L6: DuoStim: the alternative of oocytes/embryos accumulation programs Carlo Alviggi
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1 L6: DuoStim: the alternative of oocytes/embryos accumulation programs Carlo Alviggi Italy
2 What is the aim of IVF? What is the measure of success in IVF? Cumulative live birth rate per started cycle Live birth of an healthy baby Courtesy by F. Ubaldi
3 Live birth rate (%) Number of oocytes retrieved and live birth rates 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Observed live birth rate number of oocytes that best optimized LBR was ,135 IVF cycles Predicted live birth rate Oocyte number Sunkara et al. Hum Reprod 2011
4 Can we ever collect too many oocytes?
5 if we retrieve many oocytes this means that we will have less competent oocytes and less competent blastocysts? Courtesy by F. Ubaldi
6 Mean number of MII oocytes Mean number of MII oocytes More oocytes means more euploid blastocysts 915 PGS cycles (2610 blastocysts, 24 chr analysis, one Centre), mean female age 39,2 years Pearson s correlation R=0,636 P<0,01 Pearson s correlation R=0,426 P<0,01 34,8% 35,2% 27,6% Mean number of blastocyst Mean number of euploid blastocyst Euploidy rate is consistent across the number of MII oocytes retrieved Colamaria, Ubaldi oral presentation, ESHRE 2015
7 Euploidy rate is independent from the number of obtained blastocysts but not from female age Number of blastocysts % normal embryos egg donors <35 y y y y >42 years % 61% 51% 39% 22% 13% % 60% 52% 38% 23% 17% % 62% 51% 36% 21% 14% >10 68% 63% 55% 37% 25% n/a N. = 4,747 cycles and 29,803 embryos. (Modified from Munne) Ata, Munne et al. (2012) Reprod Biomed Online and unpublished data
8 The more oocytes, the higher is the CLBR
9 The more oocytes, the higher is the CLBR Ji et al Hum Reprod 2013 Fatemi et al Hum Reprod 2013
10 Can we overcome POR/poor prognosis by increasing the FSH dose? Yes, if the cause of POR is: - Not reaching the threshold for stimulation - SNPs for FSH-R associated with lower follicular sensitivity NO, if the cause of POR is: - The presence of very few antral follicles - Higher doses of Gn will not create follicles de-novo and then how to increase the number of oocytes to maximize live birth rates? Courtesy by F. Ubaldi
11 Four Groups of Patient with Low Prognosis GROUP 1 Young patients <35 years with adequate ovarian reserve parameters (AFC 5; AMH 1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response GROUP 2 Older patients 35 years with adequate ovarian reserve parameters (AFC 5; AMH 1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response GROUP 3 Young patients (<35 years) with poor ovarian reserve prestimulation parameters (AFC <5; AMH <1.2 ng/ml) GROUP 4 Older patients ( 35 years) with poor ovarian reserve prestimulation parameters (AFC <5; AMH <1.2 ng/ml) Poseidon Group, Fertil Steril 2016
12 Four Groups of Patient with Low Prognosis Poseidon groups where oocyte/blastocyst accumulation is an option GROUP 3 GROUP 4 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC <5; AMH <1.2 ng/ml) Older patients ( 35 years) with poor ovarian reserve prestimulation parameters (AFC <5; AMH <1.2 ng/ml) Poseidon Group, Fertil Steril 2016
13 Four Four Groups of of Patient with Low Prognosis But how many eggs we need? GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC <5; AMH <1.2 ng/ml) GROUP 4 Older patients ( 35 years) with poor ovarian reserve prestimulation parameters (AFC <5; AMH <1.2 ng/ml) Poseidon Group, Fertil Steril 2016
14 Mean number of oocytes needed and age Age < COCs 11 COCs 18 COCs 5 MII oocytes 9 MII oocytes 16 MII oocytes 4 fertilized oocytes 7 fertilized oocytes 13 fertilized oocytes 2 blastocysts 3 blastocysts 5 blastocysts Euploidy rate 60% Euploidy rate 30% Euploidy rate 20% 1 euploid blastocys 1 euploid blastocys 1 euploid blastocys
15 Four Groups of Patient with Low Prognosis Four Four Groups Groups of of Patient Patient with with Low Prognosis Prognosis So we need many eggs from women with low reserve How can we do it if no Gn can compensate? GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC <5; AMH <1.2 ng/ml) GROUP 4 Older patients ( 35 years) with poor ovarian reserve prestimulation parameters (AFC <5; AMH <1.2 ng/ml) Poseidon Group, Fertil Steril 2016
16 DUO-STIM Introduction In 2003, based on ultrasonographic studies, two or three follicular waves during the intraovulatory period of healthy women. It was suggested that follicles developing during the LP may have the potential to ovulate in the presence of an luteinizing hormone (LH) surge, offering new possibilities for ovary stimulation (Baerwald et al. 2003) Previous studies have shown that existing antral follicles in the luteal phase enable ovarian stimulation (Huang et al. 2013) Luteal-phase stimulation was originally used to produce mature oocytes and embryos for cryopreservation in case reports of emergency fertility preservation and letrozole cycle (Huang et al Bedoschi et al. 2010; Sonmezer et al. 2011)
17 Documentation of major and minor follicular waves during the menstrual cycle challenges the traditional theory that a single cohort of antral follicles grows only during the follicular phase of the menstrual cycle. Sixty-eight percent of women exhibited two waves of follicle development during the IOI and 32 %exhibited three waves. Waves were characterized by an increase and subsequent decrease in the number of follicles 5 mm occurring in association with the growth of 2 follicles to 6 mm.
18 Follicle waves in a menstrual cycle Day of cycle 2 Baerwald et al Hum Reprod Update 2013 Adams GP et al., J Reprod Fertil, n. of follicles >5 mm diameter of the largest follicle Baerwald et al, Fertil Steril 2003
19 DUOSTIM in low prognosis patients Ubaldi, Vaiarelli, Alviggi, Trabucco, Zullo, Capalbo, Cimadomo, Rienzi ASRM, 2015
20 DUOSTIM in low prognosis patients Patient Age AMH AFC (1 stim) 1 stim oocytes retrieved 2 stim CA 38 0,6 7 DV 38 0,4 6 DG 35 0,5 4 IM 38 1,0 7 LS 32 1,3 6 BA 41 0,1 5 SI 37 0,6 5 VS 43 0,5 5 DO 37 1,2 9 MS 36 0,7 5 BF 40 0,2 4 SMF 42 0,7 6 SC 34 0,4 5 SE 38 0,8 2 no follicles 1 stimulation 2 stimulation P Oocytes (mean SD) ns oocytes blastocysts
21 DuoStim in POR/poor prognosis patients 51 patients started the first stimulation cycle 45 patients to egg retrieval 6 excluded: -no response to the stimulation 2 excluded: -2 no sperm available Ubaldi et al Fertil Steril patients with poor ovarian reserve (AMH <1,5 ng/ml, AFC < 6 follicles and/or < 5 oocyte retrieved in previous COH) undergoing ICSI treatment and PGT-A Primary outcome measure: euploid blastocyst rate. Secondary outcome measures: #of retrieved COCS and MII oocytes 43 patients to egg retrieval 42 patients performing FP ICSI 18 FP stimulation cycles with euploid blastocyst obtained 42 patients performing LP ICSI 23 LP stimulation cycles with euploid blastocyst obtained
22 Huge intra & inter-cycle variability MII oocytes that did not reach blastocyst stage MII oocytes that made aneuploid blastocyst MII oocytes that made euploid blastocyst
23 DuoStim in POR/poor prognosis patients % 23 53% 30 70% Follicular phase (FP) stimulation Luteal phase (LP) stimulation Cumulative Patients with 1 euploid blastocyst Patients with no euploid blastocysts Courtesy by F. Ubaldi
24 Take-home message Cumulative live birth rates per started cycle should be considered as a measure of success in IVF The number of oocytes is a key factor to maximize CLBR and it must optimized according to the ovarian reserve of the patients Luteal phase stimulation gives competent oocytes with live births In low prognosis patients (Groups 3 4 Poseidon) DuoStim can maximize the number of oocytes per menstrual cycle increasing the chance of obtaining the embryo that can give a live birth and it could be applied in all patients with few fertile time left available
25 The Duo-Stim approach a) Consists of two consecutive ovarian stimulation taken during two consecutive menstrual cycles b) Could be suggested in Poseidon groups 3 or 4 c) Requires maximum gonadotropin dosage during controlled ovarian stimulation d) Usually allows fresh embryo transfer *The correct answer is the green one 25
26 G. De Placido I. Strina T. Pagano A. Conforti P. De Rosa R. Vallone S. Picarelli C. Buonfantino I.Nuzzo F.M. Ubaldi Università degli Studi di Napoli Federico II
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