimic luteal P kinetics pattern
Maximal P to coincide with implantation window
Maximal luteal P in relation to maximal follicular E2.
hCG trigger is still the “gold standard”, further individualization?

46. Benefits and limitation
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
Thank you