Metaphase II oocytes obtained after luteal phase stimulation have the same intrinsic quality as eggs from the follicular phase stimulation.Results from a multicentre prospective study

Study question: Are metaphase II (MII) oocytes obtained after the follicular phase stimulation (FPS) and luteal phase stimulation (LPS) equivalent in terms of developmental and reproductive competence? Summary answer: MII oocytes from LPS showed a similar intrinsic quality as eggs from FPS for fertilization,blastulation,euploidy rates and ongoing pregnancy after euploid single embryo transfer (eSET) What is known already: Follicular development is a dynamic process. Evidences suggest that ‘waves”of antral follicles develop cyclically 2-3 times during the same menstrual cycle, overtaking the classic theory that in women only one cohort of antral follicles grows during the follicular phase (FP) of a menstrual cycle. Indeed, ovarian stimulation could be initiated at any time of the cycle, also in the luteal phase (LP). These observations led to the introduction of two new protocols for ovarian stimulation: double stimulation in the same menstrual cycle (Duostim) for poor prognosis patients and random-start for fertility preservation.Preliminary promising clinical data stimulated a deeper investigation of these strategies Study design, size, duration: Multicenter prospective study performed between January2015-October2016. 208 patients(mean female age=39.7 ± 3.2 range 30.0-44.0)with reduced ovarian reserve(AMH≤1,5 ng/ml,antral follicular count ≤6,and/or ≤ 5oocytes retrieved in a previous cycle)underwent oocyte retrieval after FPS and LPS.The primary outcomes were MII oocytes’ intrinsic quality defined as fertilization,blastulation,euploidy rates and ongoing implantation after eSET of blastocyst obtained in the LPS versus FPS from the same patients.Secondary outcomes were the number of MII oocytes,blastocysts, euploid blastocysts and ongoing pregnancies obtained in LPS versus FPS. Participants/materials, setting, methods: Both FPS and LPS were performed with rFSH in an antagonist protocol. After the first oocyte retrieval from FPS we waited five days before starting LPS. All embryos obtained were cultured to blastocyst, underwent trophectoderm biopsy and vitrification. A single chromosomal analysis was performed through qPCR on all the biopsies obtained after both FPS and LPS. eSETs were performed in a subsequent natural or artificial cycle Main results and the role of chance: The number of MII oocytes after FPS and LPS were 763 (3.6 ± 2.3;1-16) and 960 (4.5 ± 2.9;1-15), respectively (p < 0.001). The fertilized oocytes were 509 (2.4 ± 2.0;0-15) and 707 (3.3 ± 2.0;0-13), (p < 0.001). The fertilization rate was 66.7% versus 73.6% (NS). The blastocyst obtained after FPS and LPS were 234 (1.1 ± 1.0;0-4) and 364 (1.7 ± 1.6;0-9) (p < 0.001). The blastulation rate was 46.0% versus 51.5% (NS). The euploid blastocysts obtained after FPS and LPS were 99 (0.5 ± 0.7;0- 3) and 154 (0.7 ± 1.0,0-6), respectively (p = 0.005). The euploidy rate was 42.3% (n = 99/234;95%CI:35.9%-48.9%) versus 42.3% (n = 154/364;95% CI:37.1%-47.5%) in FPS and LPS and 12.9% (n = 99/763; 95%CI=10.7%- 15.6%) and 16.0% (n = 154/960; 95%CI=13.8%-18.5%) in FPS and LPS, per biopsied blastocyst and MII oocytes, respectively (NS). Overall, the rate of cycles with at least one euploid blastocyst increased from 34.4% (n = 74/215; 95%CI=28.1%-41.1%) in the FPS-only to 57.7% (n = 124/215; 95%CI=48.4%- 61.7%) after Duostim (p < 0.001). Thirty-four eSETs of blastocysts from the FPS and 37 from the LPS were performed up to date and no difference was shown in terms of ongoing pregnancy rate: 41.2% (n = 14/34; 95%CI=24.7%- 59.3%) versus 45.9% (n = 17/37; 95%CI=29.5%-63.1%) (NS). Limitations, reasons for caution: A more thorough assessment of oocyte quality after LPS versus FPS in terms of gene expression, metabolism and dynamic developmental parameters is still eagerly needed. Moreover, the neonatal outcomes and the cost-effectiveness especially of Duostim need yet to be evaluated. Wider implications of the findings: The evidence of multiple follicular waves during a single menstrual cycle in women opened important implications for the treatment of infertility. Here, we report that LPS allows higher yields without affecting the developmental and reproductive potential of the oocytes obtained.Thus, Duostim and random-start ovarian stimulation may be considered clinically-valuable strategies. Trial registration number: none.