Associations between Non-Essential Trace Elements in Women's Biofluids and IVF Outcomes in Euploid Single-Embryo Transfer Cycles.

Previous studies have found inconsistent associations between heavy metals and metalloids (cadmium, lead, mercury, and arsenic), and reproductive outcomes. The biofluid concentrations of ten non-essential trace elements (Hg, Pb, As, Ba, Sr, Rb, Cs, Sn, Ni, and Co) were evaluated in 51 Spanish women undergoing ICSI, PGT-A, and SET/FET. Nine out of ten non-essential elements were detectable in follicular fluid, whole blood, and urine collected the day of vaginal oocyte retrieval (VOR) and the day of embryo transfer and then analyzed by ICP-MS or Tricell DMA-80 for mercury. Elevated mercury and strontium concentrations in follicular fluid were associated with poor ovarian response and preimplantation outcomes. Worst preimplantation outcomes were also identified in women with elevated whole-blood strontium or mercury, urinary arsenic, barium, and tin the day of VOR. High concentrations of urinary rubidium on VOR day were linked with enhanced fertilization and blastocyst development. Excessive titanium in whole blood was associated with lower odds of implantation, clinical pregnancy, and achieving a live birth in a given IVF cycle. Excessive urinary arsenic on the day of embryo transfer was associated with lower odds of live birth. Although these preliminary results need to be confirmed in larger populations, distinguishing organic and inorganic element forms, our findings show that some non-essential elements have a detrimental impact on human IVF outcomes.

Higher Concentrations of Essential Trace Elements in Women Undergoing IVF May Be Associated with Poor Reproductive Outcomes Following Single Euploid Embryo Transfer.

Essential trace elements are micronutrients whose deficiency has been associated with altered fertility and/or adverse pregnancy outcomes, while surplus may be toxic. The concentrations of eight essential trace elements were measured using inductively coupled mass spectrometry (ICP-MS) and assessed with respect to clinical in vitro fertilization (IVF) outcomes in a population of 51 women undergoing IVF with intracytoplasmic sperm injection (ICSI), pre-implantation genetic screening for aneuploidy (PGT-A), and single frozen euploid embryo transfer (SET/FET). Specifically, copper (Cu), zinc (Zn), molybdenum, selenium, lithium, iron, chromium, and manganese were quantified in follicular fluid and whole blood collected the day of vaginal oocyte retrieval (VOR) and in urine collected the day of VOR and embryo transfer. We found that the whole blood Cu/Zn ratio was significantly associated with superior responses to ovarian stimulation. Conversely, the whole blood zinc and selenium concentrations were significantly associated with poor ovarian response outcomes. Higher levels of whole blood zinc and selenium, urinary selenium, lithium, and iron had significant negative associations with embryologic outcomes following IVF. Regarding clinical IVF outcomes, higher urinary molybdenum concentrations the day of VOR were associated with significantly lower odds of implantation and live birth, while higher urinary Cu/Mo ratios on the day of VOR were associated with significantly higher odds of implantation, clinical pregnancy, and live birth. Our results suggest that essential trace element levels may directly influence the IVF outcomes of Spanish patients, with selenium and molybdenum exerting negative effects and copper-related ratios exerting positive effects. Additional studies are warranted to confirm these relationships in other human populations.

Transcriptome analysis of adenomyosis eutopic endometrium reveals molecular mechanisms involved in adenomyosis-related implantation failure and pregnancy disorders.

BACKGROUND: Women with adenomyosis are characterized by having defective decidualization, impaired endometrial receptivity and/or embryo-maternal communication, and implantation failure. However, the molecular mechanisms underlying adenomyosis-related infertility remain unknown, mainly because of the restricted accessibility and the difficult preservation of endometrial tissue in vitro. We have recently shown that adenomyosis patient-derived endometrial organoids, maintain disease-specific features while differentiated into mid-secretory and gestational endometrial phase, overcoming these research barriers and providing a robust platform to study adenomyosis pathogenesis and the associated molecular dysregulation related to implantation and pregnancy disorders. For this reason, we aim to characterize the dysregulated mechanisms in the mid-secretory and gestational endometrium of patients with adenomyosis by RNA-sequencing. METHODS: Endometrial organoids were derived from endometrial biopsies collected in the proliferative phase of women with adenomyosis (ADENO) or healthy oocyte donors (CONTROL) (n = 15/group) and differentiated into mid-secretory (-SECorg) and gestational (-GESTorg) phases in vitro. Following RNA-sequencing, the significantly differentially expressed genes (DEGs) (FDR < 0.05) were identified and selected for subsequent functional enrichment analysis and QIAGEN Ingenuity Pathway Analysis (IPA). Statistical differences in gene expression were evaluated with the Student's t-test or Wilcoxon test. RESULTS: We identified 1,430 DEGs in ADENO-SECorg and 1,999 DEGs in ADENO-GESTorg. In ADENO-SECorg, upregulated genes included OLFM1, FXYD5, and RUNX2, which are involved in impaired endometrial receptivity and implantation failure, while downregulated genes included RRM2, SOSTDC1, and CHAC2 implicated in recurrent implantation failure. In ADENO-GESTorg, upregulated CXCL14 and CYP24A1 and downregulated PGR were related to pregnancy loss. IPA predicted a significant inhibition of ID1 signaling, histamine degradation, and activation of HMGB1 and Senescence pathways, which are related to implantation failure. Alternatively, IPA predicted an inhibition of D-myo-inositol biosynthesis and VEGF signaling, and upregulation of Rho pathway, which are related to pregnancy loss and preeclampsia. CONCLUSIONS: Identifying dysregulated molecular mechanisms in mid-secretory and gestational endometrium of adenomyosis women contributes to the understanding of adenomyosis-related implantation failure and/or pregnancy disorders revealing potential therapeutic targets. Following experimental validation of our transcriptomic and in silico findings, our differentiated adenomyosis patient-derived organoids have the potential to provide a reliable platform for drug discovery, development, and personalized drug screening for affected patients.

Progestin-primed ovarian stimulation.

PURPOSE OF REVIEW: The use of progestins as pituitary suppressors has increased progressively, along with more detailed indications for their use, thereby consolidating an alternative approach to the personalization of ovarian stimulation. RECENT FINDINGS: Based on the ability of progesterone to inhibit ovulation, progestins have been used in ovarian stimulation (OS) follicular protocols to prevent a luteinizing hormone surge in patients undergoing in vitro fertilization (IVF), as an alternative to gonadotropin-releasing hormone (GnRH) analogue administration. This review explores the different types of progestogen protocols and their efficacy depending on the type of population or reproductive procedure in which they are administered and in comparison with that of GnRH analogues. Their effect on oocytes and embryos and their safety and cost-effectiveness are also analyzed. SUMMARY: Progestins have proven their effectiveness as a gonadotropin adjuvant in terms of ovarian response, reproductive outcome, and safety. In addition, they offer the convenience of oral administration and a lower cost than GnRH analogues. Whereas oocytes or embryos should be vitrified as it displaces the receptive period with the consequent asynchrony between embryo and endometrium. The evidence endorses progestins as a more friendly approach to OS, especially when frozen-thawed embryo transfer is planned.

Medroxyprogesterone acetate: an alternative to GnRH-antagonist in oocyte vitrification for social fertility preservation and preimplantation genetic testing for aneuploidy.

RESEARCH QUESTION: Can medroxyprogesterone acetate (MPA) be used as a pituitary suppressor instead of a gonadotrophin releasing hormone (GnRH) antagonist during ovarian stimulation in elective fertility preservation and preimplantation genetic testing for aneuploidy (PGT-A) cycles? DESIGN: A multicentre, retrospective, observational, cohort study conducted in 11 IVIRMA centres affiliated to private universities. Of a total of 1652 cycles of social fertility preservation, 267 patients were stimulated using a progestin-primed ovarian stimulation protocol (PPOS), and 1385 patients received a GnRH antagonist. In the PGT-A cycles, 5661 treatments were analysed: 635 patients received MPA and 5026 patients received GnRH antagonist. A further 66 fertility preservation and 1299 PGT-A cycles were cancelled. All cycles took place between June 2019 and December 2021. RESULTS: In the social fertility preservation cycles, the number of mature oocytes vitrified in MPA was similar to the number of those treated with an antagonist, a trend that was seen regardless of age (≤35 or >35 years). In the PGT-A cycles, no differences were found in number of metaphase II, two pronuclei, number of biopsied embryos (4.4 ± 3.1 versus 4.5 ± 3.1), rate of euploidy (57.9% versus 56.4%) or ongoing pregnancy rate (50.4% versus 47.1%, P = 0.119) between the group receiving MPA versus a GnRH antagonist, whereas the clinical miscarriage rate was higher in the antagonist group (10.4% versus 14.8%, P = 0.019). CONCLUSIONS: Administration of PPOS yields similar results to GnRH antagonists in oocytes retrieved, rate of euploid embryos and clinical outcome. Hence, PPOS can be recommended for ovarian stimulation in social fertility preservation and PGT-A cycles, as it allows greater patient comfort.

Extracellular vesicles secreted by adenomyosis endometrial organoids contain miRNAs involved in embryo implantation and pregnancy.

RESEARCH QUESTION: Do extracellular vesicles secreted by the endometrium of women with adenomyosis contain miRNAs involved in adenomyosis-related infertility? DESIGN: A descriptive study using organoids from eutopic endometrium of women with adenomyosis (n = 4) generated and differentiated to secretory and gestational phases, in which miRNA cargo from extracellular vesicles secreted by these differentiated organoids in each phase was analysed by next-generation sequencing. miRNAs in secretory-extracellular vesicles and gestational-extracellular vesicles were selected based on the counts per million. miRNAs target genes in each phase were obtained from miRNet and gene ontology was used for enrichment analysis. RESULTS: miRNA sequencing identified 80 miRNAs in secretory-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-24-3p, hsa-miR-26a-5p, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-200c-3p and hsa-miR-423a-5p, related to adenomyosis pathogenesis and implantation failure. Further, 60 miRNAs were identified in gestational-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-26a-5p, hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-222-3p and hsa-miR-423a-5p were associated with preeclampsia and miscarriage. Among the target genes of these miRNAs, PTEN, MDM4, PLAGL2 and CELF1, whose downregulation (P = 0.0003, P < 0.0001, P = 0.0002 and P = 0.0003, respectively) contributes to adenomyosis pathogenesis, and impaired early embryo development, leading to implantation failure and miscarriage, are highlihghted. Further, functional enrichment analyses of the target genes revealed their involvement in cell differentiation, proliferation, apoptosis, cell cycle regulation and response to extracellular stimuli. CONCLUSIONS: Eutopic endometrium in secretory and gestational phase from women with adenomyosis releases extracellular vesicles containing miRNAs involved in adenomyosis progression, impaired embryo implantation and pregnancy complications.

Establishment of Adenomyosis Organoids as a Preclinical Model to Study Infertility.

Adenomyosis is related to infertility and miscarriages, but so far there are no robust in vitro models that reproduce its pathological features to study the molecular mechanisms involved in this disease. Endometrial organoids are in vitro 3D models that recapitulate the native microenvironment and reproduce tissue characteristics that would allow the study of adenomyosis pathogenesis and related infertility disorders. In our study, human endometrial biopsies from adenomyosis (n = 6) and healthy women (n = 6) were recruited. Organoids were established and hormonally differentiated to recapitulate midsecretory and gestational endometrial phases. Physiological and pathological characteristics were evaluated by immunohistochemistry, immunofluorescence, qRT-PCR, and ELISA. Secretory and gestational organoids recapitulated in vivo glandular epithelial phenotype (pan-cytokeratin, Muc-1, PAS, Laminin, and Ki67) and secretory and gestational features (α-tubulin, SOX9, SPP1, PAEP, LIF, and 17ßHSD2 expression and SPP1 secretion). Adenomyosis organoids showed higher expression of TGF-ß2 and SMAD3 and increased gene expression of SPP1, PAEP, LIF, and 17ßHSD2 compared with control organoids. Our results demonstrate that organoids derived from endometria of adenomyosis patients and differentiated to secretory and gestational phases recapitulate native endometrial-tissue-specific features and disease-specific traits. Adenomyosis-derived organoids are a promising in vitro preclinical model to study impaired implantation and pregnancy disorders in adenomyosis and enable personalized drug screening.

Obesity Affects Endometrial Receptivity by Displacing the Window of Implantation.

Our aim was to determine prospectively whether increased body mass index (BMI) affects endometrial receptivity through displacement of the window of implantation (dWOI) using the endometrial receptivity analysis (ERA), and whether this effect is BMI-dependent. We recruited a population of 170 infertile women with a normal uterus and no clinical history of recurrent miscarriage or implantation failure. These women were divided into four groups according to BMI: normal weight (18.5-24.9 kg/m2; n = 44), overweight (25-29.9 kg/m2; n = 29), class I obese (30.0-34.9 kg/m2; n = 54), and class II and III obese (> 35 kg/m2; n = 43). We also assigned the patients to one of two larger BMI cohorts: non-obese (normal weight and overweight; n = 73) and obese (class I, II, and III obese; n = 97). We compared analytical and clinical data and dWOI in these categories, finding significant metabolic differences in glycemia, TSH, insulin, HDL cholesterol, LDL cholesterol, triglycerides, and systolic and diastolic blood pressure among the different BMI groups. One-day dWOI increased significantly with BMI, and significant differences were observed in the non-obese versus obese categories (9.7% vs 25.3 %, respectively (p = 0.02)). dWOI was most pronounced in patients with class II-III obesity. In addition, displacement was longer as BMI increased since ERA revealed a higher proportion of displacements of 1 day than of 12 h and showed they were predominantly pre-receptive. In conclusion, obesity has a negative effect on endometrial receptivity through delaying of the WOI, which increases in function of BMI as well as the metabolic disturbances of the patient.

Medroxyprogesterone acetate is a useful alternative to a gonadotropin-releasing hormone antagonist in oocyte donation: a randomized, controlled trial.

OBJECTIVE: To compare ovarian response and reproductive outcomes in oocyte donors undergoing pituitary suppression with medroxyprogesterone acetate (MPA) versus those undergoing conventional treatment with a gonadotropin-releasing hormone (GnRH) antagonist. DESIGN: A prospective, randomized, controlled trial of cycles was conducted from October 2017 to June 2019 to evaluate ovarian response in terms of the number of oocytes. The reproductive outcomes of the recipients were retrospectively analyzed later. SETTING: A university-affiliated private in vitro fertilization center. PATIENT(S): We randomly divided 318 donors into 2 groups in a 1:1 ratio. The oocytes obtained were assigned to 364 recipients. One hundred sixty-one donors were treated with a daily dose of 10 mg of MPA administered orally from the beginning of ovarian stimulation (OS), and 156 were treated with a GnRH antagonist (initiated once the leading follicle reached a diameter of 13 mm). Transvaginal ultrasound was performed, and serum estradiol, luteinizing hormone, and progesterone levels were recorded during monitoring. The following additional parameters were analyzed: endocrine profile (in follicular fluid), number of metaphase II oocytes, and pregnancy outcome. INTERVENTION(S): The donors included in the study group were stimulated using recombinant follicle-stimulating hormone and MPA at 10 mg/day, simultaneously begun on cycle day 2 or 3. Ovulation was induced using a GnRH agonist when dominant follicles matured. A short protocol with ganirelix at 0.25 mg/day was used for the control group. Oocytes were assigned to the recipients, followed by routine in vitro fertilization procedures in which 1 embryo was usually transferred. MAIN OUTCOME MEASURE(S): The primary outcome measure was the numbers of oocytes and metaphase II oocytes retrieved. The secondary outcomes were the incidence of premature luteinizing hormone surge, serum and follicular fluid hormone profiles, and clinical pregnancy outcomes in the recipient group. RESULT(S): The number of oocytes retrieved was 21.4 ± 11.7 in the MPA group and 21.2 ± 9.2 in the antagonist group (mean difference 0.14; 95% confidence interval -2.233, 2.517). The total dose of recombinant follicle-stimulating hormone, duration of OS, and endocrine profiles of the serum and follicular fluids were comparable in the 2 groups. No early ovulation was observed in either group. No statistically significant differences with respect to implantation rate (68.1% in the MPA group vs. 62% in the antagonist group), clinical pregnancy rate (64.5% in the MPA group vs. 57.8 in the antagonist group), ongoing pregnancy rate (55.4% in the MPA group vs. 48.5% in the antagonist group), live birth rate (55.1% in the MPA group vs. 48.5% in the antagonist group), or cumulative live birth rate (73.8% in the MPA group vs. 70.7% in the antagonist group) were observed between the groups. CONCLUSION(S): The administration of MPA resulted in oocyte retrieval rates, endocrine profiles, viable embryo numbers, and pregnancy outcomes similar to those achieved with the GnRH antagonist. Therefore, MPA can be recommended for OS in oocyte donation because it permits a more patient-friendly approach. CLINICAL TRIAL REGISTRATION NUMBER: NCT03300960.

Number needed to freeze: cumulative live birth rate after fertility preservation in women with endometriosis.

RESEARCH QUESTION: How does the number of oocytes used affect the cumulative live birth rate (CLBR) in endometriosis patients who had their oocytes vitrified for fertility preservation? DESIGN: Retrospective observational study including data from 485 women with endometriosis who underwent fertility preservation from January 2007 to July 2018. Survival curves and Kaplan-Meier plots were used to analyse the CLBR according to the number of vitrified oocytes used. Endometriosis curves were compared with plots developed using elective fertility preservation (EFP) patients as control group. Log-rank, Breslow and Tarone-Ware tests were used to compare the survival curves. RESULTS: The CLBR increased as the number of oocytes used per patient rose, reaching 89.5% (95% confidence interval [CI] 80.0-99.1%) using 22 oocytes. Higher outcomes were observed in young women (≤35 years old versus >35 years old). In the younger group, the CLBR was 95.4% (95% CI 87.2-103.6%) using approximately 20 oocytes versus 79.6% (95% CI 58.1-101.1%) in older women (log-rank [Mantel-Cox] P = 0.002). The mean age was higher in EFP patients (37.2 ± 4.9 versus 35.7 ± 3.7; P < 0.001). The outcome was better in the endometriosis group as compared with EFP: a CLBR of 89.5% (95% CI 80.0-99.1%) versus 59.9% (95% CI 51.4-68.6%) when 22 oocytes were used (log-rank [Mantel-Cox] P < 0.00001). CONCLUSION: The probability of live birth increases as the number of oocytes used increases in patients with endometriosis, but better outcomes were observed among young women. The information provided here may be of interest to both patients and treating physicians for counselling purposes.

Impact of low serum progesterone levels on the day of embryo transfer on pregnancy outcome: a prospective cohort study in artificial cycles with vaginal progesterone.

STUDY QUESTION: Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER: Serum P levels <8.8 ng/ml on the day of ET lower ongoing pregnancy rate (OPR) in both own or donated oocyte cycles. WHAT IS KNOWN ALREADY: We previously found that serum P levels <9.2 ng/ml on the day of ET significantly decrease OPR in a sample of 211 oocyte donation recipients. Here, we assessed whether these results are applicable to all infertile patients under an artificial endometrial preparation cycle, regardless of the oocyte origin. STUDY DESIGN, SIZE, DURATION: This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE: Women with serum P levels <8.8 ng/ml (30th percentile) had a significantly lower OPR (36.6% vs 54.4%) and live birth rate (35.5% vs 52.0%) than the rest of the patients. Multivariate logistic regression showed that serum P < 8.8 ng/ml was an independent factor influencing OPR in the overall population and in the three treatment groups. A significant negative correlation was observed between serum P levels and BMI, weight and time between the last P dose and blood tests and a positive correlation was found with age, height and number of days on HRT. Multivariate logistic regression showed that only body weight was an independent factor for presenting serum P levels <8.8 ng/ml. Obstetrical and perinatal outcomes did not differ in patients with ongoing pregnancy regardless of serum P levels being above/below 8.8 ng/ml. LIMITATIONS, REASONS FOR CAUTION: Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS: This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NCT03272412.

Preimplantation genetic testing for aneuploidy in patients with partial X monosomy using their own oocytes: is this a suitable indication?

OBJECTIVE: To describe the outcome of preimplantation genetic testing (PGT-A) using their own oocytes in patients with mosaic Turner Syndrome (MTS). The impact of the assisted reproduction technique (ART) performed (PGT-A or oocyte donation) and the type of absence of the X chromosome (total or partial) were considered. DESIGN: Retrospective observational multicenter study. SETTING: University-affiliated private in vitro fertilization center. PATIENT(S): Fifty-six patients with MTS with whom 65 ovarian stimulation cycles for PGT-A (fluorescence in situ hybridization/arrays-next generation sequencing) were performed. The study included 90 women with MTS and 20 women with pure Turner Syndrome (PTS) who underwent 140 and 25 oocyte donation (OD) cycles, respectively. INTERVENTION(S): In vitro fertilization for PGT-A (fluorescence in situ hybridization/arrays-next generation sequencing) or OD. MAIN OUTCOME MEASURE (S): Reproductive outcome and feto-maternal outcomes. RESULTS: The live birth rate (LBR) per embryo transfer in patients with MTS tended to be higher in OD 37.7% (95% confidence interval [CI]: 29.3-46.1) than that observed for PGT-A 22.5% (95% CI 7.8-38.2), and the cumulative LBR (CLBR), with 77.6% vs. 43.3%, respectively. Likewise, the LBR per patient was significant when comparing PGT-A vs. OD, with 12.5% (95 CI 3.9-21.1) vs. 51.1% (40.7-61.4), respectively. While focusing on the X chromosome, partial MTS (PTS), we found significant differences in the CLBR per embryo transfer, with 77.6% vs. 29.2%, and also in the LBR per patient: 51.1% (40.7-61.4) in MTS vs. 15% (95 CI 0.0-30.1) in PTS. CONCLUSION(S): Oocyte donation is the best reproductive option in females with Turner Syndrome with or without mosaicisms. Nevertheless, PGT-A is a valid therapeutic option in patients with MTS using their own oocytes, and OD should not necessarily be directly recommended.

A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF.

RESEARCH QUESTION: Does clinical performance of personalized embryo transfer (PET) guided by endometrial receptivity analysis (ERA) differ from frozen embryo transfer (FET) or fresh embryo transfer in infertile patients undergoing IVF? DESIGN: Multicentre, open-label randomized controlled trial; 458 patients aged 37 years or younger undergoing IVF with blastocyst transfer at first appointment were randomized to PET guided by ERA, FET or fresh embryo transfer in 16 reproductive clinics. RESULTS: Clinical outcomes by intention-to-treat analysis were comparable, but cumulative pregnancy rate was significantly higher in the PET (93.6%) compared with FET (79.7%) (P = 0.0005) and fresh embryo transfer groups (80.7%) (P = 0.0013). Analysis per protocol demonstrates that live birth rates at first embryo transfer were 56.2% in PET versus 42.4% in FET (P = 0.09), and 45.7% in fresh embryo transfer groups (P = 0.17). Cumulative live birth rates after 12 months were 71.2% in PET versus 55.4% in FET (P = 0.04), and 48.9% in fresh embryo transfer (P = 0.003). Pregnancy rates at the first embryo transfer in PET, FET and fresh embryo transfer arms were 72.5% versus 54.3% (P = 0.01) and 58.5% (P = 0.05), respectively. Implantation rates at first embryo transfer were 57.3% versus 43.2% (P = 0.03), and 38.6% (P = 0.004), respectively. Obstetrical outcomes, type of delivery and neonatal outcomes were similar in all groups. CONCLUSIONS: Despite 50% of patients dropping out compared with 30% initially planned, per protocol analysis demonstrates statistically significant improvement in pregnancy, implantation and cumulative live birth rates in PET compared with FET and fresh embryo transfer arms, indicating the potential utility of PET guided by the ERA test at the first appointment.

Oocyte vitrification for fertility preservation in women with endometriosis: an observational study.

OBJECTIVE: To describe the outcome of fertility preservation (FP) using vitrified oocytes in patients with endometriosis and to determine the impact of ovarian surgery. DESIGN: Retrospective observational study. SETTING: University-affiliated private in vitro fertilization (IVF) center. PATIENT(S): Four hundred and eighty-five women with endometriosis who underwent FP from January 2007 to July 2018. INTERVENTION(S): Vitrification of metaphase II (MII) oocytes for future use. MAIN OUTCOME MEASURE(S): Oocyte survival rate and cumulative live-birth rate (CLBR). RESULT(S): Mean age at vitrification was 35.7 ± 3.7 years. The women undergoing operations were younger than the nonsurgical patients (33.4 ± 3.6 years vs. 36.7 ± 3.7 years). The survival rate and CLBR were 83.2% and 46.4%, respectively. The number of vitrified oocytes per cycle (6.2 ± 5.8) was higher for the nonsurgical patients compared with the unilateral (5.0 ± 4.5) or bilateral (4.5 ± 4.4) surgery groups, but was comparable among the surgical patients. The effect of age (adjusted odds ratio [OR] 0.904; 95% CI, 0.858-0.952), number of oocytes (adjusted OR 1.050; 95% CI, 1.025-1.091), and survival (adjusted OR 1.011; 95% CI, 1.001-1.020) on the CLBR was confirmed. However, the effect of surgery was not observed (adjusted OR 1.142; 95% CI, 0.778-1.677). Nonetheless, the ovarian response (vitrified oocytes = 8.6 ± 6.9 vs. 5.1 ± 4.8) and CLBR (72.5% vs. 52.8%) were higher in young (≤35 years) nonsurgical patient versus the surgical patients; older women showed similar outcomes. CONCLUSION(S): Fertility preservation gives patients with endometriosis a valid treatment option to help them increase their reproductive chances. We suggest performing surgery after ovarian stimulation for FP in young women. In older women, an individualized treatment should be considered.

GnRH antagonist for endometrial priming in an oocyte donation programme: a prospective, randomized controlled trial.

RESEARCH QUESTION: Can gonadotrophin releasing hormone (GnRH) antagonist be used in egg donation recipients with ovulatory cycles for the purpose of achieving synchronization between the donor´s and recipient´s cycle? DESIGN: Prospective randomized controlled trial to compare 7-day dosage of GnRH antagonist for endometrial priming in an oocyte donation programme with a single dose of long-acting GnRH agonist. A total of 563 women were randomized in a private single centre, and 473 women underwent embryo transfer. Ongoing pregnancy rate was the primary end point. Analysis was adjusted for embryonic stage at the time of embryo transfer; data collected included days on the waiting list; number of fresh-vitrified oocytes collected; and oocyte donor´s age at the time of retrieval. RESULTS: No statistically significant differences were found between groups in per intention-to-treat analysis: adjusted OR 1.42 (CI 0.97 to 2.09); per treatment received: adjusted OR 1.43 (CI 0.97 to 2.09); per embryo transfer: adjusted OR for ongoing pregnancy rate 1.47 (CI 1.01 to 2.13), P = 0.047. CONCLUSIONS: For women with ovulatory cycles undergoing oocyte donation, the outcomes are similar between GnRH antagonist and down-regulated hormone replacement protocols.

In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study.

OBJECTIVE: To determine the clinical value of preimplantation genetic diagnosis for aneuploidy screening (PGD-A) in women of advanced maternal age (AMA; between 38 and 41 years). DESIGN: This was a multicenter, randomized trial with two arms: a PGD-A group with blastocyst transfer, and a control group with blastocyst transfer without PGD-A. SETTING: Private reproductive centers. PATIENT(S): A total of 326 recruited patients fit the inclusion criteria, and 205 completed the study (100 in the PGD-A group and 105 in the control group). INTERVENTION(S): Day-3 embryo biopsy, array comparative genomic hybridization, blastocyst transfer, and vitrification. MAIN OUTCOME MEASURE(S): Primary outcomes were delivery and live birth rates in the first transfer and cumulative outcome rates. RESULT(S): The PGD-A group exhibited significantly fewer ETs (68.0% vs. 90.5% for control) and lower miscarriage rates (2.7% vs. 39.0% for control). Delivery rate after the first transfer attempt was significantly higher in the PGD-A group per transfer (52.9% vs 24.2%) and per patient (36.0% vs. 21.9%). No significant differences were observed in the cumulative delivery rates per patient 6 months after closing the study. However, the mean number of ETs needed per live birth was lower in the PGD-A group compared with the control group (1.8 vs. 3.7), as was the time to pregnancy (7.7 vs. 14.9 weeks). CONCLUSION(S): Preimplantation genetic diagnosis for aneuploidy screening is superior compared with controls not only in clinical outcome at the first ET but also in dramatically decreasing miscarriage rates and shortening the time to pregnancy.

GnRH analogues in the prevention of ovarian hyperstimulation syndrome.

The GnRH analogue (agonist and antagonist GnRH) changed ovarian stimulation. On the one hand, it improved chances of pregnancy to obtain more oocytes and better embryos. This leads to an ovarian hyper-response, which can be complicated by the ovarian hyperstimulation syndrome (OHSS). On the other hand, the GnRH analogue can prevent the incidence of OHSS: GnRH antagonist protocols, GnRH agonist for triggering final oocyte maturation, either together or separately, coasting, and the GnRH analogue may prove useful for avoiding OHSS in high-risk patients. We review these topics in this article.

Preimplantation genetic screening using fluorescence in situ hybridization in patients with repetitive implantation failure and advanced maternal age: two randomized trials.

OBJECTIVE: To evaluate the usefulness of preimplantation genetic screening (PGS) using fluorescence in situ hybridization (FISH) for two different indications: repetitive implantation failure (RIF) and advanced maternal age (AMA). DESIGN: Two prospective, randomized controlled trials with patients allocated in two arms: blastocyst transfer on day 5 (group A) or PGS with transfer on day 5 (group B). SETTING: University-affiliated private clinics. PATIENT(S): The RIF study included women <40 years with three or more failed IVF cycles without other known causal factors (91 patients). The AMA study included intracytoplasmic sperm injection patients aged between 41 and 44 (183 patients). INTERVENTION(S): In the PGS group, single-cell day 3 biopsy was performed with aneuploidy screening for chromosomes 13, 15, 16, 17, 18, 21, 22, X, and Y. In both the blastocyst transfer group and the PGS group, ET was performed on day 5. MAIN OUTCOME MEASURE(S): Live-birth rate per patient and per started cycle. RESULT(S): A significant increase in live-birth rates per patient was found in the PGS group compared with the blastocyst group for the AMA study (30/93 patients [32.3%] vs. 14/90 patients [15.5%]; odds ratio, 2.585; confidence interval, [1.262-5.295]). In the RIF study no significant differences were observed (23/48 patients [47.9%] vs. 12/43 patients [27.9%]). CONCLUSION(S): PGS with FISH was shown to be beneficial for the AMA group.

GnRH analogue for the prevention of ovarian hyperstimulation syndrome: a pilot study.

Continuation of GnRH analogue after ovum retrieval produces a faster decline in vascular endothelial growth factor levels and ascitis in women at risk of ovarian hyperstimulation syndrome.