Poor & Hyper responders: what is the best approach? A. La Marca ObGyn Dept University of Modena and Reggio Emilia Italy Center for Reproductive Medicine University Hospital of Modena Italy
Criteria used to define POR in medical literature <3-5 developed follicles <3-5 retrieved oocytes Peak E2 Day 3 FSH Inhibin B AMH >40 years Daily or total Gonadotrophin dose Days of stimulation Previous cycle cancellation....
Proposed criteria of POR (2 out of 3) 1. Previous cycle with less than 4 retrieved oocytes following maximal gonadotropin stimulation 2. Age > 40, or any other (genetic or acquired) risk factor for reduced ovarian reserve 3. Abnormal ovarian reserve tests Two previous cycles with < 4 oocytes are sufficient to define POR Any other criteria in the absence of ovarian stimulation define the expected poor response POR i. Two <4 oocytes-cycles ii. One <4 oocytes-cycle + age >40 iii. One <4 oocytes-cycle + abnormal marker ov reserve iv. age >40 and/abnormal markers (Expected POR) Age ESHRE consensus 2011 Abnormal ORT
Treatment strategies for poor responders High FSH dose Alternative GnRH aagonist protocol GnRH antagonist LH supplementation Adjunctive treatments (DHEA, estradiol priming)
Gonadotrophin dose for poor responders o Worldwide survey on gonadotrophin dose for poor responders (IVF Worldwide.com 2010) 150-225 IU/ day, 11.4% > 600 IU/ day, 0.3% 450-600 IU/ day, 23.7% 300-375 IU/ day, 36.7% 375-450 IU/day, 27.9% 196 centers from 45 countries involving 124,000 IVF cycles
No benefits from 450 IU (vs 300) in women with previous response N= 73 patients with previous poor response 450 IU vs 300 IU with mini dose flare-up GnRH agonist regimen High dose: similar pregnancy rates significantly high FSH consuption Cedrin-Durnerin Fertil Steril, 2000 300 450
F&S 2010 Prospective study N= 119 patients AFC < 12 Microdose flare up GnRH agonist protocol
Low number of antral follicles will result in a low number of oocytes, even with high FSH dose N= 52 patients (AFC<5) 150 IU rfsh vs 300 IU rfsh No effect of high dose strategy Same number oocytes Same rate of cancellation Same rate of poor response Same rate of ongoing pregnancy Klinkert et al, Hum Reprod 2006 150 IU daily 300 IU daily
Treatment strategies for poor responders High FSH dose Alternative GnRH aagonist protocol GnRH antagonist LH supplementation Adjunctive treatments (DHEA, estradiol priming)
The GnRH analogue in poor responders o Worldwide survey on poor responders (IVF Worldwide.com 2010) 196 centers from 45 countries involving 124,000 IVF cycles
The PRINT trial: how to suppress pituitary in poor responders 111 patient with previous POR to 300 IU FSH Mean age > 36 Mena FSH > 10 IU/L Mean AFC < 7 Primary outcome: no. oocytes + 450 IU FSH OPR Sunkara et al F&S 2014 8.1% 8.1 % 16.2%
If the agonist long protocol offers no benefits compared to an antagonist protocol in poor responders, treatment with antagonists should be considered for poor responders as this would mean a shorter duration of treatment and a lower dose of medication.
Treatment strategies for poor responders High FSH dose Alternative GnRH aagonist protocol GnRH antagonist LH supplementation Adjunctive treatments (DHEA, estradiol priming)
Poor response was the leading indication for the 2:1 FSH/LH clinical use German multicentric study 2220 cycles Buhler et al 2014
Meta-analysis of Rec LH improving oocyte yield 40 RCTs 6443 patients Poor responders treated with rlh produced a statistically significant increase of 0.75 oocytes/pt This difference is not seen in normal responders and all patients Lehert et al 2014
Meta-analysis better outcomes seen in poor responders Poor responders treated with rlh produced a statistically significant increase of 30% relative increase in Clinical PR This difference is not seen in normal responders and all Lehert et al 2014
Treatment strategies for poor responders High FSH dose Alternative GnRH aagonist protocol GnRH antagonist LH supplementation Adjunctive treatments (DHEA, estradiol priming)
Mostly case-series, retrospective or small prospective studies
22 articles Only 3 controlled studies included 200 IVF cycles investigated No difference in number of oocytes, pregnancy rate, miscarriage rate
DHEA in PORs: a randomized controlled trial 32 women Age < 40 AFC < 5 DHEA 75 mg for 3 months 450 IU hmg for 2 days, then 300 IU Placebo Fixed GnRH antagonist Primary Outcome: changes in AFC Yeung et al. F&S 2014
DHEA in PORs: a randomized controlled trial OPR LBR 18.8% 12.5% 12.5% 12.5% NS NS Yeung et al. F&S 2014
Poor responders - Conclusions -Predict, counsel and individualize - Overmaximal FSH stimulation is useless (300 IU is sufficient) - Long GnRH agonist and Antagonist suitable for pituitary suppression - The GnRH agonist «flare» protocol is the less effective scheme - reclh may increase the number of oocytes and the outcome of the cycle - DHEA is useless
Definition of hyper - response Broer et al., 2011
Implications for high response in IVF Live birth and oocyte yield Increased risk of cancellation or freeze all Increased risk of OHSS Reduced pregnancy rate at least in the fresh cycle N = 400 135 Implantation rate and oocyte yield Verberg et al., Hum Reprod Update 2009 Sunkara et al., Hum Reprod 2011
15..the magic number 256,381 IVF cycles using the 2008 2010 Society for Assisted Reproductive Technology 15 oocytes Steward et al., F&S, 2014
AFC the high number of antral follicles at young age largely explains the high rate of hyperresponse Rate of hyper-response (>15 oocytes) (n=827) La Marca, Fertil Steril 2010 50 % 45 40 Hyper 35 30 25 20 15 10 5 0 <=30 31-32 33-34 35-36 37-38 39-40 41-42 43-44
Retrospective study 37 women with previous OHSS 130 normal responders association between the BMP allele and high response (OR = 2.7, 95% CI = 1.3 5.7)
Activating mutations in the FSHR and OHSS have been reported in the last years Mutant FSH receptors displayed abnormally high sensitivity to HCG broaden the specificity of the FSHR so that it responds to another ligand, HCG. May such mutations lead to increased susceptibility to iatrogenic OHSS in patients undergoing ovulation induction?. Kaiser 2003
Women anticipated to be hyper responders: what is the best approach? - Submaximal ovarian stimulation - GnRH antagonist control
In normal responder women the lower the FSH dose, the lower the number of oocytes Sterrenburg et al., 2011
RCT N=124 Age: 23-41 Normal responders
Clomiphene + FSH is an option to submaximally stimulate ovary CC+FSH OHSS FSH OR 0.23 expected prevalence 3.5 % 0.5-2% High cycle cancellation rate (OR 1.83) Expected cancellation rate: 11% 17-31% Gibreel et al., 2012
GnRH antagonist control is the first choice in hyper responder patients 2014-1.61 oocytes Metanalysis by Pundir et al. RBMonline 2013 Cycle cancellation (RR 0.47) OHSS (RR 0.61) GnRH ant vs GnRHa Similar CPR (RR 1.01)
To trigger, or not to trigger High response although low FSH and GnRH antagonist control Cancellation Coasting GnRHa triggering
GnRHa Trigger avoids OHSS Humaiden et al. Hum Reprod Update 2011 not always.. 2014
Reduced LBR with GnRHa triggering Humaidan et al. 2011
GnRH-a + 1500IU di hcg hcg Patients, n 152 150 Oocytes, n 8,9±5,4 9,3±5 MII 85,2% 81,5% betahcg + per ET 48% 48% Early Abortion 21% 17% Ongoing PR 26% 33% DR 24% 31% OHSS, n 0 3 Humaidan, Fertil Steril 2010
Tailoring triggering, luteal support and embryo transfer in high responders High no. Follicles (>25) «Freeze all» and segmentation High response and GnRHa triggering Low No. Follicles (< 25) +hcg 1500 IU (OPUd) Fresh embryo transfer Humaidan et al., 2013 Alternative and still underinvestigated protocols -Dual triggering -ultra low hcg supplementation -Luteal rec LH supplementation
Hyper responders - Conclusions -Predict, counsel and individualize - Submaximal FSH stimulation is mandatory - The FSH dose should be tailored on the basis of ovarian reserve markers (the higher the ovarian reserve, the lower the dose) - GnRH antagonist control is the first choice - In the case of high response, GnRHa triggering greatly reduces OHSS rate