High progesterone levels on the day of embryo transfer are associated with a reduced clinical pregnancy rate

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Abstract

Context:Low progesterone levels on the day of embryo transfer have an adverse effect on pregnancy outcomes, but the effect of high progesterone levels on pregnancy outcomes is unclear. Objective: In POSEIDON group 1 patients,we investigated how progesterone levels on the day of embryo transfer affect the clinical pregnancy rate.All patients were prepared for transfer using artificial cycles with a combination of vaginal micronized progesterone and oral dydrogesterone. Design, Setting, and Participants:This is a retrospective cohort study, with data from the Reproductive Center of Yantai Yuhuangding Hospital between January 2016 and December 2023.This study enrolled 402 patients who underwent the transfer of one or two embryos on Day 5 or Day 6. Serum progesterone and estradiol levels were measured on the day of embryo transfer (ET). The primary endpoint was the clinical pregnancy rate. Main Outcome Measures:All patients were divided into three groups according to the 10th and 90th percentile serum P values.All the categorical variables were compared with a Pearson Chi-square test or Fisher’s exact test among two groups.The Student’s t-test was used to compare two sets of continuous variables.One-way analysis of variance compares multiple sets of quantitative data.A multivariate logistic regression analysis was performed with all the potential confounding variables. Results: Serum P levels were divided into three groups according to the critical points of 9.45 ng/ml and 23.32 ng/ml.The clinical pregnancy rate with 9.45≤serum P<23.32ng/ml was higher than others.There was no significant difference in clinical pregnancy rate among the three groups for 46.2%(serum P<9.45 ng/ml),56.7%(9.45≤serum P<23.32ng/ml) and 40% (serum P ≥23.32 ng/ml.)(F=5.04,P=0.08).Adjusted multivariate logistic regression indicated that women with serum P levels of 9.45≤serum P<23.32ng/ml had significantly higher odds of clinical pregnancy compared to other patients (OR: 1.454; 95% CI: 1.032-2.048; P=0.032). Conclusions: We conclude that serum P levels on the day of ET have an optimal range. Deviations from this range are significantly associated with reduced clinical pregnancy rates.
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Data may be preliminary. 22 November 2025 V1 Latest version Share on High progesterone levels on the day of embryo transfer are associated with a reduced clinical pregnancy rate Authors : Xin Wang 0009-0008-9872-1485 , Lili Zhuang , Luqing Zhang , Zhenteng Liu , Huishan Zhao , Dongmei Zhao , Yingqian Peng , and Hongchu Bao [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176379320.02360384/v1 345 views 97 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Context:Low progesterone levels on the day of embryo transfer have an adverse effect on pregnancy outcomes, but the effect of high progesterone levels on pregnancy outcomes is unclear. Objective:In POSEIDON group 1 patients,we investigated how progesterone levels on the day of embryo transfer affect the clinical pregnancy rate.All patients were prepared for transfer using artificial cycles with a combination of vaginal micronized progesterone and oral dydrogesterone. Design, Setting, and Participants:This is a retrospective cohort study, with data from the Reproductive Center of Yantai Yuhuangding Hospital between January 2016 and December 2023.This study enrolled 402 patients who underwent the transfer of one or two embryos on Day 5 or Day 6. Serum progesterone and estradiol levels were measured on the day of embryo transfer (ET). The primary endpoint was the clinical pregnancy rate. Main Outcome Measures:All patients were divided into three groups according to the 10th and 90th percentile serum P values.All the categorical variables were compared with a Pearson Chi-square test or Fisher’s exact test among two groups.The Student’s t-test was used to compare two sets of continuous variables.One-way analysis of variance compares multiple sets of quantitative data.A multivariate logistic regression analysis was performed with all the potential confounding variables. Results:Serum P levels were divided into three groups according to the critical points of 9.45 ng/ml and 23.32 ng/ml.The clinical pregnancy rate with 9.45≤serum P<23.32ng/ml was higher than others.There was no significant difference in clinical pregnancy rate among the three groups for 46.2%(serum P<9.45 ng/ml),56.7%(9.45≤serum P<23.32ng/ml) and 40% (serum P ≥23.32 ng/ml.)(F=5.04,P=0.08).Adjusted multivariate logistic regression indicated that women with serum P levels of 9.45≤serum P<23.32ng/ml had significantly higher odds of clinical pregnancy compared to other patients (OR: 1.454; 95% CI: 1.032-2.048; P=0.032). Conclusions:We conclude that serum P levels on the day of ET have an optimal range. Deviations from this range are significantly associated with reduced clinical pregnancy rates. High progesterone levels on the day of embryo transfer are associated with a reduced clinical pregnancy rate Xin Wang Ϯ1 , Lili Zhuang Ϯ1 ,Luqing Zhang Ϯ1 ,Zhenteng Liu 1 ,Huishan Zhao 1 ,Dongmei Zhao ✱1 ,Yingqian Peng ✱1 ,Hongchu Bao ✱1 1 Department of Reproductive Medicine, Qingdao University Medical College Affiliated Yantai Yuhuangding Hospital, No. 20 Yuhuangding East Road, Yantai 264000, China. ✱ Correspondence author;Hongchu Bao,E-mail: [email protected] ,ORCID;0000-0002-5888-5484.Dongmei Zhao,E-mail: [email protected] Peng,E-mail: [email protected] . Ϯ Contributed equally. ABSTRACT Context:Low progesterone levels on the day of embryo transfer have an adverse effect on pregnancy outcomes, but the effect of high progesterone levels on pregnancy outcomes is unclear. Objective:In POSEIDON group 1 patients,we investigated how progesterone levels on the day of embryo transfer affect the clinical pregnancy rate.All patients were prepared for transfer using artificial cycles with a combination of vaginal micronized progesterone and oral dydrogesterone. Design, Setting, and Participants:This is a retrospective cohort study, with data from the Reproductive Center of Yantai Yuhuangding Hospital between January 2016 and December 2023.This study enrolled 402 patients who underwent the transfer of one or two embryos on Day 5 or Day 6. Serum progesterone and estradiol levels were measured on the day of embryo transfer (ET). The primary endpoint was the clinical pregnancy rate. Main Outcome Measures:All patients were divided into three groups according to the 10th and 90th percentile serum P values.All the categorical variables were compared with a Pearson Chi-square test or Fisher’s exact test among two groups.The Student’s t-test was used to compare two sets of continuous variables.One-way analysis of variance compares multiple sets of quantitative data.A multivariate logistic regression analysis was performed with all the potential confounding variables. Results:Serum P levels were divided into three groups according to the critical points of 9.45 ng/ml and 23.32 ng/ml.The clinical pregnancy rate with 9.45≤serum P<23.32ng/ml was higher than others.There was no significant difference in clinical pregnancy rate among the three groups for 46.2%(serum P<9.45 ng/ml),56.7%(9.45≤serum P<23.32ng/ml) and 40% (serum P ≥23.32 ng/ml.)(F=5.04,P=0.08).Adjusted multivariate logistic regression indicated that women with serum P levels of 9.45≤serum P<23.32ng/ml had significantly higher odds of clinical pregnancy compared to other patients (OR: 1.454; 95% CI: 1.032-2.048; P=0.032). Conclusions:We conclude that serum P levels on the day of ET have an optimal range. Deviations from this range are significantly associated with reduced clinical pregnancy rates. Keywords: serum P,clinical pregnancy rate,ET,vaginal progesterone,desdrogesterone Introduction In recent years,with the improvement of cryopreservation embryo technology and the increase of patients undergoing Preimplantation Genetic Testing(PGT) and fertility preservation,the number of frozen embryo transfers(FET) is increasing around the world.At the same time,the risk of late-onset OHSS in fresh cycle and the adverse effects of high estrogen levels on endometrial receptivity were reduced [1] .Progesterone is necessary for endometrial transformation,embryo implantation and maintenance of pregnancy.Compared to the natural and the stimulated cycles,the artificial endometrium preparation cycles with hormonal replacement therapy (HRT) is more popular.Because it can control the number of days of exposure to exogenous progesterone and accurately determine the transplantation time,to synchronize the embryo with endometrial development [2] .Therefore,there is no endogenous progesterone release in the artificial cycle,so the supplement of exogenous progesterone is the key to the success of embryo transfer.HRT mimics the natural cycles,supplementing estrogen from the 2nd to 3rd day of menstruation,until the endometrium reaches 8mm,and progesterone conversion is performed. It has been found that in the natural cycles,the increase of progesterone before ovulation leads to premature luteinization and impaired endometrial receptivity,and the implantation rate is reduced [3] .However,insufficient progesterone supplementation before embryo transfer(ET) also adversely affects the implantation rate [4] . Currently,progesterone can be administered by different routes,including vaginal,intramuscular, subcutaneous,rectal or oral routes,with different pharmacokinetics.Some scholars believe that intrauterine progesterone levels are more critical to pregnancy success than serum P [5] .However,some studies have shown that the systemic anti-inflammatory effects of serum P are equally important [6] ,and progesterone in the endometrium is derived from arterial blood [7] .At present,there is no consensus on the optimal route,dose and duration of progesterone administration of FET,which directly affect the serum P levels on the day of ET. Previous studies have suggested that the higher the levels of serum P on the day of ET,the better the pregnancy outcome [8] .However,some studies have found that there is an optimal threshold of serum P on the day of transplantation,and too low or too high progesterone also has adverse effects on pregnancy outcomes [9] . Given this background, we aimed to evaluate the impact of serum progesterone concentration on the day of embryo transfer on pregnancy outcomes. This analysis specifically focuses on POSEIDON group 1 patients undergoing hormone replacement therapy (HRT) cycles with endometrial preparation via vaginal micronized progesterone combined with oral dydrogesterone. Materials and methods Design and setting This study is a retrospective cohort study.Patients who underwent HRT cycles for FET at the Reproductive Center of Yuhuangding Hospital,Yantai from January 2016 to December 2023 were selected. Study population This study included 402 infertile patients undergoing their first fresh oocyte retrieval cycle.All the patients underwent a single ET in the cleavage or blastocyst stage after HRT. Eligible patients were aged <35 years,AMH ≥1.2 ng/ml,the number of eggs in fresh autologous cycles was <10,had no systemic diseases,a triple layer endometrium ≥8 mm after HRT and 1-2 embryos transferred on Day 5 or Day 6 of progesterone rise. We excluded those patients with recurrent miscarriages,repeated implantation failure(RIF) (RIF is defined as failure to achieve clinical pregnancy in adult women under 40 years of age after transferring at least 3 high-quality embryos within 3 fresh or frozen cycles,including: Day 3 embryos (≥8 cells,uniform blastomere size,fragmentation rate < 10%,and blastocyst ≥3BB)),severe male factor,uterine diseases (e.g.mediastinal uterus,uterus unicornis,adenomyosis of uterus,multiple uterine fibroids),chromosomal abnormality or immune abnormality. Endometeial preparation and Embryo transfer All the patients received HRT for endometrial preparation,and they were treated with an estrogen escalation regimen.Treatment started on Day 2/3 of menstruation,estradiol was administered orally 2mg/day of estradiol valerate(Progynova®,Bayer Hispania,Barcelona,Spain).After 4 days,estradiol valerate was adjusted to 4mg/day, After 4 days,estradiol valerate was adjusted to 6mg/day.After 12-16 days on estrogens,a vaginal 2D ultrasound was performed to measure endometrial thickness and to confirm a triple-layer pattern,and a blood sample was drawn for estradiol(E2) and progesterone determinations to ensure that no spontaneous ovulation had occurred. If endometrial thickness was≥0.8cm,the endometrial pattern was trilaminar,and serum P<1.0 ng/ml,ET was scheduled.Luteal phase support(LPS) was administered with vaginal micronized progesterone at a dose of 200mg three times/day(Utrogestan®,Cyndea Pharma,S.L.,Spain) and oral desdrogesterone at a dose of 10mg twice/day(Duphaston®,Abbott biologicals B.V.,Netherlands).The day 3 cleavage embryos were transferred on the 5th day of progesterone rise and day 5 or 6 blastocyst embryos were transferred on the 6th day of progesterone rise.On the day of ET,all patients will have their blood collected at 7 a.m. after taking the medicine.ET was performed through the same flexible catheter under the guidance of transabdominal ultrasound.After ET,continue to take estrogen and progesterone daily.If serum levels of β-hCG was negative on the 14th day after ET,and the drug was discontinued.If pregnancy occurred,hormone treatment was maintained until pregnancy week 10. Endpoints The primary endpoint was the clinical pregnancy rate.The secondary endpoints were live birth rate, biochemical pregnancy and miscarriage rate.Pregnancy was defined as a positive urinary pregnancy test (β-hCG, Hangzhou AllTest Biotech Co., Ltd., Hangzhou, China) conducted 14 days after the FET.Clinical pregnancy was defined as a visible gestational sac determined by use of vaginal ultrasonography performed at 7-8 weeks of pregnancy. Biochemical pregnancy was defined as a positive hCG urine measurement and absence of clinical pregnancy. Miscarriage was defined as loss of pregnancy up to 21+6 weeks of pregnancy, following an initially positive pregnancy test. Live birth was defined as delivery of a living offspring from 22+0 weeks of pregnancy. Progesterone and estradiol measurement Hormone measurements taken the day of ET (serum E2 and serum P) were analyzed by an electrochemical iuminescenceimmuno assay (Cobas® e601 analyzer, Roche diagnostics GmbH, Germany) in the laboratory of our hospital.Progesterone:the result is expressed in ng/mL,estradiol:the result is expressed in pg/mL.The intra-and inter-assay variation coefficients for the serum P determinations were 2.3-11.9% and 3.2-22.5%, respectively,for serum P values between 0.02 and 1.8 ng/ml,and sensitivity was 0.05 ng/ml.The intra- and inter-assay variations coefficients for the E2 determinations were 1.1-6.7% and 1.9-10.6%,with a measurement range of 5.0-3000 pg/ml and sensitivity was 5 pg/ml. Statistical Analysis Statistical analysis was performed using IBM SPSS Statistics v25 software (SPSS Inc., Chicago, IL, USA).Serum P on the day of ET was classified according to the 5th,10th,25th,50th,75th,90th,and 95th percentiles.All the categorical variables were compared with a Pearson Chi-square test or Fisher’s exact test among groups.The Student’s t-test was used to compare two sets of continuous variables.Normality distribution was analyzed by the F-test,but non-normal distribution was analyzed by Welch’s t-test.A multivariate logistic regression analysis was performed with all the potential confounding variables. Patients were categorized into three groups based on serum progesterone levels, using the 10th and 90th percentiles as cutoff value. The clinical, biochemical, and live birth rates, as well as the spontaneous abortion rate, were compared across these groups. A logistic regression analysis was performed to specify the impact of serum progesterone on the clinical pregnancy rate. The model was adjusted for the following potential confounders: age, BMI, AMH level, infertility type and duration, number of oocytes retrieved in the fresh cycle, fresh cycle insemination method, endometrial thickness, number and type of embryos transferred, number of high-quality embryos transferred, and serum estradiol (E2) level. Results Descriptive analysis A total of 402 infertile patients were included in the study.The mean overall population age was 30.70±2.42 years,mean BMI was 24.34±3.91 kg/m2,mean AMH was 5.41±4.58ng/ml,mean infertility years was 3.65±2.05 years,mean number of eggs in fresh cycle was 6.76±1.89,mean endometrial thickness was 1.01±0.18cm,mean number of transferred embryos was 1.33±0.18,mean high-quality embryo number was 0.89±0.71,mean serum E2 of ET was 282.36±235.28pg/mL,mean serum P of ET was 15.41±6.07ng/mL.There were 258 cases of primary infertility and 144 cases of secondary infertility.In Vitro Fertilization(IVF)was 357,Intracytoplasmic Sperm Injection(ICSI)was 45.The cleavage stage of transplantation was 156,and the blastocyst stage of transplantation was 246.The clinical pregnancy of overall population was 217,the live birth was 179,the dead birth was 1,the biochemical pregnancy was 30 and the spontaneous abortion was 37.The overall clinical pregnancy rate was 53.98% (95% CI: 49–59%) and live birth rate was 44.53% (95% CI: 40-49%). Clinical outcome according to serum P on the day of embryo transfer The mean serum P levels on the day of ET was 15.41±6.07ng/ml.Table I shows the 5th,10th,25th,50th,75th,90th and 95th percentile values of serum P.Patients were divided in 8 groups by serum P levels and clinical pregnancy rate was calculated in each group(Figure 1).The clinical pregnancy rate with 9.45≤ serum P<23.32ng/ml was higher than that with serum P<9.45 ng/ml or ≥23.32 ng/ml.Therefore, serum P levels were divided into three groups according to the critical points of 9.45ng/ml and 23.32ng/ml.They were described as three groups,group A:serum P<9.45ng/ml,group B:9.45≤serum P<23.32ng/ml and group C:serum P≥23.32ng/ml.The clinical pregnancy rate of the three groups were 46.2%,56.73% and 40% for group A-C,respectively.The clinical pregnancy rate in group B was significantly higher than that in group C,and the difference was statistically significant of 56.7% vs 40%(χ2=3.987,P=0.046).The clinical pregnancy rate in group B was higher than that in group A,but there was no statistical difference of 56.7% vs 46.2% (χ2=1.554, P=0.212).(Table III).The live birth rate of group B was higher than that of groups A and C,but there was no statistical difference among the two groups for 46.4% vs 38.5%(χ2=0.893,P=0.345)and46.4%vs35%(χ2=1.881,P=0.170). There was no significant difference in biochemical pregnancy rate for group B vs group A (p=0.108) and group B vs group C (p=0.496) .There was no significant difference in spontaneous abortion rate for group B vs group A (p=0.463) and group B vs group C (p=0.562) (Table III). Multivariate logistic regression showed that serum P of 9.45–23.32 ng/ml remained an independent factor for clinical pregnancy rate in the three different populations after adjusting for all confounding variables (Table IV).The resulting adjusted OR (95% CI) for clinical pregnancy rate was 0.57(0.52-0.63; P<0.05) for patients with serum P of 9.45–23.32ng/ml on the day of ET.Fresh cycle insemination(OR:2.031;95%CI: 1.015-4.065; P=0.045) and number of high-quality embryo(OR: 2.785;95%CI:1.929-4.021;P=0.00) remained an independent factor for clinical pregnancy rate in the three different populations after adjusting. Exploratory analysis of factors related to serum P levels on the day of ET Correlation analysis identified which variables could impact serum P levels.There were significant differences in BMI (F=4.532,P=0.011)and estradiol levels (F=4.86,P=0.008) among the three groups.With the increase of progesterone levels,estradiol concentration increased gradually,Patients with serum P ≥23.32 ng/ml had a significantly higher estradiol levels than the rest(Table II).For age,BMI,AMH,infertility type,infertility years,number of eggs in fresh cycle,fresh cycle insemination,endometrial thickness,number of transferred embryos,Type of embryo transferred,number of high-quality embryo,there was no statistical difference between the three groups. Discussion The present study found that a serum P level between 9.45 and 23.32 ng/ml on the day of embryo transfer (ET) was associated with a significantly higher clinical pregnancy rate. This analysis was conducted in patients under 35 years of age with good ovarian function to minimize the confounding effects of advanced age and diminished ovarian reserve. Furthermore, all patients received the same progesterone dose for the same duration before ET. After adjusting for potential confounders, the significant association between the defined serum P range and clinical pregnancy remained. Mechanistically,the precise synchronization of embryo implantation and endometrial development is the key to a successful pregnancy.As we studied,during the HRT,when day 3 cleavage embryos were transferred on the 5th day of progesterone rise and day 5 or 6 blastocyst embryos were transferred on the 6th day of progesterone rise.Moreover our study found an optimal serum P concentration interval,while values outside this interval significantly related to low clinical pregnancy rate.It supported the view that the implantation window is time-sensitive [7] .Lower serum P may delay or hinder endometrial development.Our findings regarding a lower progesterone threshold align with existing literature.Labarta et al. [10] demonstrated that serum P levels below 9.2 ng/ml predicted a decreased clinical pregnancy rate in artificially prepared cycles, a result corroborated by a prospective cohort study establishing a similar threshold of 8.8 ng/ml [11] .While these studies confirm the detrimental effect of insufficient progesterone, they are distinguished from our work by a key finding: neither prior investigation identified a significant upper limit of serum P impacting pregnancy success, a critical relationship which our study has now established. The observed negative association between elevated serum P and clinical pregnancy rates may be explained by two primary hypotheses. The first involves the specific hormone replacement therapy (HRT) protocol. Unlike regimens that employ GnRH analogues for pituitary suppression, our protocol carried a potential, albeit rare (<1% incidence), risk of spontaneous ovulation that could disrupt endometrial synchrony [12] .The second, and more plausible, hypothesis is that supra-physiological progesterone levels prematurely advance the endometrial secretory transformation, closing the implantation window before embryo-endometrial synchronization can occur, a mechanism described by John et al. [7] .Although we corroborate the principle of an upper threshold, our specific limit (23.32 ng/ml) is lower than the 32.14 ng/ml reported by John et al. Several methodological differences may account for this. Their study used a higher progesterone dose (900 mg vs. 600 mg), measured levels later in the luteal phase (2-3 days post-ET), and importantly, the use of dydrogesterone confounds direct comparison, as it is not measured by standard immunoassays [13] .This is critical, as serum P levels do not increase proportionally with vaginal progesterone dosage [14] .Conversely, our findings conflict with those of Cozzolino et al. [15] ,who reported no detrimental effect on live birth even with serum P levels exceeding 40 ng/ml. During the luteal phase of the natural cycle,the pulsing release of progesterone causes the serum P to fluctuate greatly [16] ,varying by up to 6 times in a few hours [17] ,and the measurement is not accurate.However,in the artificial cycle,progesterone peaks rapidly and stabilizes within 24 hours [14] ,so its measurement is more reliable.Studies found that for women of childbearing age,a very small amount of serum P was needed to transform the inner membrane and receive embryo implantation.They treated the endometrium with low concentrations of progesterone (4-6ng/ml) and high concentrations of progesterone (15-20ng/ml), respectively,and found no significant differences in markers of human endometrial structure and function between the two groups,despite a four-fold difference in progesterone.Further reduction of progesterone dose revealed no significant changes in the structure or function of the human endometrium [17] .Although we did not assess endometrial marker changes, our study found no statistically significant difference in clinical pregnancy rates between the low and high serum P groups. This finding can be explained by two factors. First, as Young et al. [17] demonstrated, low serum P may not significantly alter endometrial structure or function, thereby preserving pregnancy outcomes. Second, the use of oral dydrogesterone means that the actual progestogenic activity was higher than the measured serum progesterone concentration suggests, which could have compensated for the low measured serum P levels and protected the pregnancy rate. The route of progesterone administration significantly influences its distribution. Vaginal administration benefits from a uterine first-pass effect, leading to higher endometrial concentrations than serum levels. This has led some to propose that intrauterine levels are the primary determinant of reproductive success [5] .However, others emphasize the importance of systemic exposure, suggesting serum progesterone’s anti-inflammatory effects are crucial for mediating the immune-endocrine environment during implantation and early placentation [18] .Current ESHRE guidelines endorse any non-oral natural progesterone for luteal phase support (LPS) and recognize dydrogesterone as the sole oral alternative, noting its comparable safety and tolerability [19] .Dydrogesterone’s unique biochemical configuration, which is stabilized by exposure to ultraviolet light, allows for effective oral absorption [20] .In our cohort, the combination of vaginal micronized progesterone and oral dydrogesterone showed no significant improvement in clinical pregnancy or live birth rates over vaginal dosing alone [11] ,a finding aligned with Metello et al. [21] , who reported no benefit from adding dydrogesterone on the day of ET. Consequently, the question of whether the systemic effects of serum progesterone confer an independent clinical advantage remains unresolved and warrants further investigation. In this study, we identified variables related to serum P levels.With the increase of serum P levels,BMI decreased gradually,Patients with serum P ≥23.32 ng/ml had a significantly lower BMI than the rest,which is consistent with some research results [11] .These interpersonal variations could be due to a variable capacity of absorption, clearance and different distribution in fat tissue.The impact of embryo quality on pregnancy outcomes is beyond doubt, and the clinical pregnancy rate of high-quality embryos is relatively high.This study found that the clinical pregnancy rate of ICSI insemination patients was higher than that of IVF patients. On the one hand, it was considered that the majority of ICSI-assisted pregnancy patients were infertile due to male factors, so ICSI insemination solved the main problem,It is consistent with research results [22] . On the other hand, there were relatively few patients undergoing ICSI fertilization in this study, which might lead to deviations. In conclusion, our analysis defines a specific serum progesterone window on the day of embryo transfer that is associated with optimal clinical pregnancy rates in a well-characterized cohort of POSEIDON Group 1 patients. This supports the concept of personalized luteal phase support, where progesterone supplementation could be adjusted based on serum levels measured on or shortly before the day of ET. While these results provide a valuable strategy for patients with a specific profile (young age, good ovarian response) undergoing HRT cycles, the generalizability of this optimal range to broader patient populations and different protocols must be confirmed by future large-scale studies. Acknowledgements The investigators would like to thank the study participants for volunteering to take part, as well as the researchers’ guidance on my article. Ethics approval and consent to participate This study was approved by the Ethics Committee of Yantai Yuhuangding Hospital, with the ethics number: 2025-182 Consent for publication Written informed consent was obtained from the patient for publication. Availability of data and material The datasets generated or analyzed during this study areavailable from the corresponding author on reasonablerequest. Competing interests The authors declare that they have no conflicts of interest. Funding None. Author contributions Xin Wang: conception, idea, design of the study and writing of the original draft; Lili Zhuang and Luqing Zhang:data collection and collation, review, and editing of the draft; Zhenteng Liu and Huishan Zhao: methodology and data analysis; Dongmei Zhao,Yingqian Peng and Hongchu Bao: supervision, project administration, guidance and paper finalization. All the authors have read and approved the final manuscript. References [1] Mourad, S., Brown, J., Farquhar, C. Interventions for the prevention of OHSS in ART cycles: an overview of Cochrane reviews[J]. The Cochrane database of systematic reviews, 2017, 1(1):CD012103.[2] Blesa, D., Ruiz-Alonso, M., Simón, C. Clinical management of endometrial receptivity[J]. Seminars in reproductive medicine, 2014, 32(5):410-3.[3] Lepage, J., Keromnes, G., Epelboin, S., Luton, D., Yazbeck, C. Premature progesterone rise on day of hCG negatively correlated with live birth rate in IVF cycles: An analysis of 1022 cycles[J]. 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Pregnancy rates relative to recipient plasma progesterone levels on the day of nonsurgical transfer of frozen/thawed bovine embryos[J]. Theriogenology, 1985, 23(4).[10] Labarta, E., Mariani, G., Holtmann, N., Celada, P., Remohi, J., Bosch, E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study[J]. Hum Reprod, 2017, 32(12):2437-2442.[11] Labarta, E., Mariani, G., Paolelli, S., Rodriguez-Varela, C., Vidal, C., Giles, J., Bellver, J., Cruz, F., Marzal, A., Celada, P., Olmo, I., Alama, P., Remohi, J., Bosch, E. Impact of low serum progesterone levels on the day of embryo transfer on pregnancy outcome: a prospective cohort study in artificial cycles with vaginal progesterone[J]. Hum Reprod, 2021, 36(3):683-692.[12] Yovich, J. L., Conceicao, J. L., Hinchliffe, P. M. GnRH agonist is not required for frozen embryo transfers conducted under artificial hormone therapy[J]. Reprod Biomed Online, 2015, 30(5):560.[13] Georg, G., Herman, T., Nick, M., Felice, P., Petra, A., Christophe, B., Peter, v. A., Claire, P.-F., Bart Cjm, F. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction[J]. Reprod Biomed Online, 2019, 38(2).[14] Richard J, P., Michael G, C., Vladimir I, Y. Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert[J]. J Clin Endocrinol Metab, 2014, 99(11).[15] Cozzolino, M., Hervas, I., Ergun, Y., Massaro, M. G., Pellicer, N., de Angelis, F., Labarta, E., Galliano, D. Higher serum progesterone level has no negative impact on live birth rate in frozen embryo transfer[J]. Eur J Obstet Gynecol Reprod Biol, 2024, 303:15-21.[16] Filicori, M., Butler, J., Crowley, W. Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion[J]. The Journal of clinical investigation, 1984, 73(6):1638-47.[17] Young, S. L. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity[J]. Reprod Biomed Online, 2013, 27(5):497-505.[18] E, L., P, S.-L., A, D.-P., P, C., C, V., J, G., C, R.-V., E, B., P, D.-G. Analysis of serum and endometrial progesterone in determining endometrial receptivity[J]. Hum Reprod, 2021, 36(11).[19] Ovarian Stimulation, T., Bosch, E., Broer, S., Griesinger, G., Grynberg, M., Humaidan, P., Kolibianakis, E., Kunicki, M., La Marca, A., Lainas, G., Le Clef, N., Massin, N., Mastenbroek, S., Polyzos, N., Sunkara, S. K., Timeva, T., Toyli, M., Urbancsek, J., Vermeulen, N., Broekmans, F. ESHRE guideline: ovarian stimulation for IVF/ICSI(dagger)[J]. Hum Reprod Open, 2020, 2020(2):hoaa009.[20] Barbosa, M. W. P., Valadares, N. P. B., Barbosa, A. C. P., Amaral, A. S., Iglesias, J. R., Nastri, C. O., Martins, W. P., Nakagawa, H. M. Oral dydrogesterone vs. vaginal progesterone capsules for luteal-phase support in women undergoing embryo transfer: a systematic review and meta-analysis[J]. JBRA Assist Reprod, 2018, 22(2):148-156.[21] Metello, J., Tomas, C., Ferreira, P., Natario, I., Santos-Ribeiro, S. Impact of dydrogesterone use in cycles with low progesterone levels on the day of frozen embryo transfer[J]. J Assist Reprod Genet, 2024, 41(6):1577-1584.[22] Lintsen, A. M., Eijkemans, M. J., Hunault, C. C., Bouwmans, C. A., Hakkaart, L., Habbema, J. D., Braat, D. D. Predicting ongoing pregnancy chances after IVF and ICSI: a national prospective study[J]. Hum Reprod, 2007, 22(9):2455-62. Supplementary Material File (figure1.doc) Download 2.20 MB File (table i.doc) Download 14.00 KB File (table ii.doc) Download 40.50 KB File (table iii.doc) Download 22.50 KB File (table iv.doc) Download 35.00 KB Information & Authors Information Version history V1 Version 1 22 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords fertility and assisted reproduction infertility: assisted conception Authors Affiliations Xin Wang 0009-0008-9872-1485 Yantai Yuhuangding Hospital View all articles by this author Lili Zhuang Yantai Yuhuangding Hospital View all articles by this author Luqing Zhang Yantai Yuhuangding Hospital View all articles by this author Zhenteng Liu Yantai Yuhuangding Hospital View all articles by this author Huishan Zhao Yantai Yuhuangding Hospital View all articles by this author Dongmei Zhao Yantai Yuhuangding Hospital View all articles by this author Yingqian Peng Yantai Yuhuangding Hospital View all articles by this author Hongchu Bao [email protected] Yantai Yuhuangding Hospital View all articles by this author Metrics & Citations Metrics Article Usage 345 views 97 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Xin Wang, Lili Zhuang, Luqing Zhang, et al. 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