Luteal coasting post GnRH agonist trigger Shahar Kol

Disclaimer The following presentation reflects my own experience and opinion. The presentation does not necessarily reflect drug companies’ policies. I mention off-label use of medications, this use is not endorsed by drug companies.

COS

Agonist trigger and OHSS prevention The secret is simple: quick and irreversible luteolysis.

Luteal phase Natural cycle day 7-9= 75 pg/ml vs. 18 Nevo et al, 2003

Summary The lower levels of luteal steroidal and non- steroidal hormones reflect luteolysis, and may explain the mechanism of OHSS prevention by GnRH-a. Pregnancy post agonist trigger does not rescue the CL!!! Nevo et al, 2003

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, 2013

Conclusion: complete luteolysis by day of OPU + 5 Implication: luteal support is mandatory

Luteal phase post agonist trigger in high responders Freeze all Fresh transfer

LUTEAL PHASE: INTENSIVE E+P OHSS high-risk patients Engmann et al, 2008

Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders Patients <40 years old with peak E2 <4,000 pg/mL at risk of OHSS Triggered with GnRHa alone or GnRHa plus 1,000 IU hCG (dual trigger) for oocyte maturation Griffin et al ,2012

Griffin et al, 2012

The concept of “tailored” luteal phase support: Extreme response (>25 follicles >11 mm): freeze all High response (15-25 follicles): a bolus of 1,500 IU hCG on retrieval day Normal response: an alternative to hCG trigger Humaidan and plyzos F&S 2014

hCG (1,500IU) day 3 after oocyte retrieval Haas et al, 2014

HCG-based luteal support: fixed time points? 1,000 IU with trigger (Griffin) 1,500 IU with OPU (Humaidan) 1,500 IU 3 days post OPU (Haas) Can we be more patient specific??? Can we tailor hCG support to a specific patient endocrine response???

Coasting A popular OHSS prevention strategy. So far, follicular phase only. In OHSS high risk situation: stop gonadotropin. Follow E2 level daily. Individualized approach. 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.

Patients 21 patients at risk for OHSS. Mean age 28 9.8±2.3 1,570±633 Stimulation (days) 9.8±2.3 FSH (units) 1,570±633 Follicles>12 mm 18.0±4.8 E2 trigger day (pmol/l) 1,6839±3,919 Oocytes retrieved 16.9±5.4 Fertilizations 8.5±3.7 Embryos transferred 1.86±0.48 Embryos frozen 3.1±2.6

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)

Luteolysis kinetics Day 0 = day of oocyte retrieval Most patients (12) received hCG bolus on day 3 Quick luteolysis: 1 patient on day 2 Slow luteolysis: 5 patients on day 4 Very slow luteolysis: 1 patient on each days 5, 7, 8

Luteolysis: E2 , P, LH Day of hCG vs. day 2 (percent change) 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 Day of hCG vs. day 2 (percent change) P: 38% ± 19 E2: 87% ± 46

Luteolysis: recovery Mid luteal P=140±42 nmol/l (n=4): securing adequate P during implantation window. In ongoing pregnancy, Day +14: P>190 in all cases, E2=10,304±5,048 - no need for further luteal support.

Reproductive outcome Positive hCG n, (%) 9/21 (43) Clinical pregnancy n, (%) 6/21 (29) Early pregnancy loss n, (%) 3/9 (33)

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, 1995 Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period. Pellicer et al, 1996 Is it secondary to insufficient P during implantation window?

Mid-luteal progesterone and early pregnancy loss Humaidan et al 2005, 2010, 2013

Importance of mid-luteal P in stimulated cycles Threshold P level in a natural cycle=30 nmol/l Following ovarian stimulation we need>90 nmol/l Why? Possible positive correlation between peak follicular E2 and luteal P to secure implantation? Hull et al 1982, Yovich et al 1986

Conclus on Luteal coasting in high responders is a viable option if fresh transfer is desirable. Cutoff P levels yet to be determined. LH activity –dependent luteal support does not require additional E2 and/or P : patient comfort. Despite extreme E2 levels, good clinical outcome is possible if endogenous P secretion is high enough during implantation window. Big differences between patients re luteolysis kinetics. Thank you