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Purpose: To assess the primary sex ratio (males-to-females at time of conception) in blastocysts from consanguine couples undergoing IVF/ICSI treatments and its correlation with chromosomal constitution., Method: A total of 5135 blastocysts were analyzed by preimplantation-genetic testing for aneuploidy (PGT-A) with next-generation sequencing (NGS) from November 2016 to December 2020. From those, a total of 1138 blastocysts were from consanguine couples (CS) and 3997 from non-consanguine couples (NCS). Only blastocysts presenting normal sex chromosome constitution with or without autosomal aneuploidies were included. Primary sex ratio (PSR) of biopsied blastocysts was compared between CS and NCS couples., Results: Expanded blastocysts derived from CS had 47.7% XY versus 52.3% XX constitutions, presenting a PSR of 0.91. In NCS, 48.9% of expanded blastocysts were XY and 51.2% XX, with a less pronounced PSR of 0.95. When stratifying embryos by ploidy, euploid embryos from CS had the lowest PSR (0.87) with 46.6% XY versus 53.4% XX blastocysts (OR 0.89, 95% CI 0.70-1.14; NS), but it did not achieve statistical significance. The lower PSR seemed rather related to euploid embryos from first-degree cousins (PSR = 0.80 versus 0.98 in second-degree cousins, NS). Euploid embryos from NCS presented a PSR of 0.96, with 49.1% XY versus 50.9% XX blastocysts (OR 0.98, 95% CI 0.79-1.22; NS). Significant differences in prevalence of euploidy of specific chromosomes were encountered between CS and NCS., Conclusions: The primary sex ratio was generally similar in expanded blastocysts from consanguine and non-consanguine couples, with a slight decrease in primary sex ratio of euploid blastocysts from consanguine couples., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate whether endometrial thickness (ET) independently affects the live birth rate (LBR) after embryo transfer., Design: Retrospective study., Setting: Private assisted reproductive technology center., Patient(s): A total of 959 single euploid frozen embryo transfers., Intervention(s): Vitrified euploid blastocyst transfer., Main Outcome Measure(s): Live birth rate per embryo transfer., Result(s): The conditional density plots did not demonstrate either a linear relationship between the ET and LBR or a threshold below which the LBR decreased perceivably. Receiver operating characteristic curve analyses did not suggest a predictive value of the ET for the LBR. The area under the curve values were 0.55, 0.54, and 0.54 in the overall, programmed, and natural cycle transfers, respectively. Logistic regression analyses with age, embryo quality, day of trophectoderm biopsy, body mass index, and ET did not suggest an independent effect of the ET on the LBR., Conclusion(s): We did not identify a threshold of the ET that either precluded live birth or under which the LBR decreases perceivably. Common practice of cancelling embryo transfers when the ET is <7 mm may not be justified. Prospective studies, in which the management of the transfer cycle would not be altered by ET, would provide higher-quality evidence on the subject., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to analyze the morphokinetic behaviour between conventional IVF and ICSI, in cycles with preimplantation genetic testing for aneuploidies (PGT-A)., Materials: A randomized controlled trial (NCT03708991) was conducted in a private fertility center. Thirty couples with non-male factor infertility were recruited between November 2018 and April 2019. A total of 568 sibling cumulus oocyte complexes were randomly inseminated with conventional IVF and ICSI and cultured in an Embryoscope time-lapse system. The morphokinetic behaviour of IVF/ICSI sibling oocytes was analysed as primary endpoint. As secondary endpoints, morphokinetic parameters that predict blastocysts that will be biopsied, the day of biopsy, gender and euploid outcome was assessed., Results: When comparing IVF to ICSI, only the time to reach the 2-cell stage (t2) was significantly delayed for IVF embryos: OR: 1.282 [1.020-1.612], p = 0.033. After standardizing for tPNf (ct parameters), only Blast(tStartBlastulation-t2) remained significant: OR: 0.803 [0.648-0.994], p = 0.044. For the analysis of zygotes that will be biopsied on day 5/6 versus zygotes without biopsy, only early morphokinetic parameters were considered. All parameters were different in the multivariate model: ct2: OR: 0.840 [0.709-0.996], p = 0.045; ct6: OR: 0.943 [0.890-0.998], p = 0.043; cc2(t3-t2): OR: 1.148 [1.044-1.263], p = 0.004; cc3(t5-t3): OR: 1.177 [1.107-1.251], p<0.0001. When comparing the development between blastocysts biopsied on day 5 versus day 6, only three morphokinetic parameters were significant: cc2(t3-t2): OR: 1.394 [1.010-1.926], p = 0.044; ctBlastocyst: OR: 0.613 [0.489-0.768], p<0.0001 and ctExpandedBlastocyst: OR: 0.913 [0.868-0.960], p = 0.0004. Multivariate analysis of gender and ploidy did not reveal differences in morphokinetic behaviour., Conclusion: Minor morphokinetic differences are observed between IVF and ICSI. Early in the development, distinct cleavage patterns are observed between embryos that will be biopsied or not., Competing Interests: The authors have declared that no competing interests exist.

Objective: This was a non-blinded randomized controlled study to evaluate whether endometrial irrigation via office hysteroscopy during the early follicular phase would lead to a higher level of live birth rates compared to no irrigation in the fresh embryo transfer cycle., Method: The study was conducted in Tehran university of medical sciences from June 2015 to June 2016. women under the age of 40 with primary infertility without history of previous IVF/ICSI or hysteroscopic examination, were included. Controlled ovarian hyperstimulation was done. Hysteroscopy was performed in the early mid-follicular phase of a stimulation cycle (day 5-7) with a vaginoscopy approach and saline irrigation in hysteroscopy group. Embryo-transfer was done in the same cycle., Results: 228 patients completed their participation in the study. In the fresh cycle, clinical pregnancy rate was 46% in the hysteroscopy group and 40.43% in the control group. ( p-value= 0.326, RR= 1.16 [95%CI: 0.862 to 1.56] ). Live birth rate was 41.28% in the hysteroscopic group and 31.93% in the control group ( p-value=0.143, RR= 1.293 [95%CI: 0.916 to 1.825] ). For those patients having surplus cryopreserved embryos, after 2 months, a second embryo transfer was performed. The cumulative LBR was 44.05% in the hysteroscopic group and 32.25% in the control group ( p-value=0.029, RR= 1.368 [95%CI: 1.031 to 1.815], RD= 11.9% [95%CI: 1.2% to 22.3%] and NNT= 8 [95%CI: 4 to 85] )., Conclusion: The current study clearly demonstrated a significantly higher cumulative live birth rate in the intervention group., Clinical Trial Registration: [https://www.irct.ir/trial/19586], identifier IRCT2016011022795N2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ghasemi, Aleyasin, Fatemi, Ghaemdoust and Shahrakipour.)

Objective: To determine whether euploidy rates and blastocyst development differ in a continuous culture medium under different CO 2 concentrations., Design and Method: A single-center retrospective study was performed from July 2018 to October 2019 including 44 fresh cycles with at least four fresh mature oocytes (MII) without severe male factor infertility. Sibling MII were injected and cultured in Global®Total®LP under 6.0% (pHe = 7.374 ± 0.014) or 7.0% (pHe = 7.300 ± 0.013) CO 2 , 5.0% O 2 , and 89.0% or 88.0% N 2 . Analyzed variables were normally fertilized oocytes (2PN), cleavage rate, blastulation rate on day 5/2PN, usable blastocyst (blastocysts biopsied/2PN), and euploidy rates. Blastocyst's trophectoderm biopsy was performed on day 5, 6, or 7 for genetic testing and mitochondrial DNA (mtDNA) quantification by next-generation sequencing., Results: Women's mean age was 33.0 ± 6.6 years old. From a total of 604 MII, no differences were found in normal fertilization and cleavage rates on day 3 between 6.0 and 7.0% CO 2 (72.3% vs 67.1%, p = 0.169 and 96.6% vs 96.3%, p = 0.897, respectively). Blastulation rate on day 5/2PN was comparable between 6.0 and 7.0% CO 2 (68.1% vs 64.2%, p = 0.409). Although usable blastocyst rate was not different (54.3% vs 55.3%, p = 0.922), total euploidy rates differed significantly (58.7% vs 42.8%, p = 0.016) between 6.0% and 7.0% CO 2 , respectively. The mean blastocyst mtDNA content was significantly lower in 6.0% CO 2 (30.4 ± 9.1 vs 32.9 ± 10.3, p = 0.037)., Conclusion: Blastocyst development is not affected when embryos are cultured in vitro at 6.0% or 7.0% CO 2 , while euploidy rates are significantly decreased at a higher CO 2 concentration, therefore at a lower pHe., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To determine if euploidy rates and embryo development differ when blastocysts are cultured in CCM or SCM., Method: A single-center retrospective observational study was performed from September 2018 to March 2019. Patients [23-46 years] with at least four fresh mature oocytes (MII) without severe male factor infertility were included. Sibling MII were injected and cultured in Global®Total®LP (CCM) or Sage Quinn's Advantage® Cleavage and Blastocyst media (SCM) under 6% CO 2 , 5% O 2 , and 89% N 2 . Fertilization, cleavage, day (D) 5 blastulation, usable blastocyst (blastocysts biopsied/normally fertilized oocytes), and euploidy rates were recorded. Blastocysts were graded prior to trophectoderm (TE) biopsy on D5, 6, or 7 for genetic testing and mitochondrial DNA (mtDNA) quantification., Results: According to clinical practice, 1452 MII were randomly distributed: 751 in CCM and 701 in SCM. No differences were observed in fertilization and cleavages rates for CCM and SCM (77.4% vs 75.5%, p = 0.429 and 97.6% vs 99.1%, p = 0.094, respectively). Blastulation rate on D5 was higher in CCM (70.6% vs 62.2, p = 0.009); however, usable blastocyst rates were comparable (CCM: 58.3% vs SCM: 56.7%, p = 0.625). From a Poisson regression model adjusted for confounding factors, euploidy rates were not different between media (aOR = 1.18, [0.94-1.48], p = 0.157). Euploid blastocyst's mtDNA values were similar (CCM: 32.2, [30.5, 34.1] and SCM: 33.5, [31.8, 35.2], p = 0.345) and top-quality blastocysts (AA/BA) were increased in SCM (OR=1.04, [1.00-1.09], p = 0.037)., Conclusion: Under controlled in vitro conditions, euploidy rates and embryo development are comparable when embryos are cultured in CCM or SCM., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment., Methods: Ten experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%., Results: Eighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged <35 years. Oocyte number and live birth rate are strongly correlated; there is a positive linear correlation with cumulative live birth rate. Different r-hFSH preparations have identical polypeptide chains but different glycosylation patterns, affecting the biospecific activity of r-hFSH. r-hFSH plus recombinant human LH (r-hFSH:r-hLH) demonstrates improved pregnancy rates and cost efficacy versus human menopausal gonadotropin (hMG) in patients with severe FSH and LH deficiency. (2) Pituitary suppression (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (3) Final oocyte maturation triggering (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (4) Luteal-phase support (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support., Conclusions: This Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes., Competing Interests: TD and SL are employees of Merck KGaA, Darmstadt, Germany. RO received speaker fees/honoraria from Ferring and Merck KGaA, Darmstadt, Germany. CV is supported by a NHMRC Early Career Fellowship (GNT1147154). He also has equity interests in Virtus Health and reports grants, personal fees and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees and non-financial support from MSD, grants and non-financial support from Ferring, personal fees from Besins Healthcare, and grants and non-financial support from Abbott. HF received speaker fees/honoraria/grants from MSD, Ferring, Besin, Merck KGaA, Darmstadt, Germany, and Sun Pharma. RF received consulting fees and honoraria from Merck KGaA, Darmstadt, Germany. YK received speaker fees/honoraria/grants from MSD, Merck KGaA, Darmstadt, Germany, Besins Healthcare, Gedeon Richter, Abbott, Bayer, and Sun Pharma. MH declares receipt of research grants from Merck KGaA, Darmstadt, Germany, and lecture fees from Merck KGaA, Darmstadt, Germany and Ferring. MG received fees from Merck KGaA, Darmstadt, Germany, Ferring, Gedeon Richter, MSD, IBSA. SE declares receipt of unrestricted research grants from Merck KGaA, Darmstadt, Germany, and lecture fees from Merck KGaA, Darmstadt, Germany, Gedeon Richter and Medical Education Academy. SS was speaker at non-promotional educational symposia by Merck KGaA, Darmstadt, Germany and Ferring in the last 12 months. YL received speaker fees/grants from Merck KGaA, Darmstadt, Germany, MSD, and Bayer. CA received consulting fees and payment/honoraria from Merck KGaA, Darmstadt, Germany., (Copyright © 2021 Orvieto, Venetis, Fatemi, D’Hooghe, Fischer, Koloda, Horton, Grynberg, Longobardi, Esteves, Sunkara, Li and Alviggi.)

Purpose: To determine whether the blastocyst mitochondrial DNA (mtDNA) content is related to the miscarriage rate in patients undergoing single euploid frozen embryo transfer (SEFET)., Methods: A total of 355 single euploid frozen embryo transfer cycles were studied retrospectively between April 2017 and December 2018. A trophectoderm biopsy was performed on day 5/6 blastocysts. Post next-generation sequencing (NGS), the mtDNA content was calculated as the ratio of mitochondrial DNA over nuclear DNA, and the association between blastocyst mtDNA content and miscarriage rate was evaluated., Result(s): Three hundred fifty-five euploid blastocysts were selected for SEFET in 314 patients with an average age of 33.7 ± 5.6 years; 255 were biopsied on day 5 (71.8%) and 100 on day 6 (28.2%). Frozen embryo transfer (FET) was performed either in a hormone replacement therapy (HRT) cycle (71.8%; n = 255) or in a natural cycle (NC) (28.2%; n = 100). A pregnancy rate of 66.2% (235/355) was obtained with clinical pregnancy and miscarriage rates of 52.4% (n = 186) and 5.6% (n = 20), respectively. There was no significant difference neither between the blastocyst mtDNA content of pregnant and nonpregnant patients (27.7 ± 9.2 vs. 29.4 ± 8.6, P = 0.095) nor between patients with a clinical pregnancy and miscarriage (30.5 ± 9.3 vs. 27.3 ± 9.2, P = 0.136). Multivariate logistic regression analysis showed the same nonsignificant relationship, except for the miscarriage rate and BMI (OR 1.149, 95% CI 1.03-1.28; P = 0.012)., Conclusion(s): Mitochondrial DNA content is unable to predict the miscarriage of implanted human euploid blastocysts.

The number of mature oocytes is a key factor in the success of Assisted Reproductive Techniques (ART). Exogenous gonadotropins are administered during ovarian stimulation in order to maximize the number of oocytes available for fertilization. During stimulation, monitoring is mandatory to evaluate individual response, to avoid treatment complications and assist in the determination of the optimal day for final oocyte maturation and oocyte retrieval. Routine monitoring during stimulation includes transvaginal ultrasound examinations and measurement of serum estradiol (E2). Due to multifollicular growth of follicles of varying size, serum E2 levels are commonly supraphysiological and often variable, rendering E2-measurement during ovarian stimulation unreliable as a determinant of oocyte maturity. In contrast to serum E2, serum Inhibin A levels increase once a minimum follicle size of 12-15 mm is achieved. Due to this fact, serum Inhibin A levels could present in combination with ultrasound monitoring a more reliable parameter to determine the optimal follicle size for final oocyte maturation, as only follicles with a size of 12 mm and beyond will contribute to the serum Inhibin A level. This prospective observational, cross-sectional study demonstrates, that on the day of final oocyte maturation serum Inhibin A is strongly correlated to the number of follicles ≥15 mm (0.72) and to the number of retrieved and mature oocytes (ρ 0.82/0.77, respectively), whereas serum E2 is moderately correlated to the parameters mentioned above (ρ 0.64/0.69/0.69, respectively). With an area under the curve (AUC) of 0.91 for Inhibin A, compared to an AUC of 0.84 for E2, Inhibin A can be regarded as a better predictor for the optimal timing of trigger medication with a threshold number of ≥10 mature oocytes. It can be concluded from this data that serum Inhibin A in combination with transvaginal ultrasound monitoring may be a more powerful tool in the decision making process on trigger timing as compared to E2., (Copyright © 2020 Lawrenz, Depret Bixio, Coughlan, Andersen, Melado, Kalra, Savjani, Fatemi and Kumar.)

Purpose of Review: The aim of this review is to summarize the different aspects of luteal phase deficiency in IVF treatment and the possibilities of individualized luteal phase support., Recent Findings: After the application of human chorionic gonadotrophin (hCG) for final oocyte maturation, the vaginal route for progesterone administration is sufficient to maintain an adequate luteal phase support. New data point toward the possibility of oral medication; however, those data have yet to be confirmed in larger studies. Luteolysis after gonadotropinrealzing hormone (GnRH) agonist trigger is patient specific and not always severe. According to the progesterone level, individualized low dosages of hCG can be applied as luteal phase support without the risk of ovarian hyperstimulation syndrome (OHSS) development., Summary: It is the task of the reproductive medicine specialist to individualize luteal phase support according to the patient's specific characteristics, needs and desires and the type of treatment performed. The greatest indication for individualization of the luteal phase is following GnRH agonist trigger in high responder patients in order to tailor luteal phase support to the patient-specific pattern of luteolysis and minimize the risk of causing OHSS with unnecessary high hCG dosages.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The premature rise of progesterone during the late follicular phase in stimulated IVF cycles is a frequent event, and emerging evidence shows that premature progesterone rise does negatively affect the outcome of assisted reproductive techniques. The effect of elevated peripheral progesterone levels in the late follicular phase seems to be on the endometrium and the window of implantation, which may lead to asynchrony between the endometrium and the developing embryo. In stimulated cycles, endometrial maturation is advanced on the day of oocyte retrieval, and patients with a progesterone level above 1.5 ng/ml on the day of final oocyte maturation have different endometrial gene expression profiles. This progesterone level seems to represent the critical threshold, at which a negative effect on the ongoing pregnancy rate in fresh IVF cycles can be observed. Moreover, no association exists between progesterone elevation in the fresh cycle, and the probability of pregnancy after transfer of frozen-thawed embryos, originating from that cycle. The causes of premature progesterone elevation during ovarian stimulation are still unclear; however, recent studies point towards enhanced FSH-stimulation as a cause for progesterone elevation., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Over the past few years, the use of Gonadotropin-releasing-hormone (GnRH)-agonist for final oocyte maturation in GnRH-antagonist-protocols in stimulated IVF/ICSI cycles has gained worldwide acceptance, as this approach reduces significantly the risk for development of ovarian hyperstimulation syndrome (OHSS). Final oocyte maturation with GnRH-agonist leads to sever luteolysis, which cannot be counterbalanced using standard luteal phase support with purely progesterone (P4) application and therefore administration of hCG or high doses of P4 is considered to be essential to prevent/counteract luteolysis. However, lately publications indicate, that luteolysis is not always complete after GnRH-agonist for trigger. This case-series evaluates the degree of luteolysis in high-responder-patients, who received GnRH-agonist for final oocyte maturation. Assessment of estradiol (E2)- and P4-levels 48 h after oocyte-pick-up (OPU) procedure demonstrate clearly, that luteolysis after GnRH-agonist trigger is individual-specific, even in high-responder patients with the same number of oocytes. Hence, individualization of luteal phase support with the focus on avoiding unnecessary administration of hCG, bearing the risk for development of OHSS, a new concept of luteal coasting needs to be developed, based on severity of luteolysis following luteal coasting.

Study Question: Does hormonal stimulation with corifollitropin alpha (CFA) only, mimicking a step down protocol, result in lower incidence of progesterone elevation on the day of hCGtrigger as compared to sustained stimulation with recombinant FSH (rFSH)?, Summary Answer: The current findings support the concept that sustained FSH stimulus contributes to premature progesterone elevation in stimulated IVF cycles., What Is Known Already: Serum progesterone rise during the follicular phase of ovarian stimulation for IVF treatment seems to be related to a poorer reproductive outcome. However, the mechanism by which the rise in progesterone is caused is not yet fully understood., Study Design, Size, Duration: This study was a post hoc analysis of data from two multi-center, randomized, double-blind, double-dummy, active-controlled, non-inferiority trials, ENGAGE and PURSUE, conducted from June 2006 to January 2008 and from July 2010 to October 2012 respectively., Participants/materials, Setting, Methods: In the ENGAGE-study, 1506 women, aged 18-36 years, were allocated to either a single injection of 150 mg CFA or daily injections of 200 IU rFSH in the first week of stimulation, using a standard GnRH antagonist protocol. In the PURSUE-study, a total of 1390 women, aged 35-42 years, were allocated to either a single injection of 150 mg of CFA or daily 300 IU of rFSH for the first week, again using a standard GnRH antagonist protocol. In both trials, daily rFSH was continued until three follicles reached >17 mm in size. All women had a body weight of between 50 and 90 kg, regular menstrual cycles and an indication for ovarian stimulation before IVF. The incidence of progesterone elevation on day of hCG-trigger in patients with CFA only or rFSH stimulation, and triggered on Day 8 of stimulation, was analyzed., Main Results and the Role of Chance: Of patients with CFA only stimulation, 5.4% (13/239 patients) showed a progesterone elevation above 1.5 ng/ml on day of hCG-trigger, whereas patients with rFSH stimulation had a significant higher incidence of progesterone elevation (18.3%; 62/339 patients) (P < 0.001)., Limitations, Reasons for Caution: Post hoc analysis of data from previously published trials could be considered as a reason for caution., Wider Implications of the Findings: Future studies should evaluate whether it would be possible to prevent a premature progesterone rise in cycles stimulated with daily FSH by using a step down protocol towards the end of the follicular phase., Study Funding/competing Interests: Financial/Material Support was provided by Merck & Co., Inc., Kenilworth, NJ, USA. Davis Gates is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own stock and/or hold stock options in the company. Fabiola Beligotti is an employee of MSD, Italy, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own stock and/or hold stock options in the company. Barbara Lawrenz, Nils Engelmann and Human M. Fatemi have no conflict of interest., Trial Registration Number: ENGAGE study: ClinicalTrials.gov identifier NTC00696800. PURSUE-study: NCT01144416., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose of Review: The current review will focus on the cause of premature progesterone and its impact on endometrial receptivity and endometrial gene expression., Recent Findings: Premature progesterone rise in stimulated IVF cycles seems to have a negative impact on the pregnancy rate. The current knowledge on the cause of a premature progesterone rise is still limited; however, it seems that overstimulating the ovaries during the end of the follicular phase will lead to a premature progesterone rise. The negative impact on the outcome is mainly due to reduced endometrial receptivity as can be seen in the altered endometrial gene expression., Summary: Future studies should focus on how ovarian stimulation can be tailored according to individual requirements of the patients, aiming on preventing a possible progesterone rise during follicular phase of stimulated IVF cycles.

Objective: To assess endocrine differences during early luteal phase according to mode of triggering final oocyte maturation with or without luteal phase support (LPS)., Design: A prospective randomized study., Setting: University center for reproductive medicine., Patient(s): Four oocyte donors each underwent four consecutive cycles., Intervention(s): To avoid interpatient variation, each donor underwent the same stimulation regimen. However, different modes of triggering final oocyte maturation and LPS were administered: A) 10,000 IU hCG and standard LPS; B) GnRH agonist (GnRHa; 0.2 mg triptorelin), and 35 hours later 1,500 IU hCG, and standard LPS; C) GnRH agonist (0.2 mg triptorelin) and standard LPS; and D) GnRH agonist (0.2 mg triptorelin) without LPS., Main Outcome Measure(s): Blood sampling was performed on the day of ovulation trigger, ovulation trigger + 1 day, and ovum pick-up + 5 days. Serum E2, FSH, LH, and P were measured., Result(s): The early luteal phase steroid levels following GnRHa trigger and modified luteal phase support (B) were similar to those seen after hCG trigger (A). However, significant differences were seen between groups A and B compared with C and D, as well as between groups C and D., Conclusion(s): Administration of a single bolus of GnRHa effectively induced LH and FSH surges in oocyte donors stimulated with recombinant FSH and cotreated with a GnRH antagonist. However, gonadotropin and steroid levels differed significantly according to the type of luteal phase support used after GnRHa trigger., European Community Clinical Trial System (eudract) Number: 2009-009429-26., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular phase in ovarian stimulation. It also explores the origin of the progesterone rise, potential modifying factors and possible methods to prevent its rise during ovarian stimulation. This review draws on information already published from monitoring progesterone concentrations at the end of follicular phase in ovarian stimulation. The databases of Medline and PubMed were searched to identify relevant publications. Good-quality evidence supports the negative impact on endometrial receptivity of elevated progesterone concentrations at the end of the follicular phase in ovarian stimulation. Future trials should document the cause and origin of premature progesterone in stimulated IVF cycles. There is an ongoing debate regarding the impact of premature progesterone rise on the IVF outcome. The objective of this review is to assess evidence of poorer ongoing pregnancy rate in IVF cycles with elevated serum progesterone at the end of follicular phase in ovarian stimulation. It also explores the origin of the progesterone rise, potential modifying factors and possible methods to prevent its rise during ovarian stimulation. This review draws on information already published from monitoring progesterone concentrations at the end of follicular phase in ovarian stimulation. The databases of Medline and PubMed were searched to identify relevant publications. Good-quality evidence supports the negative impact on endometrial receptivity of elevated progesterone concentrations at the end of follicular phase in ovarian stimulation. Future trials should document the cause and origin of premature progesterone in stimulated IVF cycles., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Chronic endometritis is associated with abnormal uterine bleeding, recurrent abortion and infertility. It is a subtle condition, and therefore is difficult to diagnose. The diagnosis is ultimately based on the presence of plasma cells in the endometrial stroma on histopathological examination. Literature on the reproducibility of the diagnosis of chronic endometritis is lacking. Therefore, the aim of the current study was to assess the interobserver agreement of two pathologists in diagnosing chronic endometritis in asymptomatic, infertile patients., Methods: In the context of a randomized controlled trial, an endometrial biopsy was taken during a screening hysteroscopy prior to IVF. All endometrial samples were independently examined by two pathologist. The slides diagnosed with chronic endometritis were replenished with a random sample of the remaining slides up to a total of 100, then exchanged between the two pathologists and reassessed., Results: Of the 678 patients who underwent hysteroscopy, 19 patients were diagnosed with at least possible chronic endometritis (2.8%). Perfect agreement between the pathologists, before and after inclusion of 13 slides with additional immunohistochemistry staining, was found in 88 and 86% of reviews, respectively. The interobserver agreement was substantial, with kappa-values of 0.55 and 0.66, respectively., Conclusions: The interobserver agreement in diagnosing chronic endometritis in asymptomatic infertile patients was found to be substantial. Although the diagnostic reliability is sufficient with the methods in the present study, the low prevalence and unknown clinical significance of endometritis warrants further study.

Objective: To evaluate the association of timing of hCG administration and probability of pregnancy in patients stimulated with recombinant FSH/GnRH antagonists for IVF., Design: Prospective randomized controlled clinical trial., Setting: Dutch-speaking Free University of Brussels., Patient(s): One hundred twenty patients, aged <40 years, treated by IVF or intracytoplasmic sperm injection., Intervention(s): Ovarian stimulation was achieved using recombinant FSH starting on day 2 of the menstrual cycle at a fixed dose. To inhibit premature LH surge, daily GnRH antagonist was used from day 6 of stimulation. Triggering of final oocyte maturation was performed using 10,000 IU of hCG. Patients were randomized to receive hCG either as soon as three or more follicles of size ≥16 mm were present on ultrasonography (early-hCG group) or 1 day after the above criterion was met (late-hCG group)., Main Outcome Measure(s): Ongoing pregnancy rate., Result(s): Significant differences were observed between the early-hCG and the late-hCG group regarding E(2) (1,388 ± 931 [mean ± SD] vs. 2,040 ± 1,231 pg/mL, respectively) and P (0.8 ± 0.3 vs. 1.1 ± 0.5 ng/mL, respectively) levels on the day of hCG administration and the number of metaphase II oocytes (9.2 ± 7.1 vs. 6.1 ± 4.9, respectively). No significant differences were observed between the early-hCG and the late-hCG group regarding positive hCG (46.2% vs. 50%, respectively) and ongoing pregnancy rates (34.6% vs. 40.7%, respectively)., Conclusion(s): The current study provides evidence that earlier administration of hCG is not associated with the probability of pregnancy in cycles stimulated with recombinant FSH and GnRH antagonists., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this systematic review and meta-analysis was to evaluate whether the addition of GnRH agonist for luteal support in ICSI/IVF cycles enhances the probability of live birth., Methods: Systematic literature search (MEDLINE, EMBASE, CENTRAL and RCT registries) was conducted to identify relevant randomized controlled trials published as full manuscripts. Meta-analysis of data yielded pooled risk differences (RDs) and 95% confidence intervals (CIs). A random effects model was applied for pooling the studies., Results: Six relevant RCTs were identified including a total of 2012 patients. The probability of live birth rate (RD: +16%, 95% CI: +10 to +22%) was significantly higher in patients who received GnRH agonist support compared with those who did not. The subgroup analysis according to the type of GnRH analogue used for LH suppression did not change the effect observed (studies in which GnRH agonist was used during ovarian stimulation, RD: +15%, 95% CI: +5 to +23%); (studies in which GnRH antagonist was used during ovarian stimulation, RD: +19%, 95% CI: +11 to +27%)., Conclusions: The best available evidence suggests that GnRH agonist addition during the luteal phase significantly increases the probability of live birth rates.

Objective: To investigate the association between the probability of pregnancy and hormone exposure between the end of menstruation and the day of triggering final oocyte maturation (menstruation-free interval)., Design: Prospective study., Setting: University., Patient(s): One hundred women (aged ≤ 39 years) stimulated with a fixed dose of recombinant follicle-stimulating hormone (200 IU)., Intervention(s): Daily gonadotropin-releasing hormone antagonist (GnRH, 0.25 mg) used from day 6 of stimulation onward, final oocyte maturation triggered by administration of 10,000 IU of human chorionic gonadotropin (hCG) as soon as ≥ 3 follicles ≥ 17 mm were present, and hormone assessment performed at initiation of stimulation, on the first day after menstruation had stopped, on the day of antagonist initiation, and on the day of hCG administration., Main Outcome Measure(s): The association between hormone exposure during the menstruation-free interval and the probability of ongoing pregnancy., Result(s): The exposure to progesterone during the menstruation-free interval was statistically significantly higher in patients who did not become pregnant compared with those who did (4.20 ± 2.54 vs. 3.13 ± 1.14, respectively). Binary logistic regression confirmed the adverse effect of the increased exposure to progesterone for the achievement of pregnancy., Conclusion(s): In recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in vitro fertilization/intracytoplasmic sperm injection cycles, a lower probability of pregnancy is associated with a higher exposure to progesterone during the menstruation-free interval., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

BACKGROUND Hysteroscopy is known as the most accurate test for diagnosing intrauterine pathology. To optimize fertility treatment, it is increasingly common to perform hysteroscopy as a routine procedure prior to IVF. However, literature on the reproducibility of screening hysteroscopy is lacking. Therefore, the aim of the study was to assess the intra- and inter-observer agreement in the individual evaluation of the uterine cavity using video recordings of hysteroscopy procedures in asymptomatic patients prior to IVF. METHODS Screening hysteroscopies of 123 unselected, asymptomatic, infertile women with an indication for IVF/ICSI treatment were recorded on DVD. After editing, the hysteroscopy performer and three other experienced gynecologists independently assessed all recordings, focusing on the appearance of predefined intrauterine abnormalities (i.e. endometrial polyps, myomas, adhesions or septa). The intra- and inter-observer agreement was calculated and expressed as perfect agreement and κ coefficient or intraclass correlation coefficient. RESULTS In total, 123 hysteroscopy procedures were recorded. After editing and selection, based on the record quality, 107 remained for assessment and analysis. The intraobserver agreement on the appearance of any of the predefined intrauterine abnormalities was substantial (κ = 0.707), whereas the interobserver agreement was moderate (κ = 0.491). Perfect agreement occurred only in 77.6% of the cases. CONCLUSIONS Interobserver agreement among experienced gynecologists appeared to be rather disappointing. The latter may have implications for the diagnostic accuracy of screening hysteroscopy prior to IVF, as well as for its clinical significance in IVF programs.

The gene expression of human endometrium on the day of oocyte retrieval of pregnant and nonpregnant patients in a stimulated IVF cycle was compared in two independent groups with different GnRH-antagonist ovarian stimulation protocols. The present data suggest that increased gene expression of cyclooxygenase-2, together with the expression of other molecules in the cyclooxygenase-2 network, on the day of oocyte retrieval in GnRH-antagonist cycles coincides with a lower probability of achieving a clinical pregnancy in this cycle., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 μg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation., (Copyright © 2010. Published by Elsevier Inc.)

Objective: To report an in vitro fertilization (IVF) pregnancy in a patient with histologically confirmed chronic endometritis before the IVF treatment without prior antibiotherapy., Design: Case report., Setting: Academic reproductive medicine unit., Patient(s): A 30-year-old woman with primary infertility due to mild oligoasthenoteratospermia of the male partner., Intervention(s): Diagnostic hysteroscopy and endometrial biopsy., Main Outcome Measure(s): Delivery after the first IVF., Result(s): Histologic examination of the endometrium revealed chronic endometritis. The patient delivered a healthy boy at 40 weeks' gestation after the first IVF treatment., Conclusion(s): Our findings suggest that the impact of chronic endometritis on infertility and IVF outcome should be further investigated in prospective randomized studies.

The luteal phases of all stimulated IVF cycles are abnormal. The main cause of the luteal phase defect (LPD) observed in stimulated IVF cycles is related to the multifollicular development achieved during ovarian stimulation. This may be related to the supra-physiological concentrations of steroids secreted by a high number of corpora lutea during the early luteal phase, which directly inhibit LH release via negative feedback actions at the hypothalamic-pituary axis level, rather than a central pituitary cause or steroidogenic abnormality in the corpus luteum. To correct the LPD in stimulated IVF cycles, human chorionic gonadotrophin (HCG) or progesterone can be administered. HCG is associated with a greater risk of ovarian hyperstimulation syndrome. Natural micronized progesterone is not efficient if taken orally. Vaginal and intramuscular progesterone do have comparable implantation, clinical pregnancy and delivery rates. However, because of severe side effects, intramuscular progesterone administration should be avoided.

Objective: To explore luteal phase hormone profiles in patients stimulated with recombinant FSH and GnRH antagonist for IVF under two different modes of luteal support: P and P with E(2)., Design: Prospective randomized study., Setting: Patients in an academic reproductive medicine unit., Patient(s): One hundred and three patients undergoing ovarian stimulation with a fixed dose of 200 IU recombinant FSH and GnRH antagonist., Intervention(s): Patients were randomized to receive luteal phase supplementation, either P vaginally (n = 49) or P and 4 mg E(2) orally (n = 54)., Main Outcome Measure(s): Hormonal assessment during the luteal phase on days 1, 4, 7, and 10 after the administration of hCG., Result(s): Hormone levels did not differ during the luteal phase between the two groups with the exception of E(2) concentration on day 10 after hCG, which was significantly higher in the E(2)-supplemented group compared with the P group (median 760 pg/mL, range 2,496 vs. median 589.50 pg/mL, range 2,098)., Conclusion(s): Addition of 4 mg E(2) for luteal support after stimulation with recombinant FSH and GnRH antagonist does not alter significantly the endocrine profile of the luteal phase until day 7 after hCG. At day 10 after hCG, the E(2) levels are significantly higher in the E(2)-supplemented group.

Background: The role of progesterone for luteal support in stimulated cycles for IVF is well established. However, controversy still surrounds the benefit of additional supplementation with estradiol (E2) in GnRH agonist (GnRHa) cycles, while no such data are available for GnRH antagonists. The aim of this randomized controlled trial (RCT) was to compare ongoing pregnancy rates in patients stimulated with recombinant FSH (rFSH) and GnRH antagonist for IVF, who received micronized progesterone for luteal phase supplementation, with or without the addition of E2., Methods: Two hundred and one patients underwent ovarian stimulation with a fixed dose of 200 IU rFSH and GnRH antagonist. Patients were randomized to receive, for luteal phase supplementation, either 600 mg of micronized progesterone vaginally (n=100, progesterone group) or 600 mg of micronized progesterone and 4 mg of E2 valerate orally (n=101, progesterone/E2 group). The main outcome measure was ongoing pregnancy at 12 weeks per patient randomized., Results: Demographics, stimulation parameters and embryological data were comparable for the two groups compared. Twenty-six ongoing pregnancies were achieved in the progesterone (26%) and 30 in the progesterone/E2 group (29.7%). (Difference: 3.7 and 95%, CI: -15.8 to 8.6%)., Conclusion: It appears that the addition of E2 to progesterone in the luteal phase after stimulation with rFSH and GnRH antagonist does not enhance the probability of pregnancy.

Objective: To determine the incidence of ovarian hyperstimulation syndrome (OHSS) in a large series of GnRH antagonist-stimulated cycles and to assess the predictive value of E2 and the number of follicles on the day of hCG administration., Design: Prospective cohort study of women undergoing IVF treatment with a GnRH antagonist protocol over a 2-year period., Setting: Tertiary university hospital., Patient(s): One thousand eight hundred one patients who underwent 2,524 cycles., Intervention(s): Multifollicular ovarian stimulation with recombinant FSH and GnRH antagonist for IVF-ICSI treatment., Main Outcome Measure(s): Incidence of OHSS in GnRH antagonist cycles, predictive value of E2, and number of follicles on the day of hCG for OHSS occurrence., Result(s): Fifty-three patients were hospitalized because of OHSS (2.1%; 95% confidence interval [CI]:1.6-2.8). Early OHSS presented in 31 patients (1.2%; 95% CI: 0.9-1.8), whereas the late type was a complication in 22 patients (0.9%; 95% CI: 0.5-1.3). Late OHSS cases compared with the early OHSS cases always occurred in a pregnancy cycle (100% vs. 40%); had higher probability of being severe (72.7% vs. 42%), and more often were related to a multiple pregnancy (40% vs. 0). Receiver operating characteristic curve analysis for several E2 concentrations and number of follicles with a diameter of > or =11 mm revealed that the predictive value of the optimal threshold of > or =13 follicles (85.5% sensitivity; 69% specificity) was statistically significantly superior to the optimal threshold of 2,560 ng/L for E2 concentrations (53% sensitivity, 77% specificity) in identifying patients at risk for OHSS. Considering that severe OHSS represents the most clinically significant pattern, the combination of a threshold of > or =18 follicles and/or E2 of > or =5,000 ng/L yields a 83% sensitivity rate with a specificity as high as 84% for the severe OHSS cases., Conclusion(s): Clinically significant OHSS still remains a limitation of multifollicular ovarian stimulation for IVF even with the use of GnRH antagonist protocols. The number of follicles can discriminate the patients who are at risk for developing OHSS, whereas E2 concentrations are less reliable for the purpose of prediction. There is more than ever an urgent need for alternative final oocyte maturation-triggering medication.

The major risks of exogenous gonadotrophin therapy for ovulation induction in a patient with polycystic ovaries (PCO) are multiple pregnancies and ovarian hyperstimulation syndrome (OHSS). This case report describes a 23-year-old patient, who was referred to the Centre for Reproductive Medicine in Brussels because of a high risk of developing OHSS and rising LH following ovulation induction with a low-dose step-up protocol using gonadotrophins. After counselling the patient, the decision was made to perform a rescue IVF cycle. The patient was first coasted with 0.25 mg ganirelix; the serum oestradiol concentrations decreased and the LH peak was successfully suppressed. No OHSS occurred. An ongoing twin pregnancy was achieved after the transfer of two embryos. This case report demonstrates the feasibility of coasting with LH-releasing hormone (LHRH) antagonists (0.25 mg ganirelix) and the usefulness of the antagonists for ovulation induction cycles in patients who need rescue IVF.

Study Question: What is the risk of developing intracavitary fluid (ICF) during ovarian stimulation in patients with an isthmocele after previous caesarean section (CS) delivery?Summary Answer: In patients with an existing isthmocele, the risk of developing ICF during hormonal stimulation for IVF is almost 40%; therefore, special attention has to be paid to exclude fluid accumulation during stimulation and particularly at the time of transfer, in which case the reproductive outcomes of frozen embryo transfer (FET) cycles appear to be uncompromised.What Is Known Already: Lately, there is an increasing focus on the long-term impact of CS delivery on the health and future fertility of the mother. Development of an isthmocele is one of the sequelae of a CS delivery. The presence of ICF in combination with an isthmocele has been described previously, and the adverse effect of endometrial fluid on implantation is well recognised by reproductive medicine specialists. Accumulation of ICF has been previously described in patients with hydrosalpinx, less commonly in patients with polycystic ovary syndrome undergoing ovarian stimulation for IVF/ICSI, and even in some patients without any identifiable reason. Assisted reproductive techniques (ARTs) are a means to overcome infertility. Reproductive medicine specialists commonly see patients with secondary infertility with a history of having had one or more previous CS and with ultrasound confirmation of an isthmocele. However, the available data pertaining to the prevalence of intracavitary fluid during ovarian stimulation in patients with ultrasound confirmation of an isthmocele is limited. Furthermore, data on the influence of ICF in a stimulated cycle on the ART outcome of a subsequent FET cycle is scarce and merits further studies.Study Design, Size, Duration: A prospective observational exploratory study was performed in IVI Middle East Fertility Clinic, Abu Dhabi, from June 2018 to March 2019, and retrospective analysis of the reproductive outcomes was performed until July 2019.Participants/materials, Setting, Methods: Patients with secondary infertility, defined as a minimum of 1 year of infertility after a previous successful pregnancy, undergoing ovarian stimulation for IVF/ICSI and having a history of one or more previous CS with ultrasonographic visible isthmocele, were included (n = 103). Patients were monitored as a clinical routine with vaginal ultrasound examinations during ovarian stimulation for IVF/ICSI treatment. All patients included in the study were asked to complete a questionnaire regarding their previous obstetric history. Development of ICF was recorded as well as changes in the measurements of the isthmocele during the course of ovarian stimulation. Reproductive outcomes of FET cycles of the patients with an isthmocele were retrospectively compared to those of patients with infertility and without isthmocele in our clinic during the same time period.Main Results and the Role Of Chance: Patients with an existing isthmocele after previous CS have a risk of ~40% of developing ultrasonographic visible fluid in the endometrial cavity during the course of ovarian stimulation. Development of ICF was significantly correlated with the depth of the isthmocele on Day 2/3 (P = 0.038) and on the day of trigger (-1/-2 days) (P = 0.049), circumference of the isthmocele on the day of trigger (-1/-2 days) (P = 0.040), distance from the C-scar to the external os (P = 0.036), number of children delivered (P = 0.047) and number of previous CS (P = 0.035). There was a statistically significant increase in the parameters related to the size of the isthmocele during ovarian stimulation. No significant differences in the reproductive outcome (pregnancy rate and rates of biochemical and ectopic pregnancies, miscarriages and ongoing/delivered pregnancies) after FET were found between the patients with and without an isthmocele, when ICF was excluded prior to embryo transfer procedure.Large-scale Data: NA.Limitations, Reasons For Caution: This study was not primarily designed to investigate the causes of ICF during ovarian stimulation or to evaluate the reproductive outcomes. Further, the small number of reported reproductive outcomes may be seen as a limitation.Wider Implications Of the Findings: The data highlights the need for an increased awareness on the part of reproductive medicine specialists towards the potentially adverse impact of an isthmocele on ART treatment, as there is a potential to develop intracavitary fluid during ovarian stimulation for IVF. The increase in the circumference of the isthmocele may increase embryo transfer difficulty.Study Funding/competing Interest(s): No funding of the study has to be reported. The authors have no competing interests.Trial Registration Number: This prospective study was registered with clinicaltrials.gov. under the number NCT03518385. [ABSTRACT FROM AUTHOR]