Cyclic Hormone Replacement Therapy Research Articles

Improving pregnancy outcomes in patients with recurrent implantation failure: The power of RNA-seq-based endometrial receptivity testing.

To evaluate whether RNA-seq-based endometrial receptivity testing (rsERT) can improve pregnancy outcomes in personalized frozen-thawed embryo transfer (pFET) during hormone replacement therapy (HRT) cycles among patients with recurrent implantation failure (RIF). We conducted a retrospective cohort study involving 98 RIF patients undergoing HRT for FET. The experimental group consisted of 58 patients who underwent pFET after rsERT, while the control group included 40 patients who refused rsERT and underwent conventional ET. We recorded and examined the subsequent pregnancy outcomes from all cycles. The results of rsERT revealed that 67.24% of the experimental group were out of the "window of implantation" (WOI), with all cases showing a delay. The HCG-positive rate, implantation rate, and clinical pregnancy rate (CPR) in the experimental group were significantly higher than those in the control group, at 75.86% versus 50.00% (P = .030), 56.38% versus 31.43% (P = .002), and 68.97% versus 47.50% (P = .033), respectively. Our study demonstrated that utilizing rsERT technology to guide pFET in HRT cycles significantly enhances implantation and CPRs in RIF patients. Importantly, our findings confirm the effectiveness of rsERT technology and establish a scientific rationale for personalized reproductive medical interventions.

Tailor-made embryo transfer considering embryonic developmental speed to overcome the dilemma of personalized embryo transfer

Research QuestionDoes tailor-made embryo transfer (TmET), timed with respect to embryonic developmental speed, affect pregnancy outcomes in patients with recurrent implantation failure? DesignAmong 741 patients identified as receptive through endometrial receptivity testing, the clinical pregnancy rates and live birth rates were retrospectively compared between those who underwent standard personalized embryo transfer and those who underwent TmET in hormone replacement therapy cycles. Personalized embryo transfer was performed according to endometrial receptivity test results (standard personalized embryo transfer group) or considering embryonic developmental speed (TmET group). For TmET, the expansion grade of warmed blastocysts was estimated based on each patient's previous embryonic developmental pattern. The embryo transfer days were set so that estimated blastocyst grades 3, 4, 5 and 6 were transferred on days P+5, P+5.5, P+6.0 and P+6.5, respectively. ResultsIn a propensity score matching analysis, the clinical pregnancy rate was significantly higher in the TmET group than the standard personalized embryo transfer group (P = 0.014), whereas the live birth rates were similar between the two groups (P = 0.65). In a subgroup analysis with euploid embryo transfers, the clinical pregnancy rate was significantly higher in the TmET group than the standard personalized embryo transfer group, although there was no difference in live birth rate between the two groups (P = 0.045 and P = 0.057, respectively). ConclusionsFor patients experiencing recurrent implantation failure and identified as receptive through endometrial receptivity testing, subsequent TmET strategies may further enhance pregnancy outcomes.

Improvement of early miscarriage rates in women with adenomyosis via oxytocin receptor antagonist during frozen embryo transfer-a propensity score-matched study

BackgroundDysfunctional uterine peristalsis seems to play a pivotal role in hindering embryo implantation among women diagnosed with adenomyosis. This research aims to investigate whether administering an oxytocin receptor antagonist during a frozen embryo transfer (FET) cycle using a hormone replacement therapy (HRT) protocol can enhance in vitro fertilization (IVF) outcomes for infertile women affected by adenomyosis.MethodsBetween January 2018 and June 2022, our reproductive center conducted IVF-FET HRT cycles for infertile women diagnosed with adenomyosis. Propensity score matching was employed to select matched subjects between the two groups in a 1:1 ratio. Following this, 168 women received an oxytocin receptor antagonist during FET, constituting the study group, while the matched 168 women underwent FET without this antagonist, forming the control group. We conducted comparative analyses of baseline and cycle characteristics between the two groups, along with additional subgroup analyses.ResultsThe study group exhibited notably lower rates of early miscarriage compared to the control group, although there were no significant differences in clinical pregnancy rates, ongoing pregnancy rates, and live birth rates between the two groups. Multivariate analysis revealed a negative correlation between the use of oxytocin receptor antagonists and early miscarriage rates in women with adenomyosis. Subgroup analyses, categorized by age, infertility types, and embryo transfer day, showed a substantial decrease in early miscarriage rates within specific subgroups: women aged ≥ 37 years, those with secondary infertility, and individuals undergoing day 3 embryo transfers in the study group compared to the control group. Furthermore, subgroup analysis based on adenomyosis types indicated significantly higher clinical pregnancy rates, ongoing pregnancy rates and live birth rates in the study group compared to the control group among women with diffuse adenomyosis.ConclusionsAdministering an oxytocin receptor antagonist during FET may reduce the early miscarriage rates in women with adenomyosis.

P-445 High serum estradiol on the day of frozen blastocyst transfer is associated with higher early miscarriage rates in hormonal replacement therapy cycles using transdermal estrogens

Abstract Study question Do serum estradiol(E2) levels on the day of frozen blastocyst transfer(FBT) affect the live birth rate (LBR) in hormonal replacement therapy(HRT) cycles using transdermal estrogens? Summary answer E2 levels ≥ 313 pg/mL on the day of FBT are associated with increased early miscarriage rates, but no significant impact on LBR. What is known already E2 plays a crucial role in endometrial receptivity during the periconceptional period and a massive role in placentation. However, the impact of serum E2 levels measured around the time of a FBT in HRT cycles outcomes remains controversial, with some studies showing a detrimental impact of high levels, and others underlining no difference. To this date, there is no study focusing on HRT cycles with transdermal estrogens only, though it is the safest way of estrogen administration regarding thrombo-embolic complications. Study design, size, duration Observational cohort study with 2364 patients undergoing HRT-FBT cycles at a university hospital, between January 2019 and December 2022. Women were only included once during the study period. Participants/materials, setting, methods Patients undergoing single autologous FBT under HRT using transdermal estrogens and vaginal micronized progesterone. The serum E2 level was measured in the morning of the FBT, in a single laboratory. The primary outcome was the LBR, secondary outcomes included clinical pregnancy rates, early miscarriage rates(EMR), and obstetrical outcomes. Patients were divided into three groups based on the 25th and the 75th percentiles of E2 levels and compared using univariate and multivariate logistic regression models. Main results and the role of chance A total of 2364 patients were divided into 3 groups: group A < 122 pg/mL (n = 590), group B 122-312 pg/mL (n = 1184), and group C ≥ 313 pg/mL (n = 590). Mean serum E2 level on the day of FBT was 247.8 pg/mL ± 209.01 pg/ml. The LBR was 32.0% (756/2364), and the early miscarriage rate was 26.3% (280/1075) in the overall population. Multivariate logistic regression showed a negative impact of high E2 levels (≥ 313 pg/mL) on EMR: an increase in the EMR was noted between group C and referent group B (30.3% versus 24.6%, OR 1.5 95%CI (1.06-2.17)). However, no significant impact of E2 levels was noted regarding the LBR (group C vs group B, adjusted OR 0.9 95%CI (0.69-1.10)), the clinical pregnancy rates, or the obstetrical outcomes (birthweight and term of delivery Limitations, reasons for caution The main limitation of our study is linked to its observational design. Extrapolation of our results to other laboratories, or other routes and/or doses of administering estrogens also needs to be validated. Wider implications of the findings Limiting high serum E2 levels on the day of FBT in HRT cycles may improve ART outcomes. Further studies are needed to evaluate if modifications of estrogen doses may improve pregnancy chances, in an approach to individualize the management of ART patients. Trial registration number not applicable

P-286 Comparative study of frozen-thawed embryo transfer with modified natural cycle versus HRT cycle in previously cancelled true natural cycle patients

Abstract Study question Is there any difference in outcome of frozen embryo transfer(FET) between hormone replacement therapy(HRT) and modified natural cycle(MNC) in previously cancelled true natural cycle patients Summary answer In patients with previous history of cancelled true natural cycle, MNC results in higher clinical pregnancy rates after FET, when compared to HRT cycle What is known already Preparation of endometrium lays down the foundation for conception and subsequent successful pregnancy.There has been a plethora of endometrial preparation protocols described in the literature. The established protocols are true natural cycle,MNC with or without luteal phase support(LPS) and HRT cycle with or without gonadotrophin releasing hormone agonist(GnRha) suppression. Nevertheless,there is no consensus on protocol which may provide the best outcome in patients who have had cancelled true natural cycle.In such situations,HRT cycle may be considered as an easy option as the cancellation rate is low.However,HRT treatment is known for higher early pregnancy and obstetric complications,compared to MNC Study design, size, duration Prospective observational study,where 155 patients undergoing FET who had minimum one true natural cycle cancellation were recruited.They were divided into group A undergoing HRT cycle(n = 77) and group B for MNC cycle(n = 78).The study was conducted in a fertility unit over six months from June-November 2023.Primary outcome measures were serum betaHCG estimation and ultrasonographic documentation of intrauterine pregnancy.Results were analysed using statistical software SPSS version25 and p value of less than 0.05 was considered statistically significant Participants/materials, setting, methods HRT patients received injectable GnRha 3.75 mg on day21 of previous cycle.Oral estradiol valerate 6mg daily started on day2 of menses. When ET was minimum 7mm, luteal phase support(LPS) was started with daily oral and vaginal progesterone(30mg and 600mcg respectively),followed by FET. MNC patients received Letrozole 5mg daily from day 2-6 of menstruation.rhCG 250mcg was given subcutaneously,when ET was at least 7mm,dominant follicle 16-18mm and progesterone(P4) less than 1ng/ml.LPS(vaginal progesterone600mcg) was started 36hours after rHCG,followed by FET Main results and the role of chance Mean ET in MNC group was 8.92mm ± SD1.38, which was higher than HRT group (8.31 mm ± SD0.89). This difference was statistically significant with a p value of 0.014.Serum beta HCG estimation was done 2weeks after FET. In HRT group beta HCG was positive in 41 out of 77(53.25%) and in MNC group positivity was higher being 48 out of 78(61.54%). However, this difference was not statistically significant. Transvaginal ultrasonography(TVS) was done to confirm intrauterine pregnancy 2weeks after beta HCG assay. Clinical pregnancy rate(CPR) was higher in MNC group with 32 out of 78(41.03%),compared to 18 out of 77(23.38%) in HRT group. This difference is statistically significant with p value of 0.019 Limitations, reasons for caution Relatively small population in this study may be the reason for caution to interpret the statistical data. Study with higher numbers may bring about more robust conclusions Wider implications of the findings Patients with failed true natural cycles may be considered for modified natural cycle(MNC) stimulation for FET, without attempt of another true natural cycle stimulation Trial registration number NOT APPLICABLE

P-613 Natural cycles monitoring for frozen embryo transfers: is it beneficial to start immediately after ovarian stimulation?

Abstract Study question Are there more advantages in performing frozen embryo transfer (FET) immediately after ovarian stimulation or in delaying it by at least one menstruation? Summary answer In natural cycles, timing of frozen embryo transfer does not affect clinical pregnancy rates, but immediate transfer is associated with higher rates of cycle cancellation. What is known already In order to achieve a reduced time to pregnancy and avoid additional stress for the couple, some Centers initiate FETs immediately, i.e. on the first menstrual cycle after ovarian stimulation. However, the detrimental effect of hormonal stimulation on ovarian function and endometrial receptivity may persist in the following cycle and immediate FETs may increase the possibility of cycle cancellation and reduce pregnancy rate. Available evidence on this subject, mainly focused on endometrial preparation with hormonal replacement therapy (HRT), showed contrasting results. Moreover, studies on FETs performed on natural cycles are lacking. Study design, size, duration This is a retrospective study conducted at the Infertility Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, Italy. A large amount of single FETs, performed between 2014 and 2021, was considered and was then divided in two groups according to their timing (immediate or delayed). The primary outcome was to assess the clinical pregnancy rate (CPR); secondary outcomes were live birth rate (LBR) and the cycle cancellation rate. Participants/materials, setting, methods True natural cycles (T-NC) and modified cycles with the use of triggered ovulation (M-NC) protocols for endometrial preparation were pursued in women with regular menses; otherwise, HRT was used. Immediate FET was defined when performed on the first menstruation following ovarian stimulation (i.e. withdrawal bleeding occurring after ovarian stimulation or after a failed fresh embryo transfer). Delayed FETs included those performed after at least two menstruations. Only the first transfer after ovarian stimulation was considered. Main results and the role of chance A total of 5,765 FET cycles were included in the study. FET cycles were achieved through T-NC in 4,477 cases (78% of all FETs), of which 364 were immediate and 4,113 were delayed. M-NC cycles accounted for 1% of the total amount of FETs and HRT protocols were pursued in 11% of cases. The analysis showed no impact of FET timing on CPR both in the whole cohort and in the subgroups based on different endometrial preparation protocols. Focusing on T-NC cycles, the CPR in the immediate group was comparable to that of the postponed group (29 vs. 32% respectively, OR 0.90 [95% CI 0.71 - 1.14]). On the other hand, LBR in T-NC cycles was significantly lower in the immediate group than in the delayed group (20% vs. 25% respectively, OR 0.74 [95% CI 0.56 - 0.96]). Consequently, immediate FETs resulted to be associated with a significantly higher rate of pregnancy loss (31% vs. 21% respectively, p = 0.03). Furthermore, cycle cancellation occurred more frequently in the immediate T-NC group, compared with the delayed group (18% vs. 12% respectively, p = 0.003). Similar results were observed in HRT cycles (15% in immediate FETs vs. 7% in delayed FETs, p = 0.08). Limitations, reasons for caution The retrospective nature of this study involves a risk of selection bias. Moreover, the reason for cycle cancellation was not always available; thus, these data were not included in the analysis. Lastly, these outcomes are only applicable to a similar cohort, that is Centers following a non-elective freeze-all policy. Wider implications of the findings This is the largest investigation on T-NC FETs and is among the very few studies providing separate results on different endometrial preparation protocols. Evidence from this study is in line with some previous retrospective analyses and in contrast with others. Thus, randomized controlled trials are needed to confirm these results. Trial registration number not applicable

P-659 Letrozole versus hormone replacement therapy for endometrial preparation in frozen-thawed embryo transfer cycles: a systematic review and meta-analysis

Abstract Study question Is the probability of pregnancy different when letrozole as compared with hormone replacement therapy (HRT) is used for endometrial preparation in frozen-thawed embryo transfer(FRET) cycles? Summary answer Α significantly higher probability of pregnancy is present when letrozole as compared with HRT is used for endometrial preparation in FRET cycles. What is known already Endometrial preparation with HRT has been a popular treatment during FRET cycles, mainly due to its convenience in cycle programming and its efficacy regarding pregnancy rates. However, recent data, focusing on obstetric outcomes after FRET, have highlighted the importance of corpus luteum (CL), favouring the adoption of strategies that lead to CL development. This is feasible either using a natural cycle or ovarian stimulation with gonadotrophins, clomiphene citrate or letrozole. Although a CL is present in letrozole stimulated cycles, whether the probability of pregnancy is maintained as compared to endometrial preparation with HRT has not yet been sufficiently elucidated. Study design, size, duration A systematic review and meta-analysis was performed aiming to identify randomized clinical trials (RCTs) comparing letrozole versus HRT in women undergoing endometrial preparation for FRET, irrespective of the type of infertility. For this purpose, a literature search was carried out until January 2024 in PubMed, Scopus, EmBase and CENTRAL. The primary outcome measure was live birth rate, while clinical pregnancy rate, ongoing pregnancy rate, endometrial thickness and miscarriage rate were evaluated as secondary outcomes. Participants/materials, setting, methods Citation, demographic, methodological and clinical data were extracted independently by two reviewers. Quality was assessed using the RoB2 Tool by Cochrane. Statistical heterogeneity was assessed by I2. Meta-analysis was performed using the random and fixed effects model depending on the presence or not of significant statistical or clinical heterogeneity. All results were combined using the intention-to-treat principle. Results are reported as relative risk (RR) or weighted mean difference (WMD) with 95% confidence interval (CI). Main results and the role of chance Four RCTs (n = 1242) were identified, published between 2014 and 2023. All of them were deemed as of high risk of bias. The number of patients included in these studies ranged from 163 to 713 patients. Letrozole was administered at doses of 2.5-5mg/day from day 2-3 of the menstrual cycle for 5 days, whereas in HRT cycles, estradiol valerate was administered at doses of 4-8mg/day from day 2-3 of the menstrual cycle. A significantly higher live birth rate was observed using letrozole for endometrial preparation as compared to HRT in women undergoing FRET (RR: 1.34, 95% CI:1.12 to 1.59; fixed effects model; heterogeneity: I2:0%; two studies, 883 patients). Similar differences between letrozole and HRT were also present regarding clinical pregnancy rate (RR: 1.23, 95% CI:1.08 to 1.39; fixed effects model; heterogeneity: I2:0%; four studies, 1240 patients) or ongoing pregnancy rate (RR:1.48, 95% CI:1.04 to 2.12; single study, 190 patients). No significant differences were observed using letrozole for endometrial preparation as compared to HRT regarding either miscarriage rate (RR:0.70, 95% CI:0.46 to 1.07; fixed effects model; heterogeneity: I2:0%; four studies, 1240 patients) or endometrial thickness (WMD:+0.09 mm, 95% CI: -0.86 to + 1.03; random effects model; heterogeneity: I2: 98.1%; three studies, 1070 patients). Limitations, reasons for caution This meta-analysis included a limited number of RCTs, which were generally of high risk of bias due to methodological limitations. Moreover, a considerable heterogeneity was present regarding the dosage of the medications administered and duration of treatment, warranting a cautious interpretation of the results obtained. Wider implications of the findings Endometrial preparation with letrozole seems to be preferable compared to HRT for FRET. In addition to an increased probability of pregnancy observed in the present meta-analysis, letrozole ensures the presence of CL which has been associated with a lower probability of hypertensive disorders of pregnancy. Trial registration number PROSPERO: CRD42024501838

P-446 Personalization of the euploid embryo transfer guided by the endometrial receptivity analysis in patients with >1 previous failed transfer

Abstract Study question Does personalized embryo transfer (pET) guided by Endometrial Receptivity Analysis (ERA) increase reproductive outcome in patients with >1 previous failed transfer of an euploid embryo? Summary answer pET guided by ERA resulted in a significantly higher Pregnancy Rate (PR), Ongoing Pregnancy Rate (OGPR) and Live Birth Rate (LBR) versus standard embryo transfer. What is known already pET consists of synchronizing embryo transfer with the optimal endometrial receptivity status by the transcriptomics identification of the personalized window of implantation (WOI). Euploid transfers improve reproductive outcome controlling the embryo contribution in the implantation. Controversial results have been published regarding the clinical usefulness of pET in a range of clinical indications. Here we present data from patients with >1 previous failed embryo transfer (ET) in a subsequent euploid ET. Study design, size, duration Multicenter retrospective study involving 270 patients with at least one previous implantation failure between 2017 and 2021. These patients were divided into two groups according to their subsequent transfer: study group (pET guided by ERA) (n = 200), and control group (standard transfer) (n = 70). All the ET were done in Hormone Replacement Therapy cycles (HRT). PR, OGPR and LBR were compared between the two groups. Participants/materials, setting, methods Age, body mass index, previous failed attempts, inner cell mass (ICM) and trophectoderm (TE) quality of the transferred embryos were compared between the groups. Study group had an ERA result as standard WOI or displaced WOI and pET of an euploid embryo was carried out in a subsequent HRT cycle (following the same conditions and recommendations provided by ERA). Wilcoxon rank sum test was applied to quantitative comparations. Chi-square test was done for categorical variables. Main results and the role of chance Clinical results in terms of PR, OGPR and LBR were significantly higher when pET guided by ERA was performed when compared to the non-ERA group. PR was 65% (130/200) in pET versus 37.14% (26/70) in control group (P = 0.000088); OGPR was 49% (98/200) in pET versus 27.14% (19/70) in control group (P = 0.0024); and LBR was 48.20% (95/197) in pET versus 26.09% (18/69) in control group (P = 0.0022). Control and demographics variables did not show differences between the two groups: Age: 35.27 ± 3.86 versus 35.77 ± 3.35 (P = 0.31); BMI: 22.99 ± 3.02 versus 23.25 ± 3.72 (P = 0.52); Previous failed attempts: 2.42 ±1.78 versus 2.17 ±1.81 (P = 0.32); P values where 0.1 and 0.36 for comparisons of optimal quality of ICM and TE, respectively. Limitations, reasons for caution This is a retrospective study, having the limitations of its nature. Wider implications of the findings These results show that pET guided by the ERA test of an euploid embryo significantly increases the reproductive outcomes (PR, OGPR and LBR) in patients with ≥1 previous failed transfer compared to the standard frozen ET. Trial registration number Hospital Clínico de Valencia Ethic Committee approval nº. 2021/018.

O-146 Serum Progesterone levels do not differ between patients with endometriosis and unaffected patients who conceive after Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) cycles

Abstract Study question Do endometriosis women who achieve a live birth (LB) after Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) have different transfer-day progesterone levels than controls? Summary answer In women achieving a LB after HRT-FET, serum progesterone levels on the day of the transfer did not differ between endometriosis and unaffected patients. What is known already In HRT-FET, several studies have highlighted the correlation between serum progesterone levels at the time of frozen embryo transfer and LB rates. In the pathophysiology of endometriosis, progesterone resistance is typically described in the eutopic endometrium. This has led to the hypothesis that women with endometriosis may require higher progesterone levels to achieve a LB, especially in HRT-FET cycles without a corpus luteum. Study design, size, duration We conducted an observational cohort study at the university-based reproductive medicine center of our institution, focusing on women who underwent a single autologous frozen blastocyst transfer after HRT using exogenous estradiol and micronized vaginal progesterone for endometrial preparation between January 2019 and December 2021. Women were included only once during the study period. Serum progesterone levels were measured on the morning of the FET by a single laboratory. Participants/materials, setting, methods Patients were divided into groups based on whether they had endometriosis or not and whether they achieved a LB. The diagnosis of endometriosis was based on published imaging criteria (transvaginal sonography/magnetic resonance imaging) and/or confirmed histology. The primary outcome was progesterone levels on the day of the HRT-FET leading to a LB in patients with endometriosis compared to unaffected women. Subgroup analyses were performed based on the presence of deep infiltrating endometriosis or adenomyosis. Main results and the role of chance A total of 1784 patients were included. The mean age of the women was 35.1 ± 4.1 years. Five hundred and sixty women had endometriosis, while 1224 did not. 179/560 (32.0%) with endometriosis and 381/1224 (31.2%) without endometriosis achieved a LB. Among women who achieved a LB after HRT-FET, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (13.6 ± 4.3 ng/mL versus 13.2 ± 4.4 ng/mL, respectively; p = 0.302). In the subgroup of women with deep infiltrating endometriosis (n = 142) and adenomyosis (n = 100), the mean progesterone level was 13.1 ± 4.1 ng/mL and 12.6 ± 3.7 ng/mL, respectively, with no significant difference compared to endometriosis-free patients. After adjustment for BMI, parity, duration of infertility, and tobacco use, neither the presence of endometriosis (coefficient 0.38; 95% CI -0.63 to 1.40; p = 0.457) nor the presence of adenomyosis (coefficient 0.97; 95%CI -0.24 to 2.19; p = 0.114) was associated with the progesterone level on the day of HRT-FET. Among women who did not conceive, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (p = 0.709). Limitations, reasons for caution The primary limitation of our study is associated with its observational design. Extrapolating our results to other laboratories or different routes and/or dosages of administering progesterone also requires validation. Wider implications of the findings This study shows that patients diagnosed with endometriosis do not require higher progesterone levels on the day of a frozen blastocyst transfer to achieve a LB in hormonal replacement therapy cycles. Trial registration number NA

P-651 Neither high nor low serum progesterone levels affect clinical outcomes in Artificially prepared-frozen embryo transfer cycles using intramuscular progesterone

Abstract Study question Does serum progesterone level on the day of frozen-thawed embryo-transfer (FET) correlate with the likelihood of achieving pregnancy in artificial FET cycles utilizing intramuscular progesterone? Summary answer Serum progesterone levels on the day of FET do not correlate with the likelihood of achieving a pregnancy in artificial FET cycles employing intramuscular progesterone. What is known already There is scientific evidence suggesting that serum progesterone levels under a specific cutoff level on the day of FET significantly decrease the clinical outcomes in patients under artificial endometrial preparation using micronized vaginal progesterone. However, no substantial evidence exists in patients under artificial endometrial preparation using intramuscular progesterone. Study design, size, duration This prospective cohort study was conducted from February to December 2022 and enrolled 353 patients undergoing FET in hormone replacement therapy (HRT) cycles using intramuscular progesterone until the day of embryo transfer. Participants/materials, setting, methods The study included women aged 21-40 years old undergoing FET, triple layer endometrium >7mm, and ≥2 high-quality embryos (Gardner’s grade 3/4/5/AA/AB/BA/BB) available. Exclusion criteria included patients with uncontrolled diabetes, hypertension, heart disease, known autoimmune diseases, uterine infertility factor, severe male factor infertility (total sperm count < 5 million/ml), and cases requiring surgically retrieved sperm for ICSI. Main results and the role of chance The cohort had an average age of 32.09 ± 4.19 years, BMI of 24.70 ± 3.07 kg/m², and endometrial thickness of 8.87 ± 1.06 mm on the day of embryo transfer. The mean serum progesterone level was 31.36 ± 13.78 ng/ml. Participants were categorized into quartiles based on serum progesterone levels. :Q1 (<21.7 ng/ml), Q2 (21.7-28.1 ng/ml), Q3 (28.2-40.0 ng/ml), and Q4 (≥40.0 ng/ml). No significant difference in Clinical Pregnancy Rate (CPR), Ongoing Pregnancy Rates (OPR), and first-trimester miscarriage rates were observed across quartiles. The OPRs according to serum progesterone quartiles were: Q1: 57.5%; Q2: 62.6%; Q3: 59.6%; Q4:62.8%, with no statistical difference among the groups. Binary logistic regression revealed no statistically significant differences in clinical pregnancy and ongoing odds among the quartiles. Limitations, reasons for caution Although a prospective study, its relatively small sample size may affect the results’ robustness and generalizability. Wider implications of the findings These findings suggest that when using intramuscular progesterone before embryo transfer in FET under HRT, serum progesterone testing may not be necessary before embryo transfer, as progesterone levels have no impact on clinical outcomes in this group of patients. Trial registration number CTRI/2022/11/046995

P-162 Embryo transfer impact: a comprehensive national cohort analysis comparing maternal outcomes across varied embryo stages in fresh and frozen transfers

Abstract Study question What is the ideal choice between fresh and frozen embryos transfer, and should the transfer be done at the cleavage or blastocyst stage? Summary answer This study highlights the clinical pregnancy and live birth superiority of frozen embryo transfer in blastocysts but not in cleavage stage embryos. What is known already Frozen embryo transfer not only improves reproductive outcomes by increasing the chances of live birth and clinical pregnancy but also enhances safety by reducing the risks of OHSS and multiple pregnancies. Due to the consistent findings, there has been a growing discussion in recent years about whether it is advisable to adopt elective frozen embryo transfer as the standard practice. Study design, size, duration In this retrospective cohort study conducted in Taiwan, a comprehensive dataset from the national assisted reproductive technology (ART) database was utilized, covering the period from January 1st, 2013, to December 31st, 2017. The final cohort study encompassed eligible 51762 female participants who had undergone ART and embryo transfer. Pregnancy outcomes and maternal complications during the follow-up were assessed using the population registry dataset from January 1st, 2013, to December 31st, 2018. Participants/materials, setting, methods The study categorizes cases into groups based on whether they underwent fresh or frozen embryo transfers, with additional subgroups based on cleavage stage and blastocyst stage transfers. Exposure variables include clinical pregnancy rate, live birth rate, ovarian hyperstimulation syndrome (OHSS), pregnancy-induced hypertension, gestational diabetes mellitus (DM), placenta previa, placental abruption, and preterm premature rupture of membranes (PPROM). Main results and the role of chance For pregnancy outcomes, frozen blastocyst transfers exhibited higher rates of clinical pregnancy (OR 1.33, 95%CI 1.25-1.42) and live births (OR 1.27, 95%CI 1.19-1.36) when compared to fresh blastocyst transfers. However, frozen cleavage stage transfers had lower rates of clinical pregnancy (OR 0.73, 95%CI 0.69-0.77) and live births (OR 0.79, 95%CI 0.74-0.84) compared to fresh cleavage stage transfers. For maternal complications, frozen embryo transfers were associated with reduced risks of OHSS (OR 0.02, 95%CI 0.02-0.03 for blastocyst and OR 0.05, 95%CI 0.03-0.09 for cleavage stage) compared to fresh embryo transfers, but were linked to a higher risk of pregnancy-induced hypertension (OR 1.43, 95%CI 1.19-1.73 for blastocyst and OR 1.23, 95%CI 1.29-1.82 for cleavage stage). No significant differences were observed in the incidence of gestational DM and PPROM among the various transfer groups. Limitations, reasons for caution Our retrospective study design may not offer the same level of rigor as a randomized controlled trial. Furthermore, the reproductive database did not provide detailed information on specific endometrial preparation methods (such as hormone replacement therapy or natural cycle), which could potentially influence implantation outcomes. Wider implications of the findings The freeze-all strategy may not be suitable for universal application. When embryos can develop to the blastocyst stage, frozen embryo transfer is a favorable choice, but embryos can only develop to the cleavage stage, fresh embryo transfer becomes a more reasonable option. Trial registration number KMUHIRB-E(I)-20210222

P-293 Influence of the endometrial microbiota composition on the clinical outcomes of egg donation PGT-A cycles with controlled endometrial receptivity

Abstract Study question Does the endometrial microbiota composition and diversity influence embryo implantation and pregnancy evolution in assisted reproduction treatment (ART) cycles? Summary answer Endometrial microbiota composition influences ART success. Detection of endometrial pathogens is associated with poor outcomes whereas sterile endometria show the highest pregnancy and live-birth rates What is known already The endometrial microbiota has emerged as a possible influencing factor in the results of ART. Recent research suggests its impact on female reproductive health, particularly in patients with chronic endometritis (CE), where the presence of microbial pathogens associated with this condition has been linked to infertility. In turn, the bioregulatory role of species of Lactobacillus in this tissue has been explored, although its essentiality or benefit for female reproductive function continues to be topics of debate. Study design, size, duration This is a case-control retrospective study analysing for the first time the influence of the endometrial microbiota composition on the clinical outcomes of 220 women undergoing egg donation cycles with Preimplantation Genetic Testing for Aneuploidy (PGT-A) and controlled endometrial receptivity between March 2016 and April 2021 in IVF-Life Alicante (Spain). ART results after the transfer of a single euploid blastocyst in the WOI of patients with different endometrial microbiota profiles were analysed and compared. Participants/materials, setting, methods Presence of 18 microbial CE pathogens and 4 Lactobacillus species was determined by high-throughput qPCR (MicrobioMap®, iGLS) in endometrial samples obtained during the WOI of a hormone replacement therapy cycle. In all cases, PGT-A by next generation sequencing (NGS) (EmbryoMap, Vitrolife) and study of endometrial receptivity by gene expression analysis (ER Map, iGLS) were performed. Clinical outcomes (β-hCG+, β+ and live birth, LB) in relation to the endometrial microbiota profile were analysed and compared. Main results and the role of chance In the study, 31.8% of patientś endometria were identified without microbial detection, 40% exclusively with Lactobacillus, 13.2% with pathogens only, and 15% with both. Clinical results revealed significant differences in β+ rates among the groups (p < 0.05). The absence of microorganisms was associated with higher success rates (β + 72.9%), while the presence of pathogens significantly reduced pregnancy success (β + 41.4%). A similar trend was observed in LB rates, although it did not reach statistical significance (44.3% and 24.1%, respectively). The presence of Lactobacillus alongside pathogens improved clinical outcomes (β + 57.6% LB 48.5%). Interestingly, exclusive presence of Lactobacillus showed lower implantation rates than patients without microbial detection (β + 58%). These findings highlight the impact of microbial composition on the clinical outcomes of ART cycles, underlining the association between endometrial microbiota patterns and pregnancy success. Limitations, reasons for caution This study is constrained by its retrospective nature, emphasizing the need for further validation through randomized controlled trials, non-selection studies, or other investigative approaches to confirm the extent of any clinical benefits. Endometrial biopsies were obtained transcervically, while executed with utmost care, risk of contamination cannot be completely excluded. Wider implications of the findings The composition and diversity of the endometrial microbiota is key for ART success. A sterile endometrial environment offers optimal conditions for implantation and pregnancy. The study highlights the potential of Lactobacillus in counteracting the negative impact of pathogenic presence. Trial registration number not applicable

Progesterone levels do not differ between patients with or without endometriosis/adenomyosis both in those who conceive after hormone replacement therapy-frozen embryo transfer cycles and those who do not.

Do women with endometriosis who achieve a live birth (LB) after HRT-frozen embryo transfer (HRT-FET) have different progesterone levels on the day of transfer compared to unaffected women? In women achieving a LB after HRT-FET, serum progesterone levels on the day of the transfer did not differ between patients with endometriosis and unaffected patients. In HRT-FET, several studies have highlighted the correlation between serum progesterone levels at the time of FET and LB rates. In the pathophysiology of endometriosis, progesterone resistance is typically described in the eutopic endometrium. This has led to the hypothesis that women with endometriosis may require higher progesterone levels to achieve a LB, especially in HRT-FET cycles without a corpus luteum. We conducted an observational cohort study at the university-based reproductive medicine center of our institution, focusing on women who underwent a single autologous frozen blastocyst transfer after HRT using exogenous estradiol and micronized vaginal progesterone for endometrial preparation between January 2019 and December 2021. Women were included only once during the study period. Serum progesterone levels were measured on the morning of the FET by a single laboratory. Patients were divided into groups based on whether they had endometriosis or not and whether they achieved a LB. The diagnosis of endometriosis was based on published imaging criteria (transvaginal sonography/magnetic resonance imaging) and/or confirmed histology. The primary outcome was progesterone levels on the day of the HRT-FET leading to a LB in patients with endometriosis compared to unaffected women. Subgroup analyses were performed based on the presence of deep infiltrating endometriosis or adenomyosis. A total of 1784 patients were included. The mean age of the women was 35.1 ± 4.1 (SD) years. Five hundred and sixty women had endometriosis, while 1224 did not. About 179/560 (32.0%) with endometriosis and 381/1224 (31.2%) without endometriosis achieved a LB. Among women who achieved a LB after HRT-FET, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (13.6 ± 4.3 ng/ml vs 13.2 ± 4.4 ng/ml, respectively; P = 0.302). In the subgroup of women with deep infiltrating endometriosis (n = 142) and adenomyosis (n = 100), the mean progesterone level was 13.1 ± 4.1 ng/ml and 12.6 ± 3.7 ng/ml, respectively, with no significant difference compared to endometriosis-free patients. After adjusting for BMI, parity, duration of infertility, tobacco use, and geographic origin, neither the presence of endometriosis (coefficient 0.38; 95% CI: -0.63 to 1.40; P = 0.457) nor the presence of adenomyosis (coefficient 0.97; 95% CI: -0.24 to 2.19; P = 0.114) was associated with the progesterone level on the day of HRT-FET. Among women who did not conceive, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (P = 0.709). The primary limitation of our study is associated with its observational design. Extrapolating our results to other laboratories or different routes and/or dosages of administering progesterone also requires validation. This study shows that patients diagnosed with endometriosis do not require higher progesterone levels on the day of a frozen blastocyst transfer to achieve a LB in hormonal replacement therapy cycles. None declared. N/A.

Autologous platelet-rich plasma as a potential new approach in the endometrial response during in vitro fertilization cycle: A pilot study

Objectives: Infertility is a global health concern, affecting ~13% of couples. Despite assisted reproductive technology (ART) attempts, implantation failure occurs due to inadequate growth of the endometrium. Increasing endometrial thickness (ET) can be increased to improve the rate of pregnancy; implantation necessitates a minimum thickness of 7 mm. Platelet-rich plasma (PRP) is a recommended treatment approach for endometrium and ovarian infertility. This approach minimizes the potential of immunogenic reactions and disease transmission because PRP comes from an autologous source. The purpose of this study was to evaluate the efficacy of PRP intrauterine infusions during the in vitro fertilization (IVF) cycle in patients with thin endometrium. Material and Methods: Ten patients with primary infertility (age: 28–40 years) were chosen for intrauterine PRP infusion at the RiSSA IVF Center, Delhi. This study was carried out between June 2020 and January 2022 over a span of 18-month period. Intrauterine infusion of PRP was an additional procedure to hormone replacement therapy (HRT) treatment cycle. PRP was prepared by centrifugation process from autologous blood. On the 10th day of HRT cycle, 2 mL of PRP was infused into the uterine cavity. In each cycle, PRP infusion was administered 1–3 times if there was no increase in ET 72 hours later. Out of ten patients, four patients received a single infusion, two patients received two infusions, and four patients received three infusions. The embryos were transferred when the ET reached ≥7 mm. ET was measured at the uterine longitudinal axis at the thickest point. To determine ET, three measurements were made, and the average of those measures was noted. The primary outcome measure was ET, determined by transvaginal sonography, and the secondary outcome measure was clinical pregnancy following embryo transfer. Results: The mean increase in ET was 1.8–2.25 mm. In 8 (80%) patients, there was an increase of 7–7.5 mm in ET. ET thickness did not improve in 2 patients (20%), and it was <6 mm after three infusions of PRP. Further, of the eight patients who had embryo transfer and became pregnant, six patients had a clinical pregnancy with visible cardiac activity at 6 weeks, while two patients had a missed abortion in the first trimester. Six patients had a successful delivery. Conclusion: This study revealed that PRP could support endometrial growth, improving pregnancy outcomes in patients who have thin endometrium. PRP is a novel treatment option for endometrial thinning and poor response to IVF. The findings of the current pilot study support the need for large-scale, randomized, controlled trials in this field.

Intrauterine Infusion and Hysteroscopic Injection of Autologous Platelet-Rich Plasma for Patients with a Persistent Thin Endometrium: A Prospective Case-Control Study.

Objectives: To evaluate the effect of intrauterine infusion and hysteroscopic injection of autologous platelet-rich plasma (PRP) in patients with a persistent thin endometrium (EM) undergoing euploid frozen embryo transfer (EFET) cycles. Methods: This prospective case-control study enrolled 116 infertile women with thin EM (<7 mm) who underwent hormone replacement therapy (HRT) for EFET. These women had experienced at least one previous unsuccessful EFET cycle, which either resulted in the cancellation of the cycle or failure of pregnancy. A total of 55 women received an intrauterine infusion of PRP before FET, 38 received a hysteroscopic injection of PRP, and 23 received standard HRT treatment without PRP (control group). Only euploid embryos were transferred in these cycles. The primary outcomes were the implantation rate (IR) and clinical pregnancy rate (CPR) after EFET. Results: After receiving intrauterine infusion and hysteroscopic injection of PRP, 78.2% and 55.3% of patients, respectively, showed an EM thickness exceeding 7 mm, followed by embryo transfer. The hysteroscopic injection group demonstrated significantly higher IR (52%), a higher trend of CPR (52%), and a higher live birth rate (38%) than the control group (18%, 22%, and 4%). Conclusions: Intrauterine infusion and hysteroscopic injection of autologous PRP may be effective methods to increase EM thickness in HRT cycles. According to our results, both methods could increase EM thickness, while hysteroscopic injection appeared to provide more significant assistance in increasing IR, CPR, and live birth rate after EFET in patients with persistent thin EM.

Resistant ovary syndrome: Two case reports and a literature review of effective controlled ovarian stimulation in IVF.

Resistant ovary syndrome (ROS) represents a rare reproductive endocrine disorder that is predominantly associated with infertility, characterized by heightened endogenous gonadotropin levels in the presence of a normal ovarian reserve. Patients with ROS typically exhibit a poor response to exogenous gonadotropins during controlled ovarian stimulation (COS). Due to the absence of a universally accepted effective COS protocol, this study aims to contribute to the existing body of literature by detailing 2 successful pregnancies achieved through conventional in vitro fertilization (c-IVF) in patients with ROS, and through retrospective analysis, seeks to elucidate the factors contributing to the successful ovarian stimulation in these cases, with the ultimate goal of establishing clinical guidelines for ROS management. The central challenge addressed in this study pertains to the effective induction of oocyte maturation during c-IVF COS in ROS patients. The study focuses on 2 infertile women diagnosed with ROS who sought to conceive via c-IVF. The patients were subjected to a COS protocol involving pituitary downregulation followed by ovarian stimulation using recombinant follicle-stimulating hormone (r-FSH) and human menopausal gonadotropin (HMG), preceded by 3 cycles of hormone replacement therapy (HRT) pretreatment. The proposed protocol elicited a favorable ovarian response, culminating in the retrieval of numerous mature oocytes and the development of multiple viable embryos via c-IVF, ultimately leading to successful live births post-embryo transfer. Our study suggests that the outlined COS protocol may serve as a viable treatment option for ROS patients aspiring to conceive through c-IVF, thereby potentially expanding the therapeutic repertoire for this challenging condition.

Evaluating the Impact of Long-Term GnRH Agonist Therapy on Pregnancy Outcomes in Endometriosis-Associated Implantation Failure and Pregnancy Loss

Purpose This study aimed to investigate the efficacy of long-term gonadotropin-releasing hormone (GnRH) agonist therapy in preventing endometriosis progression and relieving symptoms, particularly on pregnancy outcomes during thawed embryo transfer in patients experiencing endometriosis and recurrent implantation failure or recurrent pregnancy loss. Methods In individuals with clinical endometriosis and a history of recurrent implantation failure or recurrent pregnancy loss, we conducted a comparative analysis of clinical outcomes between those undergoing long-term GnRH agonist treatment for symptom relief, such as menstrual pain, followed by embryo transfer using Hormone Replacement Therapy (HRT) cycle, and those undergoing embryo transfer using an HRT cycle without GnRH agonist treatment. The study examined various clinical outcomes between the two groups. Results The primary outcomes included live birth rate (LBR), miscarriage rate, biochemical pregnancy rate, and perinatal complications. The GnRH agonist group showed significantly higher LBR than the control group (37.50% vs. 13.04%; p=0.02). Multivariable logistic regression analysis, adjusted for age and gravidity, showed significantly higher LBR in the GnRH agonist group compared to the control group (odds ratio: 15.3; 95% confidence interval: 2.30, 102.00; p=0.005). Conclusions The findings of this study suggested that employing a GnRH agonist in the embryo transfer protocol is effective for patients with endometriosis experiencing recurrent implantation failure or recurrent pregnancy loss.

A retrospective comparative study of double cleavage-stage embryo transfer versus single blastocyst in frozen-thawed cycles

BackgroundThis retrospective study aimed to compare the outcomes of day 3 double embryo transfer (DET) with single blastocyst transfer (SBT) during frozen embryo transfer (FET) cycles. A total of 999 women below the age of 38 years who underwent FET at Malaysia’s KL Fertility and Gynaecology Centre from January 2019 to December 2021 were analyzed. Patients with autologous eggs were recruited in the study. All the eggs were inseminated by intracytoplasmic sperm injection. The embryos were vitrified on day 3 cleavage-stage or blastocyst stage with Cryotop® method. The FET was performed following natural cycle (NC), modified natural cycle (m-NC), or hormone replacement therapy (HRT) cycles. The NC and m-NC groups received oral dydrogesterone for luteal phase support.ResultsThere were no statistical differences in the rates of positive pregnancy, clinical pregnancy, and ongoing pregnancy between the two groups. However, implantation rates were significantly higher in the SBT group (50.1% versus 37.6%, p < 0.05). The day 3 DET group had significantly higher multiple pregnancy rates (28.7% versus 1.1%, p < 0.05). Subgroup analysis of embryo transfers performed following NC, m-NC, or HRT cycles showed similar results.ConclusionsThis study suggests that SBT is the better choice for embryo transfers as it had higher implantation rates and its pregnancy rates were similar to day 3 DET. The SBT also significantly reduced the incidence of multiple pregnancies without compromising pregnancy rates.

Перименопаузальные расстройства у женщин после COVID-19

Aim: to assess the health-related quality of life (HRQOL) of women with perimenopause after COVID-19 and to determine the possibilities of hormone replacement therapy (HRT) in the postcovid period. Patients and Methods: 96 female patients aged 45 to 54 years were examined. Group 1 consisted of 52 female patients who were being treated in a hospital for COVID-19 12–16 weeks before study. Group 2 (comparison group) consisted of 44 female patients without COVID-19. Further, HRT was performed in 21 female patients of group 1 without contraindications (subgroup 1A). HRT regimen: estradiol hemihydrate, 1.58 mg, transdermally sequestered and dydrogesterone, 10 mg, per os. In subgroup 1B, 31 female patients did not undergo HRT. All patients were examined, which included the following: survey, follow-up, hormone blood test and hemostasiogram. HRT efficacy was evaluated after 3 months. Results: group 1 had more significant neurovegetative, psychoemotional and metabolic disorders, as well as an increase in the frequency of menstrual disorders versus group 2. In group 1, 43/52 (82,7%) of the respondents experienced hot flashes, where 23/52 (44,2%) of female patients noted the first occurrence of hot flashes after suffering COVID-19. In group 2, 16/44 (36,3%) of patients were concerned about this symptom. In group 1, 42.3% (22/52) of patients reported menstrual disorders. In patients of subgroup 1A, the severity of neurovegetative, metabolic and psychoemotional disorders decreased after HRT versus those in subgroup 1B. Conclusion: in female patients who suffered moderate to severe COVID-19, perimenopausal disorders include more significant neurovegetative, psychoemotional and metabolic symptoms. Cyclic HRT using transdermal estrogens significantly improves the life quality of women, however, the unfavorable comorbid background observed may reduce the effect of hormone therapy KEYWORDS: perimenopause, menopausal syndrome, COVID-19, postcovid syndrome, modified Kuperman Index, hormone replacement therapy FOR CITATION: Irgasheva S.U., Nadirkhanova N.S., Azamkulova N.O. Perimenopausal disorders in women after COVID-19. Russian Journal of Woman and Child Health. 2024;7(2):110–115 (in Russ.). DOI: 10.32364/2618-8430-2024-7-2-4.

#384 : Effectiveness of Progesterone Monitoring and Rescue Protocol in Frozen Embryo Transfer Cycle

Background and aim: Hormonal monitoring impact on overall pregnancy rate in frozen embryo transfer (FET) cycles and hence progesterone supplement adjustments remain debatable in current literature. This study aims to investigate the effect of monitoring and follow-up of serum progesterone level on the day of FET, and progesterone supplement adjustments effects on pregnancy outcomes for FET in programmed hormonal replacement therapy cycles. Methods: In this study, all patients who were scheduled for FET had their progesterone (P4) and estradiol (E2) level assessed in the morning of FEM and if their P4 level was less than 10 ng/ml, intramuscular progesterone was given for 7-10 days since the day of FET to rescue the cycle. Results: In 2022, in Vinmec IVF center, there were in total 659 FET cycles, all was single blastocyst transfer and applied the mention protocol to rescue the cycle in case P4 level was less than 10 ng/ml. The chemical (62,87% vs 59.94%), clinical (56,68% vs 54,83%) and ongoing pregnancy rate (46,25% vs 45,17%) were comparable between the two group (with and without parenteral progesterone), P&lt;0,05. Conclusions: Monitor P4 level on the day of FET and use parenteral progesterone in case P4 level is less than 10 ng/ml could be an effective method to rescue the cycle and improve the outcome. Further studies are needed to draw a better conclusion and recommendation in this aspect.