LUTEAL SUPPORT POST AGONIST TRIGGER FOR OHSS PREVENTION: THE INTRODUCTION OF "LUTEAL COASTING" AS A NOVEL APPROACH.

SHAHAR KOL AUGUST 2014

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 Natural cycle day 7-9= 750 pg/ml vs. 184

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

• • • • • 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 E 2 level daily. Individualized approach.

Trigger with hCG when E 2 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 E 2 .

CASE #1 • • • • 30 year old, mechanical + male factors, AFC=15 Short antagonist protocol, starting dose Menopur 112.5 daily, last 3 days 75.

On trigger (0.2 mg triptorelin) day E2=19017 pmol/l, P=2.5 nmol/l, LH=2.1 IU, >20 follicles >11 mm OPU=20 oocytes., 12 injected, 4 normal fertilization, 2 embryos transferred on day 2, 2 frozen.

200 150 100 50 0 trigger CASE #1, P POST AGONIST TRIGGER BETA=316

ET P levels

hCG 1,500 IU OPU+2 P OPU+3 OPU+17

CASE #1: E2 AND LH POST AGONIST TRIGGER

E2

20000 15000 10000 5000 0 Trigger OP+2 OPU+3 OPU+17

LH

E2 4 1 0 3 2 Trigger OPU+2 OPU+3 LH

• • Moderate OHSS Ongoing singleton pregnancy OUTCOME

CASE #2 • • • • • • • • A 27 year old patient, severe OTA syndrome.

A previous IVF cycle 7 years ago resulted in live birth. Three IVF trials failed during the last 4 years. Stimulation: antagonist-based, 150 IU Menopur.

A day before trigger E2=15768 P=3.2 LH=1.2, with >30 follicles >11 mm.

Trigger with triptorelin 0.2 mg 25 oocytes were retrieved, 23 injected with sperm, 11 normal 2pn fertilizations.

2 embryos transferred 48 hours post retrieval, 8 were frozen.

200 150 100 50 0 CASE #2, P POST AGONIST TRIGGER

P ET

hCG 1,500 IU OPU OPU+1 OPU+2 OPU+7 BETA=174 OPU+14 P

CASE #2: E 2 AND LH POST AGONIST TRIGGER

E2

15000 10000 5000 0 OPU OPU+1 OPU+2 OPU+7 OPU+14 E2

LH

8 2 0 6 4 OPU OPU+1 OPU+2 OPU+7 LH

• • No OHSS Ongoing twin pregnancy OUTCOME

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?

CONCLUSION • • • • 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.

Thank you