Premature Progesterone Research Articles

The Effect of Progesterone Elevation on the Day of Trigger Administration: A Review of the Literature.

Since the advent of assisted reproductive technology, different variables have been shown to affect pregnancy outcomes. One of the most prevalent studied events is the premature rise in serum progesterone concentrations on the day of trigger administration during cycles of ovarian stimulation. This phenomenon, classically known as premature luteinization, has been observed significantly for decades and has been linked to adverse pregnancy outcomes and lower live birth rates. Ultimately, a quest to find a precise serum progesterone concentration cut-off value that can be effectively used to predict pregnancy outcomes prior to trigger administration is still underway. The purpose of the current research was to study the available literature on the relationship between serum progesterone on the day of trigger administration in controlled ovarian stimulation cycles used for IVF in an attempt to identify a cut-off serum progesterone concentration that can be used to effectively predict future pregnancy outcomes in fresh transfers. This study is a review of the literature and is based on information and data gathered from 36 published articles. The majority of the literature shows that a serum progesterone concentration cut-off of 1.5 ng/ml (4.77 nmol/L) can be used prior to trigger administration to effectively predict pregnancy outcomes. Premature progesterone elevation on the day or prior to the trigger administration is associated with adverse pregnancy outcomes in IVF cycles. Other factors such as follicle number, serum concentration of other hormones, and ovarian response to ovarian stimulation should also be considered to predict the success of IVF protocols.

Premature Progesterone Rise Is Associated with Higher Cumulative Live Birth Rate with Freeze-All Strategy.

Background/Objectives: This paper undertakes an investigation into the implications of premature progesterone rise (PPR) on pregnancy outcomes in freeze-all strategy cycles. Methods: A retrospective cohort study encompassing 675 IVF/ICSI cycles using a freeze-all strategy was enrolled. The cycles were categorized into two groups based on serum progesterone levels at the time of hCG administration: 526 cycles had levels below 1.5 ng/mL, while 149 cycles had levels equal to or above 1.5 ng/mL. Results: The findings revealed a significantly higher number of mature follicles and retrieved oocytes in patients with PPR across all AMH categories. Multiple analyses revealed factors influencing PPR, including the duration of induction and the number of retrieved oocytes. Within the same oocyte retrieval number group, patients with PPR demonstrated non-inferior pregnancy outcomes compared to non-PPR patients. Upon adjustment for age, AMH, and total follicle-stimulating hormone (FSH) dosage, PPR maintained a positive correlation with the cumulative live birth rate (LBR). Conclusions: The study showed that PPR correlates with an increase in retrieved oocytes while maintaining similar embryo quality and oocyte retrieval rates and results in a higher cumulative LBR.

High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2ng/mL or 3-day area under the curve > 4.5ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol 4000pg/mL had a greater likelihood of GBO compared to cycles < 1000pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000pg/mL versus 1000-1999pg/mL and 1000-1999pg/mL versus 2000-2999pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999pg/mL versus 3000-3999pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999pg/mL versus 4000pg/mL, aRR 0.96, 95% CI 0.9-1.04). In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

From patient classification to optimized treatment in ART: the AMPLITUDE Delphi consensus.

A Delphi consensus was performed to evaluate expert opinions on the management of key aspects of ovarian stimulation. A Scientific Committee developed eleven statements for patient profiles corresponding to predicted ovarian responses (low, normal, and high) based on antral follicle count (AFC) and anti-Müllerian hormone (AMH). The statements were distributed (online survey) to French and Belgian fertility specialists. Consensus was reached when ≥66.7% of participants agreed or disagreed. Among 52 respondents, a consensus agreement was reached for each patient profile for personalizing the initial dose of gonadotropin, taking age, weight, body mass index, nature of the cycle, and the decision to perform a fresh transfer or a freeze-all strategy into consideration. The respondents preferred a fresh transfer for low and normal responders and a freeze-all strategy in case of high risk of hyperstimulation, newly diagnosed uterine or tubal pathology and premature progesterone elevation. A consensus was reached for 10-15 oocytes as optimal oocyte target from the first round of voting. The panel agreed to increase the gonadotropin dose in case of insufficient response and preferred a GnRH antagonist protocol for a subsequent cycle in case of excessive response. Finally, a consensual answer was obtained for using LH/hCG activity in case of hypogonadotropic hypogonadism, advanced age, inadequate response during first stimulation and suspected FSH receptor polymorphism. The AMPLITUDE consensus supports the importance of optimizing the ovarian stimulation protocol for patients undergoing assisted reproductive technology treatment. Additional studies could complete these findings and guide fertility specialists in their daily practice to improve ovarian stimulation outcomes.

Low ovarian responders produce more progesterone per follicle than normal and high responders.

Late follicular premature progesterone rise is a complex phenomenon encountered during assisted reproductive technology (ART) treatments; different etiologies can occur in the same patient. Low ovarian responders may be the best example, since higher FSH doses and ovarian aging-related changes may interact and generate a premature progesterone rise. This study aims to explore the correlation between progesterone levels on hCG day and the progesterone-to-follicle index and compare the progesterone-to-follicle index according to ovarian response. We performed a retrospective, observational, analytic, cross-sectional, and cohort study at the Reproductive Endocrinology Department at Centro Médico Nacional 20 de November between January 2015 to January 2020. After verifying for normalcy, a Spearman Rho, Principal Component Analysis, and a simple linear regression model were performed. Treatment cycles were classified according to their ovarian response. Low-ovarian responders were classified according to the Bologna Criteria. Then an ANOVA test was performed to compare each group. Our results show that the progesterone-to-follicle index correlates best with progesterone levels on hCG day. Comparing all the ovarian responses, low ovarian responders have the highest progesterone-to-follicle index of the four groups. Low ovarian responders produce more progesterone per follicle than regular and high responders.

High ovarian responders have the highest risk of premature progesterone rise.

Late follicular phase progesterone elevation is a complication that affects approximately 38% of IVF cycles. There is a lack of consensus on the appropriate cut-off levels for progesterone on hCG day. Although premature progesterone rise occurs in all kinds of ovarian responses, there is a knowledge gap regarding the ovarian response with the highest risk of this phenomenon. Our study aims to assess the relative risk of each kind of ovarian response for premature progesterone rise and evaluate the prevalence of premature progesterone rise in each ovarian response. A retrospective, cross-sectional, comparative and analytic study was performed at the Reproductive Endocrinology Department in Centro Médico Nacional 20 de Noviembre in Mexico City. All conventional-antagonist cycles were grouped according to their ovarian response and were evaluated from 2015 to 2020. Pearson's Squared-chi, Cramer's V, cross-table and the relative risk were calculated. The prevalence of premature progesterone rise oscillated from 20.8 to 67.9% for low and high ovarian responders, respectively. After calculating the relative risk, high ovarian responders had a 1.38 higher risk for premature progesterone rise than other groups. High ovarian responders have the highest risk for premature progesterone rise compared to normal and low ovarian responders. High ovarian responders have a 67.9% prevalence of premature progesterone rise.

FRI382 High Androgen And Progesterone Metabolite Concentrations In Naturally Matured Follicles Are Concurrent With High Serum Anti-Müllerian Hormone Concentrations

Abstract Disclosure: T. Du Toit: None. M. Von Wolff: None. A.C. Swart: None. M. Groessl: None. C.E. Flueck: None. Infertility in women is routinely evaluated with the assessment of circulating steroid levels. Profiling steroid levels in follicular fluid (FF) would provide a focused evaluation of the ovarian endocrine milieu and is therefore better suited to identify key hormones potentially involved in dysfunctional follicular growth. The anti-Müllerian hormone (AMH) level in serum is a well-established clinical marker to estimate the ovarian reserve in assisted reproductive technology, while the AMH level in FF serves as a new prognostic marker for oocyte developmental potential. However, AMH-linked changes in the follicular steroid milieu have not been fully explored. We conducted an AMH-dependent analysis of the FF endocrine milieu. Hormones were quantified using LC-MS (n=42) and ELISA (n=4) in FF of 83 women undergoing natural cycle in vitro fertilisation. Patients were age-matched and classified into 4 statistically different (p&amp;lt;0.0001) groups according to serum AMH levels: group A (&amp;lt;1.1 pmol/L, n=20); group B (1 - 7.14 pmol/L, n=21); group C (7.14 - 35.5 pmol/L, n=21); and group D (&amp;gt;35.5 pmol/L, n=21). Group D was designated as our polycystic ovary syndrome (PCOS)-like group, as high serum AMH is a marker for PCOS. We characterised androgen and progesterone metabolic pathways in FF. Androstenedione (A4) and testosterone (T) levels differed significantly between the groups (p&amp;lt;0.01) and were highest in group D at 60 nmol/L and 4.7 nmol/L, respectively. The levels of 11-ketoandrostenedione (11KA4) and 11β-hydroxyandrosterone (adrenal-origin) also differed between the groups (p&amp;lt;0.05), with higher 11KA4 levels (±2.7-fold) quantified in group D. In parallel with serum AMH, FF AMH differed between the groups (p&amp;lt;0.0001), together with luteinizing hormone/FSH, A4/dehydroepiandrosterone, estradiol(E2)/T and E2/A4 ratios. In comparison to groups A, B and C combined, the PCOS-like group D showed significantly increased downstream progesterone metabolite levels –11α-hydroxyprogesterone [OHP4], 17α,20α-diOHP4, 16α-OHP4 and 5α-pregnanolone, with lower FSH levels. Our results show that the follicular milieu is significantly different when high AMH levels are measured compared to when AMH levels are low, marked by: (i) higher progesterone metabolite levels in follicles and (ii) higher A4 and T levels, concomitant with unchanged E2 levels suggesting that androgens were not fully converted to estrogens in these follicles. Our study furthermore corroborates other studies reporting an intrafollicular hyperandrogenic state in women with increased circulatory AMH levels. In summary, our study not only provides data based on a broad steroid profile that the follicular androgen endocrine milieu is affected in women with high serum AMH levels, but it also provides a model for the premature progesterone increase in PCOS women which leads to a reduction in the embryo implantation rate. Presentation: Friday, June 16, 2023

P-667 The attenuated response to elevated serum progesterone levels on pregnancy outcomes of fresh IVF/ICSI cycles in older patients

Abstract Study question Whether there are different impacts of serum progesterone (P) levels on the day of trigger on pregnancy outcomes in patients of different age groups. Summary answer Our results suggest that the pregnancy outcome was less sensitive to progesterone elevation in older patients. What is known already It is now generally believed that the P elevation at the late follicular phase reduces the pregnancy rate by opening the implantation window prematurely and disrupt the embryo-endometrial synchrony. Previous studies further investigated the effect of developmental stages of embryo, number of oocytes retrieved, cause of infertility and different stimulation regimens on the association of P level and the likelihood of pregnancy. However, the study of maternal age on such association is scarce. A previous study found that LH receptor (LHCGR) and progesterone receptor (PGR) were up regulated in advanced age group. Study design, size, duration This was a non-interventional, retrospective cohort study of patients undergoing routine practice in a university-based fertility center between 2015 and 2021. One thousand five hundred and seventeen IVF/ICSI cycles among 1305 patients were included in the analysis. Participants/materials, setting, methods Fresh ET using autologous oocytes with serum P level measured on the day of hCG administration were included. Exclusion criteria include cycles without P measurement, using frozen oocytes, PGT cycles, freeze-all cycles, oocyte donation and no embryo transfer cycles. The patient age was divided into 3 groups: group 1 included patients at age 35 or below, group 2 included patients at age 36 to 39, group 3 included those at 40 years old or above. Main results and the role of chance We performed logistic regression analysis for each group to determine the contributing factors to the live birth outcome. In group 1, age, serum P level, number of usable embryos, embryo grading and endometrial thickness were found to be significantly associated with live birth. In group 2, age and number of usable embryos were significantly associated with live birth. However, total dose of gonadotropin was found to be the sole contributing factor to live birth in group 3. We also divided the P levels into low (≤0.50 ng/mL), median (0.51-1.00 ng/mL) and high (&amp;gt;1.00 ng/mL) and compared the live birth rate in each age groups. The live birth rate was found to be significantly reduced with increasing P levels (40.3% vs. 35.5% vs. 23.6%, p = 0.005). No significant difference in live birth rate between different P levels was found in age group 2 and 3. Limitations, reasons for caution The limitation of the study is its retrospective nature which may have led to bias in the interpretation of the data. There were also significantly higher proportion of cleavage-stage embryo to blastocyst transfer in the older group. Wider implications of the findings The negative association of premature progesterone rise at pre-ovulatory phase to the IVF fresh ET outcome was more prominent for younger patients. This may be one of the contributing factors that accounts for the great heterogeneity in the cut-off of P and its predicting power in different studies. Trial registration number Not applicable

P-484 PGT-A and euploid transfer is more efficient than untested transfer in patients obtaining 1 or 2 blastocysts: a propensity score matching-based study

Abstract Study question Does PGT-A and euploid transfer involve any clinical advantage with respect to untested transfer inpatients obtaining 1 or 2 blastocysts? Summary answer PGT-A involved less transfers, less miscarriages, and a shorter time from oocyte retrieval to cycletermination without affecting the cumulative-live-birth-rate per patient. What is known already Meiotic chromosomal aneuploidies are the main cause of implantation failures and miscarriages andshow a U-shaped association with women fertility. Their prevalence increases from 25-30% in women &amp;lt;35 years to &amp;gt; 90% around menopause. In IVF, PGT-A via comprehensive-chromosome-testing techniques allows identifying euploid blastocysts, whose live-birth-rate (LBR) per transferand miscarriage-rate (MR) per clinical pregnancy are respectively higher and lower than untestedblastocysts. From an intention-to-treat perspective, PGT-A cannot improve the cumulative-live-birth-rate (CLBR), but no report exists either of an impact on this key clinical outcome.Nevertheless, more data are needed about PGT-A performance in couples producing 1 or 2 blastocysts. Study design, size, duration We gathered a dataset of 369 non-PGT and 1461 PGT-A cycles with 1-2 blastocysts obtained bynaïve patients (April-2013 to July-2022). Patients were matched 1:1 for maternal age (36±3.1 years)and number of MII-oocytes inseminated (5.7±3.3) through propensity-score-matching, thereby producing a database of 242 cycles per arm. The primary outcome was LBR per transfer. Secondary outcomes were MR per clinical pregnancy, CLBR per concluded cycles and the time to cycle termination. Participants/materials, setting, methods ICSI of all own metaphase-II oocytes retrieved and blastocyst culture were systematically conducted. In the PGT-A group, trophectoderm biopsy without day3 zona-pellucida drilling andcomprehensive-chromosome-testing to assess full-chromosome non-mosaic aneuploidies wereperformed. Blastocyst cryopreservation was conducted via vitrification. Only euploid/untestedsingle transfers were conducted. The groups were comparable also for BMI, FSH, AMH, sperm factor, cumulus-oocyte-complexes, 2PN-zygotes, maturation, fertilization and blastulation rates. 99 and 143 patients obtained 1 and 2 blastocysts, respectively, in both groups. Main results and the role of chance The 242 non-PGT patients transferred 1.45±0.5 blastocysts. 57% and 43% performed one (N = 139) and two (N = 103) transfers, respectively. 165 patients (68%) did not undergo a fresh transfer because of OHSS risk (25%), premature progesterone elevation (20%), inadequate endometrium(23%), fever/COVID-19 (5%), couple’s will (27%).In the PGT-A group, the euploidy rate was 48.8±43.3%, 0.8±0.7 euploid blastocysts were obtained, and 0.6±0.6 transferred (N = 151) (p = 0.01 versus non-PGT). 45% of the PGT-A patients did not have euploid blastocysts (N = 110/242), 47% and 8% underwent one (N = 113) and two (N = 19) transfers, respectively. In the non-PGT and PGT-A group, the LBR per transfer was 17% (N = 61/351) versus 41%(N = 62/151; Multivariate-OR:3.9, 95%CI 2.4-6.3, adjusted-p=0.01; post-hoc power=99%). The MR was 30% (N = 26/87) versus 16% (N = 12/74; Multivariate-OR adjusted for blastocysts’ quality and day: 0.4,95%CI 0.2-0.9, adjusted-p=0.03), respectively. To date, 94% (N = 228/242) and 92%(N = 223/242) of the cycles were concluded (p = 0.5) and the CLBR was 25% (N = 57/228) versus 27%(N = 60/223; Multivariate-OR adjusted for maternal age:1.1, 95%CI 0.7-1.7, adjusted-p=0.6). The days between oocyte retrieval and cycle termination (PGT-A report without euploid blastocysts, last transfer without LB or first transfer with LB) were 125.1±144.4 and 74.5±95.6 (p = 0.01; confirmed adjusting for maternal age and number of blastocysts obtained in a linear regression). Limitations, reasons for caution Retrospective design. The mean maternal age at our private IVF center is 39 years with ≈70% requesting PGT-A. Nevertheless, all women are counseled about their age-specific prevalence ofaneuploidies. Wider implications of the findings PGT-A to assess full-chromosome non-mosaic aneuploidies and non-PGT involve similar CLBR incouples obtaining 1 or 2 blastocysts, but the former approach is faster (shorter time to cycletermination), safer (less miscarriages) and more efficient (less transfers). A cost-effectivenessanalysis is in our pipeline. Trial registration number not applicable

Premature progesterone rise incidence &amp; its effects on in vitro fertilization cycles

Background: Ovarian stimulation using gonadotropins is associated with premature progesterone rise (PPR) in late follicular phase compared to natural cycle. Two schools of thoughts exist concerning implications of PPR during late follicular phase with one insisting that outcome of in vitro fertilization (IVF) is adversely affected when PPR occurs while the second school of thought argues that PPR has no adverse effect on IVF outcome. The study is aimed at determining the incidence of PPR in the cohort data evaluated; pregnancy rates across the sides of adopted cut-off level of progesterone and association if any between PPR &amp; pregnancy rates.&#x0D; Methods: It was a descriptive retrospective cohort study of data of 114 patients and egg donors.. Analysis of continuous &amp; categorical data was done using IBM SPSS Statistics 25.&#x0D; Results: Mean serum progesterone on HCG day of IVF cycle among the cohort was 2.490±1.355 with a PPR incidence of 55%. The odds of having PPR was 6.7 times higher among subjects with follicular number more than 13 compared to subjects with follicular numbers ≤13 . Number of follicles retrieved &amp; age of subjects were strongly associated with progesterone level. The odds of subject with PPR getting pregnant was found to be 1.5 times less compared to the subjects with pre-HCG P4 &lt; 1.5ng/ml.&#x0D; Conclusion: Pre-HCG progesterone level is positively associated with pregnancy outcome in IVF cycles

Premature progesterone elevation during the early and mid-follicular phases in fresh in vitro fertilization (IVF) cycles is associated with lower live birth, clinical pregnancy, and implantation rates.

Evaluate follicular phase progesterone elevation (≥ 1.5ng/mL) prior to trigger during IVF stimulation and its effects on live birth rate (LBR), clinical pregnancy rate (CPR), and implantation rate (IR) in fresh IVF cycles. This was a retrospective cohort study within an academic clinic. A total of 6961 fresh IVF and IVF/ICSI cycles from October 1, 2015 to June 30, 2021 were included and grouped by progesterone (PR) prior to trigger: PR < 1.5ng/mL (low PR group) and PR ≥ 1.5ng/mL (high PR group). Main outcome measures included LBR, CPR, and IR. Among all cycle starts, 1568 (22.5%) were in the high PR group and 5393 (77.5%) were in the low PR group. Of the cycles which proceeded to an embryo transfer, 416 (11.1%) were in the high PR group and 3341 (88.9%) were in the low PR group. The high PR group had significantly lower IR (RR 0.75; 95% CI 0.64-0.88), CPR (aRR 0.74; 95% CI 0.64-0.87), and LBR (aRR 0.71; 95% CI 0.59-0.85) compared to the low PR group. When stratified by progesterone on the day of trigger (TPR), there was a clinically notable decrease in IR (16.8% vs 23.3%), CPR (28.1% vs 36.0%), and LBR (22.8% vs 28.9%) in the high PR group compared to the low PR group even when TPR < 1.5ng/mL. In fresh IVF cycles in which TPR < 1.5ng/mL, progesterone elevation ≥ 1.5ng/mL at any point in time prior to trigger negatively impacts IR, CPR, and LBR. This data supports testing of serum progesterone in the follicular phase prior to trigger, as these patients may benefit from a freeze-all approach.

Effects of sequential and fixed-dose estradiol valerate administration on premature progesterone rise in frozen-thawed embryo transfer cycles

Aim: This study investigated the risk of premature progesterone (P4) rise in the fixed and sequential estradiol valerate (EV) administration for frozen embryo transfer (FET) cycles.Material and Method: In this cross-sectional case-control study, 1272 cycles of FET were analyzed retrospectively from computer records between January 2015 to August 2020. EV was administrated in 795 patients with a fixed dose and in 477 patients with a sequential dose. P4 values were measured on the day when the endometrial thickness reached 8 mm in the patients.Results: There were 795 patients in the fixed EV administration group with a mean age of 30.75±3.39 and 477 patients in the sequential EV administration with a mean age of 30.75±3.39. P4 of the sequential-dose group (1.05±0.31) was significantly higher than the fixed-dose group (1.01±0.33). The Pairwise Z-Tests found that the abort rate was significantly higher in the sequential-dose group (p=0.04).Conclusion: Our results showed a higher P4 and abortion rate in the sequential-dose group. These findings show that premature P4 rise can be considered a risk factor.

Slightly Elevated Progesterone on HCG Trigger Day Has an Impact on Pregnancy Outcomes of Fresh Single Blastocyst Transfer Cycles Under an Early Follicular Phase Prolonged Protocol Cycle.

The effect of premature progesterone elevation on assisted reproductive technology has been debated. In different ovarian stimulation protocols, ovarian responses, and embryos transferred, conflicting results reside regarding the impact of elevated progesterone on pregnancy outcomes, according to previous studies. In addition, most studies have focused on significantly elevated progesterone levels, eg, above 1.5ng/mL, 1.75ng/mL, 2ng/mL. However, studies focusing on levels that are just slightly elevated are lacking, and some have concluded that such levels have no adverse effects on pregnancy outcomes. Clinical data of patients who underwent early follicular phase prolonged protocol cycle in vitro fertilization/intracytoplasmic sperm injection treatment were collected. Patients were divided into two groups according to progesterone level on the trigger day of human chorionic gonadotropin (HCG): Group 1: <1.0ng/mL and Group 2: 1.0-1.5ng/mL. Differences in baseline characteristics, ovulation promotion, and embryo culture, along with clinical pregnancy outcomes, were compared between the two cohorts. A total of 743 participants were included in this study, of which 587 were included in Group 1 and 156 were included in Group 2. In terms of pregnancy outcomes, Group 2 had a significantly lower clinical pregnancy rate and live birth rate per cycle than Group 1 (64.1% vs 75.7%, p <0.05; 63.5% vs 72.7%, p <0.05). After correction for maternal age, maternal body mass index, infertility duration, basal follicle-stimulating hormone, anti-Müllerian hormone, antral follicle count, total dose of gonadotropin, days of stimulation, and estradiol level on HCG trigger day, slightly elevated progesterone levels (P>1.0ng/mL) remained a risk factor for pregnancy failure in fresh single D5 blastocyst transfer under an early follicular phase prolonged protocol cycle. Slightly elevated progesterone levels on HCG trigger day may negatively affect pregnancy outcomes in early follicular phase prolonged protocol cycles.

FRESH VERSUS FREEZE: PREGNANCY OUTCOMES AND TREATMENT EFFICACY BETWEEN FRESH EMBRYO TRANSFER VS. NON PGT-A FREEZE ALL CYCLES

In 2019, 37% of initiated ART cycles included embryo or oocyte freeze all and deferred embryo transfer. Improved embryo survival with vitrification, increasing use of PGT-A, elucidation of the detrimental effects of premature progesterone elevation and supraphysiologic estradiol level on endometrial receptivity and abnormal placentation, as well as need to eliminate severe OHSS, have contributed to this trend [1-2]. The role of fresh ET in modern IVF requires reassessment in that subset of patients for whom fresh ET remains an option [3-5].

Premature Progesterone Elevation in in vitro Fertilisation Cycles - Current Perspectives.

The impact of premature elevation of progesterone (PPE) on the day of the trigger on pregnancy outcome in in vitro fertilisation (IVF) cycles has been a matter of contention and debate for decades. Research over the last 30 years has indicated that PPE >1.5 ng/ml is associated with declining live birth rates following fresh embryo transfer. Freeze-only approach has become a universal solution to overcome the issue of PPE. However, the topic is still mired with controversy. Few studies have not shown a negative impact on pregnancy rates. The impact of PPE on embryological parameters such as oocyte and embryo quality and ploidy is still very controversial. An important contentious issue is the choice of the threshold P value above which it is considered abnormal and a freeze-all strategy would be cost-effective. Currently, though a cutoff of >1.5 ng/ml is widely used, practices are not uniform and varying thresholds from 0.4 to 3 ng/ml are utilised. This review addresses the current understanding of PPE in IVF and the above controversies. The incidence, aetiology and source of progesterone rise, impact on endometrial receptivity, oocyte and embryo quality, impact on live birth and cumulative live birth and impact on frozen embryo transfer and donor oocyte cycles are discussed. Current controversies regarding the optimal threshold, assay performance and future directions are addressed.

Retrospective comparison of pregnancy outcomes of fresh and frozen-warmed single blastocyst transfer: a 5-year single-center experience.

To assess whether live birth rates (LBR) and maternal/neonatal complications differed following single fresh and frozen-warmed blastocyst transfer. The present retrospective observational study analyzed 4,613 single embryo transfers (SET) (646 fresh and 3,967 frozen) from January 1, 2014, to December 31, 2018. Fresh embryo transfer at blastocyst stage was considered according to the age of the patient and her prognosis. In case of the risk of ovarian hyperstimulation syndrome, premature progesterone rise, non-optimal endometrial growth, or supernumerary embryos, cryopreservation with subsequent frozen embryo transfer (FET) was indicated. No differences in LBR were recorded. Fresh embryo transfers yielded an increase both in neonatal complications OR 2.15 (95% CI 1.20-3.86, p 0.010), with a higher prevalence of singletons weighting below the 5th percentile (p 0.013) and of intrauterine growth retardation (p 0.015), as well as maternal complications, with a higher placenta previa occurrence OR 3.58 (95% CI 1.54-8.28, p 0.003), compared to FET. LBR appears not to be affected by the transfer procedure preferred. Fresh embryo transfer is associated with higher risk of neonatal complications (specifically a higher prevalence of singletons weighting below the 5th percentile and of intrauterine growth retardation) and placenta previa. Reflecting on the increased practice of ART procedures, it is imperative to understand whether a transfer procedure yields less complications than the other and if it is time to switch to a "freeze-all" procedure as standard practice. Clinical Trial Registration Number: NCT04310761. Date of registration: March 17, 2020, retrospectively registered.

Impact of letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF: a multicentre, randomized, double-blinded placebo-controlled trial

Does letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF reduce the proportion of women with premature progesterone levels above 1.5 ng/ml at the time of triggering final oocyte maturation? The proportion of women with premature progesterone above 1.5 ng/ml was not significantly affected by letrozole co-treatment. IVF creates multiple follicles with supraphysiological levels of sex steroids interrupting the endocrine milieu and affects the window of implantation. Letrozole is an effective aromatase inhibitor, normalizing serum oestradiol, thereby ameliorating some of the detrimental effects of IVF treatment. A randomized, double-blinded placebo-controlled trial investigated letrozole intervention during stimulation for IVF with FSH. The trial was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. A cohort of 129 women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) completed an IVF cycle with fresh embryo transfer and received co-treatment with either 5 mg/day letrozole (n = 67) or placebo (n = 62), along with the FSH. Progesterone, oestradiol, FSH, LH and androgens were analysed in repeated serum samples collected from the start of the stimulation to the mid-luteal phase. In addition, the effect of letrozole on reproductive outcomes, total FSH consumption and adverse events were assessed. The proportion of women with premature progesterone >1.5 ng/ml was similar (6% vs 0% (OR 0.0, 95% CI [0.0; 1.6], P = 0.12) in the letrozole versus placebo groups, respectively), whereas the proportion of women with mid-luteal progesterone >30 ng/ml was significantly increased in the letrozole group: (59% vs 31% (OR 3.3, 95% CI [1.4; 7.1], P = 0.005)). Letrozole versus placebo decreased oestradiol levels on the ovulation trigger day by 68% (95% CI [60%; 75%], P < 0.0001). Other hormonal profiles, measured as AUC, showed the following results. The increase in LH in the letrozole group versus placebo group was 38% (95% CI [21%; 58%], P < 0.0001) and 34% (95% CI [11%; 61%], P = 0.006) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, testosterone increased by 79% (95% CI [55%; 105%], P < 0.0001) and 49% (95% CI [30%; 72%], P < 0.0001) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, the increase in androstenedione was by 85% (95% CI [59%; 114%], P < 0.0001) and 69% (95% CI [48%; 94%], P < 0.0001) in the follicular and luteal phases, respectively. The ongoing pregnancy rate was similar between the letrozole and placebo groups (31% vs 39% (risk-difference of 8%, 95% CI [-25%; 11%], P = 0.55)). No serious adverse reactions were recorded in either group. The total duration of exogenous FSH stimulation was 1 day shorter in the intervention group, significantly reducing total FSH consumption (mean difference -100 IU, 95% CI [-192; -21], P = 0.03). Late follicular progesterone samples were collected on the day before and day of ovulation triggering for patient logistic considerations, and the recently emerged knowledge about diurnal variation of progesterone was not taken into account. The study was powered to detect hormonal variations but not differences in pregnancy outcomes. Although the use of letrozole has no effect on the primary outcome, the number of women with a premature increase in progesterone on the day of ovulation triggering, the increased progesterone in the mid-luteal phase due to letrozole may contribute to optimizing the luteal phase endocrinology. The effect of letrozole on increasing androgens and reducing FSH consumption may be used in poor responders. However, the effect of letrozole on implantation and ongoing pregnancy rates should be evaluated in a meta-analysis or larger randomized controlled trial (RCT). Funding was received from EU Interreg for ReproUnion and Ferring Pharmaceuticals, and Roche Diagnostics contributed with assays. N.S.M. and A.P. have received grants from Ferring, Merck Serono, Anecova and Gedeon Richter, and/or personal fees from IBSA, Vivoplex, ArtPred and SPD, outside the submitted work. The remaining authors have no competing interests. NCT02939898 and NCT02946684. 15 August 2016. 22 August 2016.

P–291 Searching for a suitable serum progesterone range at triggering day to achieve optimal cumulative live birth rate in high responders – Which range is better?

Abstract Study question Is there a suitable range of serum progestereone level at triggering day to optimize the cumulative live birth rate (LBR) in high responders? Summary answer Fom the point of view of cLBR, the optimal P4 range for triggering is between 1.5 to 2.5 ng/ml generally and in the high responders. What is known already It is well established that premature progesterone rise (PPR) affect adversely the pregnancy outcome in fresh embryo transfer cycle. It is inferred that PPR alters synchrony between endometrium and the embryos. However, detailed study of the effect of PPR on efficiency of oocyte retrieval , embryo quality and the subsequent cumulative pregnancy outcome is still lacking. Hence we sort to analyze the effect of PPR on the final cumulative LBR in our program especially focused on high responders. Study design, size, duration ART Database in our center was retrospectively reviewed. Total 1523 cycles between 20160101 and 20191231 were recruited under the condition of GnRH antagonist cycle with duration of ovulation induction for more than 5 days and available serum P4 level data on triggering day for data analysis for the relationship between serum P4 value and final cumulative LBRs. Participants/materials, setting, methods Cycles with serum P4 level &amp;lt; 1.5 ng/ml were defined as without PPR (Group A: n = 1383). Cycles with serum P4 level &amp;gt;1.5 were defined as with PPR: P4 between 1.5 and 2.5 as Group B (n = 113), P4 &amp;gt; 2.5 as Group C (n = 27). Those high responding cycles (n = 404) were analyzed similarly and separately as Group A’ (n = 304), B’ (n = 81) and C’(n = 19). The statistics were carried out by SPSS-PC ver. 22.0 with p &amp;lt; 0.05 as statistical significance. Main results and the role of chance Group A had significantly lower number of oocytes (9.8 + 8.0) retrieved as compared to Group B (19.3 + 11.2) and Group C (18.2 + 9.9). However there were no differences in fertilization rate, good embryo rates and BC formation rates between groups. The cumulative LBR (cLBR) were significantly higher in Group B (65.1%) as compared to Group A (40.9%, p &amp;lt; 0.001) and Group C (37.0%, p = 0.008). For the high responding cycles, Group B’ also had marginally significant higher cLBR (75.3%) as compared to group A’(63.8% ; p=0.051) and Group C’ (52.6%; p = 0.050). Comparisons between Group A’ and C revealed significantly less oocytes retrieved but significantly higher blastocyst formation rates in Group A’ and the resultant cLBR were comparable between these two groups. Comparisons between Groups B’ and C’ revealed comparable oocytes retrieved but significant lower blastocyst formation rates and cLBRs in Group C’. The baseline of the first part analysis revealed higher age and lower AMH in Group A, but comparable age and AMH between groups B and C.The lower cLBR in group A could be due to selection bias.The second part (high responders) showed comparable baselines between three groups. However, the case numbers are too few in group C’ which might also result in uncertainty. Limitations, reasons for caution Although the data revealed interesting, significantly different results between groups, this is only a retrospective analysis from our ART patient series. Selection bias could not be precluded. Analysis restricted to high responders could have a more balanced population for comparisons. However, more cases are needed to affirm the findings. Wider implications of the findings: We still do not know the tolerable ceiling of serum P4 at the triggering day in high responders if future FET already planned. Pushing P4 value too high not only could not increase mature oocyte yields and possibly may decrease the number of available good blastocysts for optimizing final cLBRs. Trial registration number Not applicable

P–663 The ratio of serum progesterone (P4) to the number of follicles (P4/Follicle) is a more objective parameter for euploidy rate as compared to systemic progesterone

Abstract Study question Does the ratio of serum progesterone (P4) to the number of follicles (P4/Follicle) on the day of final oocyte maturation affect the ploidy status of the embryos? Summary answer A high P4/Follicle ratio negatively affects the euploid rate of the embryos. What is known already During ovarian stimulation, exogenous gonadotropins are administered to achieve multifollicular growth. Intense gonadotropin stimulation towards the end of the follicular phase seems to cause a premature progesterone rise in stimulated IVF cycles. The impact of serum progesterone elevation during the follicular phase has been studied intensively. Though most studies have focused on the effect of progesterone elevation on the endometrial receptivity, little is known about its possible impact on embryo development and ploidy status. The only study that investigated the effect of progesterone on the embryo ploidy status, was unable to show any significant impact. Study design, size, duration This retrospective study was performed at ART Fertility Clinics Abu Dhabi, UAE and Muscat, Oman. All stimulation cycles (n = 975) were performed between January 2015 to December 2019 with patients aged between 18–45, Body mass index (BMI) of 18–35, stimulated either with rFSH or hMG. All embryos underwent ICSI and Preimplantation Genetic Testing for Aneuploidies (PGT-A),Patients with surgical sperm extraction, warmed oocytes or natural cycle IVF were excluded. Participants/materials, setting, methods Serum P4 was measured on the last ultrasound prior triggering for final oocyte maturation. The P4/Follicle ratio was calculated as the ratio of P4 on trigger day to the number of follicles &amp;gt; 10 mm on the last ultrasound. Serum P4 and P4/Follicle ratio were then analyzed using linear and univariate regression model to find potential correlation with the number of oocytes retrieved, number of mature oocytes, embryo quality (day 3 and 5), and euploid rate. Main results and the role of chance A total of 975 cycles were analyzed, with a mean age of 33.88±0.05 years, a mean BMI of 26.7±0.035 kg/m2. The mean number of oocytes collected was 12.53±0.058. Mean serum P4 on trigger day was 0.83±0.005 ng/ml and higher serum P4 values were observed as the number of oocytes retrieved and the number of mature oocytes increased (β = 0.026, p &amp;lt; 0.0001 and β = 0.028, p &amp;lt; 0.001, respectively). On the other hand, the mean P4/Follicle ratio was 0.056±0.00041 ng/ml and, unlike serum P4, the P4/Follicle ratio showed a negative correlation with the number of oocytes retrieved as well as with the number of mature oocytes (β=–0.001, p &amp;lt; 0.001 and β=–0.001, p &amp;lt; 0.001, respectively). While day 3 embryos were not affected by serum P4 or P4/Follicle ratio, the blastocyst quality was negatively affected by both increasing serum P4 levels and the P4/Follicle ratio (β=–0.012 p &amp;lt; 0.05, β=–0.002, p &amp;lt; 0.001, respectively). Euploid rates were positively correlated in cycles with increased serum P4 β = 0.18, p &amp;lt; 0.001), while negatively correlated in cycles with a high P4/Follicle ratio (β=–0.015, p &amp;lt; 0.001). After adjusting for potential confounders, only P4/Follicle remained as a significant negative factor for euploid rate (β=–0.004, p &amp;lt; 0.001, 95% CI: –0.007- –0.001, p &amp;lt; 0.001), which was not observed for serum P4 (p = 0.46). Limitations, reasons for caution This is an observational study based on retrospective data; an improved extrapolation of the results might be obtained by performing a prospective study. Wider implications of the findings: The findings of this study should encourage clinicians to optimize the ovarian stimulation protocols not only based on serum P4, but also considering the P4/Follicle ratio. Trial registration number Not applicable

P–665 Influence of premature progesterone elevation on embryo development

Abstract Study question Does a serum progesterone level higher than 1.3 ng/mL on the day of ovulation trigger have an impact on blastocyst development? Summary answer Elevated progesterone level has no significant impact on top blastocyst rate, usable blastocyst rate and on morphokinetics. What is known already Premature elevation of progesterone level on the day of ovulation trigger prior to IVF is common and causes a decrease in endometrial receptivity. A freeze all strategy is then recommended. However, cumulative live birth rates have also been described as lower in cases of high progesterone levels. Study design, size, duration This was a retrospective bicentric cohort follow-up study, including 1150 IVF/ICSI cycles performed between 2016 and 2018 with at least 1 day–5 blastocyst available for transfer or freezing. Among these cycles, 524 were performed with use of a time-lapse system (Embryoscope). Serum Progesterone level was measured on the day of ovulation trigger, and a value &amp;gt;1.3 ng/ml was used to identify premature progesterone elevation. Participants/materials, setting, methods The cycles were divided into 2 groups according to serum progesterone level: 1335 cycles were allocated in the normal progesterone group (P &amp;lt; 1,3) and 215 in the progesterone premature elevation group (P &amp;gt; 1.3). Patient’s characteristics, ovarian stimulation characteristics, IVF cycles characteristics and embryology parameters were anonymously recorded and compared between the 2 groups. Main results and the role of chance Female age, smoking status, AFC and AMH levels were comparable between the 2 groups. Female BMI was significantly higher in the P &amp;lt; 1,3 than in the P &amp;gt; 1.3 group (26.1 versus 24.7 kg/m² respectively). Total FSH dose, estradiol level, number of follicles &amp;gt;11mm and number of retrieved oocytes were significantly higher in the P &amp;gt; 1.3 group than in P &amp;lt; 1.3 group No difference was observed between the 2 groups in terms of top blastocyst rate per mature oocyte and usable blastocyst rate per mature oocyte. When morphokinetic analysis was available, time to blastulation was the only significantly different parameter between the 2 groups (110.4 hours in P &amp;lt; 1.3 versus 107.9 hours in P &amp;gt; 1.3, p = 0.04). Cumulative live birth rate per cycle was not statistically different between the two groups (23.1% for P &amp;lt; 1.3 versus 28.7% for P &amp;gt; 1.3) (p &amp;gt; 0.05). Limitations, reasons for caution The retrospective design of the study should lead to careful analysis of the results. The progesterone threshold refers to a specific assay, and should not be generalized to other assays. Wider implications of the findings: Premature elevation of serum progesterone level on the day of ovulation trigger does not seem to affect embryo developmental competence. This further supports the relevance of freeze all strategy in this situation. Trial registration number Not applicable