Recombinant LH, recombinant hCG and GnRH agonist to trigger ovulation in antagonist cycles: a critical Evaluation ShaharKol August 2014
The natural cycle • LH surge goes together with FSH surge.
How to imitate nature? • Use recombinant LH
recombinant LH for final oocyte maturation European Recombinant LH Study Group. J ClinEndocrinolMetab 2001;86:2607–2618
High P during implantation window: after hCG or 2 LH boluses 3 days apart
Conclusions • The results show that a single dose of rhLHis effective in inducing final follicular maturation and early luteinizationin vitro fertilization and embryo transfer patients and is comparable with 5,000 IU u-hCG. A single dose of rhLH results in a highly significant reduction in OHSS compared with hCG.
“Trial 21447” • a double-blind large (437 patients) multicenter randomized study (Trial 21447), compared the implantation and pregnancy rates following triggering ovulation by r-hLH versus HCG. • pregnancy rates and clinical pregnancy rates were significantly lower in the r-hLHgroup than in the u-HCG group (P = 0.018 and P = 0.023 respectively). • In order for r-hLH to be as efficacious as u-HCG, the dose would have to be increased to a point where the cost/benefit ratio may become adverse. • The study was not published and the manufacturer of r-hLH decided not to register or manufacture the high dose of r-hLH used for triggering ovulation. Aboulghar & Al-InanyRBMOnline, 2005
Hcg AS TRIGGER • The default trigger agent • Recombinant human hCG or urinary hCG • Question of dose
Recombinant hCG is better in: • More mature oocytes (9.4 vs. 7.1) • Higher luteal progesterone • Better injection tolerance
“There is no evidence of a difference in the clinical outcomes of life birth/ongoing pregnancy, pregnancy, miscarriage and OHSS between urinary and recombinant gonadotrophinsfor induction of final follicular maturation”. Same conclusions in a Cochrane review 2011.
What are the problems with hcg as trigger? • No FSH surge • Long half life
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 BiolChem 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
Conclusions: • Adding a bolus of FSH 450 IU at the time of hCG improves oocyte recovery and fertilization rate. Lamb at al, F&S 2011
hCG and luteal phase defect • 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
GnRH agonist trigger • This possibility was first introduced in 1988: “Induction of LH surge and oocyte maturation by GnRH analogue (Buserelin) in women undergoing ovarian stimulation for IVF.” Itskovitz et al, Gynecological Endocrinology 1988, 2:Suppl1, 165.
The physiology of agonist trigger LH surge1 FSHsurge2 Humaidan P, et al. Reprod Biomed Online 2011 2. GonenY, et al. J ClinEndocrinolMetab1990
Can agonist trigger work in antagonist-based ovarian stimulation? • Can the agonist displace the antagonist from the receptor? • Can a short LH surge promote final oocyte maturation? antagonist
Endocrine Profiles after Triggering of Final Oocyte Maturation with GnRH Agonist after Cotreatment with the GnRH Antagonist Ganirelix during Ovarian Hyperstimulation for in Vitro Fertilization The study was designed to examine whether, after daily late follicular phase treatment with 0.25 mg ganirelix, administration of a single dose of GnRH agonist is at least as effective as hCG in inducing final oocyte maturation in patients undergoing ovarian hyperstimulation for IVF Fauser et al, 2002
Clinical outcome (mean±SD) Fauser et al, 2002
What is the advantage of agonist trigger? • Agonist trigger causes quick and irreversible luteolysis. • This leaves the clinician with the options to specifically control the luteal phase.
Clinical use of agonist trigger • Egg donors • Prevention of OHSS • Patient comfort • Special cases
No OHSS! Bodri et al, FertilSteril. 2010
…and when OHSS is not the main issue? "We did find differences in the duration of the luteal phase:The period to menstrual onset in the non-hCG group wassignificantly shorter (10.2 days vs. 5.2 days; P<.001). Also, 42% of those who received hCG reported subjective complaints (mostly abdominal discomfort), whereas this percentage was 0% in those who received GnRH agonist to trigger ovulation.No OHSS was observed in either cohort." Cerrillo et al, 2009, IVI Madrid
Agonist trigger in the context of OHSS prevention • The dream of OHSS-free IVF treatment is real!
Antagonist era • Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: Short communication . Itskovitz-Eldor et al, 2000
GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles Total events 0 (GnRH) 21 (hCG) Youssef MA, et al. Human Reprod Update 2010;16:459–466
16 publications Agonist: 2,005 patients, not a single case of OHSS! hCG: 92 cases in 1,810 patients, 5.1%
Pregnancy rate post agonist trigger • We showed that agonist trigger causes quick and irreversible luteolysis. • Therefore, the right luteal support is crucial. • The evolution of post agonist luteal support.
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
The advantage for the ‘normal responder’ Agonist trigger OPU ET Antagonist 36 hours 4 days FSH/hMG 1500 IU hCG 1500 IU hCG Kol S, et al. Human Reprod2011;26:2874–2877
Dual trigger improves: • Implantation rate • Clinical pregnancy rate • Live birth rate Lin et al, 2013
Special cases • Empty follicles • Recurrent IVF failure
Is fsh surge redundant in all women??? Beck-Fruchter at al 2012
Take home message “The results of this survey indicate that GnRH trigger is widely used worldwide and therefore has become part of the standard of care today. Hence, doctors are entitled to prescribe it just as patients may ask that this option is considered in their case.”
“Agonist triggering is viewed as one of the major advances in ovarian stimulation, with the potential to eliminate OHSS…”
Revolution in the making Thank you