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

What are the needs? Follow physiology: Trigger Luteal phase

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?

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

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

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

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

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

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

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

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

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?

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

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

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

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?

The alternatives: Receombinant LH trigger GnRH agonist trigger

The physiology of agonist trigger LH surge1 FSH surge2

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

A safe and OHSS-free clinical environment

“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

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.

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

Tannus et al, Gyn Endocrinol 33:741, 2017

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

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

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, Gyn Endocrinol 33:741, 2017

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

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

Thomsen et al HR 2018

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!

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).

Robust luteal activity post day 2 hCG 1,500 Vanetik et al Gyn Endocrinol 21:1, 2017

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

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.

Very simple… Nothing…..

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