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 Usually follows with vaginal Progesterone for luteal support Can we fine-tune the trigger?

hCG trigger # physiology

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

Physiology? hCG long half life

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 (?)

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

Luteal phase: special needs for P, Not hCG

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

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

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

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

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

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

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

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

GnRHa trigger: Complete luteolysis by day 5

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.

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) 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

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 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

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?

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

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.

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.

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

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

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.

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

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 (Epub)

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

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.

Very simple… Nothing…..

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 Большое спасибо