Elonva in poor responders Shahar Kol August 2014

Who is a poor responder? Human Reproduction 2011

Etiology? Depletion of ovarian follicle pool Insufficient initial follicle number Accelerated loss Ovarian follicle dysfunction Signaling defect Enzyme deficiency Autoimmunity

Risk factors Advanced maternal age Genetic conditions Turner, FMR1, X deletions Gene mutation: FSHR, LHR Acquired conditions Endomertioma Chemo/radiotherapy Ovarian surgery

Prediction of poor ovarian response (POR) Broer et al, 2013

Which protocol? Survey on POR from 196 centers in 45 countries, 124,700 cycles

Treatment Protocols for poor responders “There is insufficient evidence to support the routine use of any particular intervention either for pituitary down regulation, ovarian stimulation or adjuvant therapy in the management of poor responders to controlled ovarian stimulation in IVF”. 2010

Adjuvant therapy Androgens (DHEA, testosterone, LH) Growth hormone Co-enzyme Q10 supplementation Other?

Significance of POR Poor prognosis for IVF success Increased miscarriage risk Early menopause

What is known about Elonva in poor responders?

Elonva in the older Age group Primary objective To examine the efficacy and safety of a single injection of corifollitropin alpha vs daily recombinant FSH (rFSH) for controlled ovarian stimulation in women aged 35-42 years

Number of oocytes Corifollitropin Alfa 150 µg rFSH 300 IU/day Estimated Difference ANOVA (95% CI) Per attempt Mean (SD) n = 694 10.7 (7.2) n = 696 10.3 (6.8) 0.5 (–0.2 to 1.2) Per oocyte pick-up n = 675 11.0 (7.0) n = 671 10.6 (6.7) 0.4 (–0.3 to 1.1)

Ongoing pregnancy rate Corifollitropin Alfa 150 µg rFSH 300 IU/day Estimated Difference (95% CI) Per started cycle, % (n/N) 22.2 (154/694) 24.0 (167/696) –1.9 (–6.1 to 2.3)

Fertil Steril 2013

Objective: To identify whether women with poor ovarian response may benefit from treatment with corifollitropin alfa in a GnRH antagonist protocol. Design: Retrospective pilot study. Intervention: Corifollitropin alfa (150 mg) followed by 300 IU rFSH in a GnRH antagonist protocol. Comparative cohort: short agonist, hMG 300-450 IU/d Polyzos et al. Fertil Steril 2013

Conclusion: Treatment of poor ovarian responders, as described by the Bologna criteria, with corifollitropin alfa in a GnRH antagonist protocol results in low pregnancy rates, similarly to conventional stimulation with a short agonist protocol. Polyzos et al. Fertil Steril 2013

Retrospective pilot study. Will sequential administration of highly purified (hp)-HMG after corifollitropin alfa in a GnRH antagonist protocol benefit women with poor ovarian response according to the Bologna criteria? Retrospective pilot study. Polyzos et al, 2013

Endocrine profiles during the follicular phase in women who are poor ovarian responders, according to age E2, estradiol. *P . 0.05 for all comparisons between age groups at Days 2, 7, 9 and day of hCG triggering.

Conclusion Corifollitropin alfa followed by hp-HMG in a GnRH antagonist protocol results in very promising pregnancy rates in young (<40 years old) poor ovarian responders fulfilling the Bologna criteria.

Results in POR by age Retrospective study 485 patients, 823 cycles 201<40 years, 284>40. Gonadotropin daily dose ≥ 300 IU (FSH and/or hMG). Polyzos et al , 2014

The aim

Follicular recruitment is a random event Recruitment occurs all the time. This explains our ability to start stimulation in luteal phase. The number of recruitable follicles in any given time point changes by chance. The specific type of gonadotropins plays a secondary role.

Potential advantage of Elonva In the natural follicular phase FSH decreases until the midcycle surge.

Flare effect Without using GnRH agonist No cysts formation, no LH rise Robust recruitment of all available responsive follicles?

Does the different pharmacokinetic Profile of corifollitropin alfa result in a significantly higher number of oocytes retrieved compared with rFSH? Engage Study, Devroey et al , 2009

Elonva: reducing Treatment burden POR patients are prone to have repeated IVF trials. Reduced complexity and treatment burden Sort treatment cycle (antagonist-based) Fewer overall injections Fewer injections per day Fewer drop-out patients.

In conclusion Elonva is an important addition to our fertility drugs arsenal. the advantage of Elonva in the treatment of POR is yet to be defined by randomized controlled studies, and by personal experience by each treating physician in the field of ART. Thank you