Efficacy of Daily 50 mg Intramuscular Progesterone for Luteal Phase Support in Frozen Embryo Transfer Cycles: Analysis of Serum Levels and Pregnancy Outcomes

Efficacy of Daily 50 mg Intramuscular Progesterone for Luteal Phase Support in Frozen Embryo Transfer Cycles: Analysis of Serum Levels and Pregnancy Outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of Daily 50 mg Intramuscular Progesterone for Luteal Phase Support in Frozen Embryo Transfer Cycles: Analysis of Serum Levels and Pregnancy Outcomes Robabeh Hatami, Ensieh Shahrokh Tehraninejad, Batool Hossein Rashidi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5875677/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Frozen embryo transfer (FET) success depends on adequate luteal phase support (LPS), with serum progesterone (P4) levels on embryo transfer (ET) day being a critical factor. While serum P4 levels have been probably associated with improved outcomes, there is ongoing debate regarding the most effective route and dosage of P4 supplementation. This prospective cohort study aimed to ( 1 ) evaluate the efficacy of 50 mg/day intramuscular (IM) progesterone in achieving optimal serum P4 levels during endometrial preparation and ( 2 ) investigate the association between serum P4 levels on ET day and subsequent fertility outcomes in hormone replacement therapy (HRT) FET cycles. Methods The study included 121 women (aged 22–45 years) undergoing HRT-FET at Imam Khomeini Hospital Complex from December 2022 to January 2024. Endometrial preparation began with oral estradiol valerate (6 mg/day) on cycle day 2, followed by daily IM P4 (50 mg) upon achieving endometrial thickness ≥ 8 mm. Serum P4 levels were measured on ET day, and oral dydrogesterone (20 mg/day) was added for patients with P4 levels < 10.0 ng/mL. Primary outcomes included chemical pregnancy, clinical pregnancy, miscarriage, and ongoing pregnancy rates. Results The mean serum P4 level on ET day was 22.8 ± 10.1 ng/mL, with 78.5% of participants achieving the target range (10-32.5 ng/mL) following IM P4 administration. Overall chemical pregnancy, clinical pregnancy, and ongoing pregnancy rates were 23.1%, 18.2%, and 14.1%, respectively, with a miscarriage rate of 5.0%. Multivariate analysis revealed that P4 levels > 27.8 ng/mL were associated with reduced odds of chemical pregnancy (OR = 0.22; 95% CI: 0.05–0.92; p = 0.04), while no significant differences were observed in other pregnancy outcomes across P4 quartiles. Conclusion Daily administration of 50 mg IM P4 effectively achieved optimal serum P4 levels in most patients. While higher P4 levels (> 27.8 ng/mL) were associated with reduced chemical pregnancy rates, the absence of significant correlations with other pregnancy outcomes highlights the multifactorial nature of embryo implantation success. These findings emphasize the need for further research to refine P4 thresholds and identify additional predictive factors influencing pregnancy outcomes in FET cycles. Frozen Embryo Transfer Luteal Phase Support Progesterone Pregnancy Outcomes Hormone Replacement Therapy Figures Figure 1 Introduction Frozen embryo transfer (FET) has undergone remarkable transformation with advancements in vitrification techniques, revolutionizing assisted reproductive technology (ART) by offering enhanced pregnancy rates and improved clinical outcomes ( 1 ). By optimizing embryo transfer conditions, FET provides clinicians and patients with a more flexible and potentially more successful approach to assisted reproduction. Endometrial preparation represents a critical determinant of reproductive success, with multiple protocols available, including natural cycle (NC), modified natural cycle (MNC), artificial cycle with hormone replacement therapy (AC-HRT), and mild ovarian stimulation ( 2 ). There is no sufficient evidence that shows which endometrium preparation protocol is the best. While natural menstrual cycles involve corpus luteum production of approximately 25–50 mg of progesterone daily, ART cycles require exogenous supplementation to support endometrial gland formation and successful trophoblast invasion ( 3 , 4 ). Luteal phase support (LPS) in FET cycles has predominantly been studied through retrospective research, revealing significant knowledge gaps ( 5 ). Recent studies have highlighted the critical importance of serum progesterone (P4) levels on the day of embryo transfer (ET) ( 6 – 8 ). Emerging evidence suggests remarkable variability in serum P4 levels among patients receiving identical hormonal protocols, with these variations potentially correlating with differential live birth rates. Most research identifies a threshold range between 10–20 ng/mL as pivotal for successful pregnancy, with levels below 5–12 ng/mL or above 30-32.5 ng/mL associated with reduced clinical pregnancy rates and increased miscarriage risks ( 6 – 13 ). Patients have traditionally received P4 supplementation uniformly, adopting a "one size fits all" approach that ignores potential inter-individual physiological variations that could impact reproductive success ( 14 , 15 ). Factors such as patient age, body mass index (BMI), metabolic characteristics, and individual hormonal profiles contribute to these complex interactions ( 9 ). Multiple administration routes exist for P4 supplementation, including intramuscular, vaginal, oral, subcutaneous, and trans-rectal, each associated with distinct serum and endometrial tissue responses ( 12 , 16 , 17 ). Comparative studies have revealed potential differences in outcomes between various P4 administration routes, with some research suggesting that combined or IM approaches might offer superior results compared to vaginal administration alone ( 17 – 20 ). Additionally, Dydrogesterone (DYD), a stereoisomer of P4, seems to be a good alternative for the treatment of LPS in an artificial cycle, especially in combination with a high dose of IM P4 during the course of oocyte donation ( 21 – 24 ). Given the intricate relationship between P4 levels and reproductive outcomes, this prospective cohort study aims to comprehensively investigate two primary objectives: first, to determine whether IM P4 administration can effectively elevate serum P4 concentrations to the optimal range during endometrial preparation; and second, to examine the correlation between these serum P4 levels on embryo transfer day and subsequent fertility outcomes in HRT-FET protocols. By elucidating these nuanced relationships, we seek to advance personalized approaches in assisted reproductive interventions and challenge the conventional uniform approach to LPS. Methods Study design and Setting This prospective cohort study was conducted at the Infertility Clinic of Imam Khomeini Hospital Complex (IKHC), a teaching center affiliated with Tehran University of Medical Sciences (TUMS) in Tehran, Iran, from December 2022 to January 2024. The study protocol received approval from the Institutional Review Board and Ethics Committee of Tehran University of Medical Sciences, with a comprehensive informed consent process implemented for all participants (approval code: IR.TUMS.IKHC.REC.1401.204). Participants The study included 121 eligible women aged 22 to 45 years who were candidates for frozen embryo transfer (FET) using hormone replacement therapy (HRT). Participants were carefully selected based on specific inclusion and exclusion criteria. Inclusion criteria comprised willingness to participate, normal uterine anatomy, and infertility requiring FET. Patients with recurrent miscarriage, repeated implantation failure, uterine abnormalities, metabolic disorders, antiphospholipid syndrome, severe male factor infertility, or the presence of hydrosalpinx were excluded. Embryo Morphology Assessment About 55% of the patients were undergoing their first FET cycle. Embryos were derived from intracytoplasmic sperm injection (ICSI) cycles. Embryo quality assessment utilized the standardized Gardner classification system (Gardner and Schoolcraft, 1999) and categorized as excellent, good, average, or poor. In the present, study patients who had poor-level embryos, according to the Gardner classification, were excluded. Endometrial preparation and Progesterone administration protocol Endometrial preparation commenced on the second day of the menstrual cycle through oral estradiol valerate administration (6 mg/day, Aburaihan Pharmaceutical Co., Tehran, Iran). Transvaginal ultrasonography (TV-USG) (Philips Healthcare, Netherlands, Model; Affiniti 70) was performed periodically by an expert infertility fellowship to measure endometrial thickness and to confirm a triple layer pattern. Once the endometrial thickness reached ≥ 8 mm, 50 mg of IM progesterone (Fertigest, Aburaihan Pharmaceutical Co., Tehran, Iran) was administered daily for LPS. Embryo transfers were conducted at two distinct time points following the initiation of progesterone (P4) administration: at day 4 for embryos at the cleavage stage and at day 6 for those that had reached the blastocyst stage. Blood sampling occurred between 7:00 and 10:00 AM on the ET day to measure serum P4 concentrations. The biochemical analysis was performed using chemiluminescent microparticle immunoassay (CMIA) (ARCHITECT Progesterone, Abbott Laboratories, Illinois, USA). For patients receiving routine LPS and having serum P4 levels < 10.0 ng/ml on the FET day, we added oral DYD (20 mg/day, Duphaston, Abbott Healthcare Co., Netherlands) to salvage the FET cycles. E2 and P4 supplementation were continued until the 10th week of pregnancy in patients with confirmed pregnancies. Participants were followed up until the 12th week to monitor miscarriage or ongoing pregnancy status. Outcome Measures Serum β-HCG levels were measured two weeks after ET day. Patients who demonstrated positive β-HCG tests (> 50 IU/L) were scheduled for their initial TV-USG two weeks later to verify the presence of a gestational sac. Chemical pregnancy (positive β-HCG test), clinical pregnancy (visualization of a gestational sac with fetal heartbeat on ultrasound), miscarriage (pregnancy loss before 12 weeks), and ongoing pregnancy (presence of fetal heartbeat beyond 12 weeks) were examined. Recognizing the optimum range of serum P4 levels on ET day (10-32.5 ng/mL) to improve pregnancy outcomes based on prior research, the primary objective of the study was to determine the efficacy of daily 50 mg intramuscular P4 administration in achieving these optimal serum P4 levels, and the second objective was to comprehensively evaluate pregnancy outcomes between participants whose serum P4 levels fall within this target range and those whose levels remain outside it. Statistical Analysis P4 levels above 10 ng/mL (including women who received only IM P4) were stratified into four quartiles to facilitate more analysis. Descriptive statistics were used to summarize patient demographic characteristics, including age, BMI, infertility type (primary or secondary), and duration of infertility. Quantitative variables were reported as mean ± standard deviation (SD), and categorical variables were presented as frequency and percentage. Quartiles of serum P4 levels were compared using analysis of variance (ANOVA) and chi-square tests for continuous and categorical variables, respectively. The relationships between serum P levels and pregnancy outcomes were evaluated using logistic regression analysis. A p-value < 0.05 was considered statistically significant. All statistical analyses were conducted using SPSS version 20 (IBM Corp., Armonk, NY, USA). Results A total of 121 eligible women were included in the final analysis. The mean age of participants was 35.6 ± 6.1 years (range: 22–45), and the mean duration of infertility was 6.0 ± 4.0 years. Most participants (70.3%) experienced primary infertility, while 29.7% had secondary infertility. Male factor infertility accounted for 22.3% of cases, with the remainder attributed to ovulatory disorders, tubal factor, unexplained, or multifactorial causes. The mean serum progesterone (P4) level on the day of embryo transfer (ET) was 22.8 ± 10.1 ng/mL, ranging from 7.5 to 60.8 ng/mL (Table 1 ). Following the administration of 50 mg/day IM P4, a significant proportion of participants (n = 95, 78.5%) achieved the target optimal serum P4 concentration. Specifically, these patients demonstrated P4 levels within the clinically favorable range of 10-32.5 ng/mL. Conversely, 5 cases (4.1%) exhibited persistently low P4 concentrations, with serum levels remaining 32.5 ng/mL. Serum Progesterone Quartiles and Baseline Characteristics Participants receiving IM P4 for luteal phase support (LPS) were stratified into quartiles based on serum P4 levels on ET day: Q1 (10.0–16.2 ng/mL), Q2 (16.3–20.9 ng/mL), Q3 (21.0–27.8 ng/mL), and Q4 (> 27.8 ng/mL). No statistically significant differences in demographic or clinical characteristics—including age, BMI, duration of infertility, endometrial thickness, and number of transferred embryos—were observed across quartiles (p > 0.05) (Table 2 ). Pregnancy Outcomes The overall chemical pregnancy rate was 23.1%, the clinical pregnancy rate was 18.2%, and the ongoing pregnancy rate was 14.1%, with a miscarriage rate of 5.0%. Pregnancy outcomes did not significantly differ between P4 administration protocols (IM P4 vs. IM P4 + DYD) (p > 0.05). Although higher chemical and clinical pregnancy rates were observed in Q4 compared to other quartiles, these differences did not reach statistical significance (p > 0.05) (Table 2 , 3 ). Multivariate Analysis Multivariate logistic regression analysis revealed that higher serum P4 levels on ET day (Q4: >27.8 ng/mL) were significantly associated with reduced odds of chemical pregnancy compared to Q1 (OR = 0.22; 95% CI: 0.05–0.92; p = 0.04) (Table 4 ). Other variables, including age, BMI, duration of infertility, endometrial thickness, duration of E2 consumption, and number of transferred embryos, were not significantly associated with pregnancy outcomes (p > 0.05) (Table 4 ). Combined Quartile Analysis To further assess the relationship between serum P4 levels and pregnancy outcomes, quartiles were grouped into two categories: Q1 & Q2 (10.0–20.9 ng/mL) and Q3 & Q4 (> 21.0 ng/mL). Figure 1 illustrates the comparison of pregnancy outcomes between these groups. Patients in Q3 & Q4 demonstrated numerically higher rates of pregnancy outcomes, but these findings lacked statistical significance. Table 1 Demographic and clinical characteristics of the patients in the study Continuous Variables Mean ± SD Range Age (year) 35.6 ± 6.1 22, 45 BMI (kg/m 2 ) 26.3 ± 4.6 17.1, 45 Duration of infertility (year) 6.0 ± 4.0 1, 20 Endometrial thickness (mm) 8.9 ± 1.7 7, 19.2 Duration of E2 consumption (day) 14.6 ± 2.1 11, 24 P4 level on ET day (ng/mL) 22.8 ± 10.1 7.5, 60.8 Categorical Variables Frequency Percentage Type of infertility Primary 85 70.3 Secondary 36 29.7 Cause of infertility Ovulatory 41 33.9 Tubal 8 6.6 Male factor 27 22.3 Un-explained 5 4.1 Multifactorial 40 33.1 Frequency of embryo transferred First 67 55.4 Second 40 33.1 Third 14 11.5 Number of transferred embryo One 7 5.8 Two 114 94.2 Days of embryo transferred 3 Days 67 55.4 5 Days 54 44.6 BMI: Body mass index, E2: Estradiol, P4: Progesterone Table 2 Comparison of variables according to serum progesterone quartiles Variable Serum P4 levels (ng/mL) p-value between quartiles IM P4 + DYD IM P4 P4 27.8) (n = 29) Age (year) 37.9 ± 5.1 35.5 ± 5.7 35.3 ± 5.3 36.1 ± 6.9 35.2 ± 6.9 0.94 BMI (kg/m 2 ) 26.8 ± 4.4 27.6 ± 4.2 26.6 ± 4.4 25.8 ± 5.4 25.0 ± 3.9 0.16 Duration of infertility (year) 8.0 ± 5.1 6.9 ± 5.5 5.9 ± 3.7 5.6 ± 2.8 5.3 ± 3.1 0.92 Endometrial thickness (mm) 9.0 ± 1.9 9.2 ± 1.5 8.9 ± 2.2 8.6 ± 1.3 9.1 ± 1.8 0.63 Duration of E2 consumption (day) 13.4 ± 1.3 14.2 ± 2.2 14.4 ± 2.3 14.9 ± 2.1 14.8 ± 1.7 0.58 N. of transferred embryos (%) One 0 (0%) 0 (0%) 0 (0%) 4 (13.8%) 3 (10.3%) 0.053 Two 5 (100%) 29 (100%) 29 (100%) 25 (86.2%) 26 (89.7%) Embryo quality Excellent 2 (40%) 10 (34.5%) 15 (51.7%) 8 (27.6%) 9 (31.1%) 0.12 Good 3 (60%) 18 (62.1%) 11 (38%) 17 (58.6%) 17 (58.6%) Average 0 (0%) 1 (3.4%) 3 (10.3%) 4 (13.8%) 3 (10.3%) Chemical pregnancy rate 2 (40%) 4 (13.8%) 8 (27.6%) 4 (13.8%) 10 (34.5%) 0.15 Clinical pregnancy rate 1 (20%) 4 (13.8%) 6 (20.6%) 3 (10.3%) 8 (27.6%) 0.75 Miscarriage rate 0 (0%) 1 (3.4%) 1 (3.4%) 1 (3.4%) 3 (10.3%) 0.90 Ongoing pregnancy rate 1 (20%) 3 (10.3%) 5 (17.2%) 2 (6.9%) 6 (20.6%) 0.91 Twin pregnancy rate 1 (20%) 1 (3.4%) 0 (0%) 0 (0%) 2 (6.9%) 0.39 Q: Quartile, BMI: Body mass index, E2: Estradiol, P4: Progesterone Table 3 Pregnancy outcomes based on serum progesterone levels on ET day Variable Total (%) Serum P4 levels (ng/mL) p-value 10 (n = 116) Chemical pregnancy rate 28 (23.1%) 2 (40%) 26 (22.4%) 0.36 Clinical pregnancy rate 22 (18.2%) 1 (20%) 21 (18.1%) 0.31 Miscarriage rate 6 (5.0%) 0 (0%) 6 (5.2%) 0.54 Ongoing pregnancy rate 17 (14.1%) 1 (20%) 16 (13.8%) 0.75 Twin pregnancy rate 4 (3.3%) 1 (20%) 3 (2.6%) 0.13 Table 4 Multivariate logistic regression analysis of factors associated with chemical pregnancy Variables B OR (95% CI) p-value Age 0.07 1.07 (0.99–1.16) 0.09 BMI -0.04 0.96 (0.87–1.06) 0.43 Duration of infertility 0.01 1.01 (0.89–1.16) 0.82 Endometrial thickness -0.14 0.87 (0.67–1.12) 0.28 Duration of E2 consumption 0.16 1.17 (0.90–1.52) 0.25 Number of transferred embryos -0.40 0.67 (0.06–7.34) 0.75 Serum P4 levels (ng/mL) Q1 (10.0-16.2) Reference group Q2 (16.3–20.9) -1.03 0.36 (0.09–1.44) 0.15 Q3 (21.0-27.8) -0.36 0.70 (0.14–3.43) 0.66 Q4 (> 27.8) -1.51 0.22 (0.05–0.92) 0.04 OR: Odds ratio, CI: Confidence interval, BMI: Body mass index, E2: Estradiol, P4: Progesterone, Q: Quartile Discussion This prospective cohort study aimed to investigate the potency of IM P4 administration to reach serum P4 levels on the day of ET to the favorable range in the HRT-FET cycles. Additionally, the study sought to comparatively assess pregnancy outcomes between two therapeutic protocols during endometrial preparation: IM P4 (50 mg/day) alone and IM P4 (50 mg/day) + oral DYD (20 mg/day). In cases where serum P4 levels were low (< 10 ng/mL), DYD was administered. According to the study results, the IM P4 protocol was identified as an effective treatment strategy. Notably, it successfully achieved the optimal P4 range of 10-31.5 ng/mL in 78.51% of participants. Statistical analysis revealed that despite the lower P4 levels on ET day, there was no statistically significant difference in clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), or miscarriage rates (MR) between this group and the group with P4 levels > 10 ng/mL using the IM P4 protocol. Importantly, the study findings demonstrated no significant correlation between serum P4 levels and pregnancy outcomes, suggesting that serum P4 levels measured on the day of ET may not be a reliable predictor of embryo transfer success in patients receiving IM P4 for LPS. Importantly, the study findings indicate a significant negative association between elevated serum P4 levels (> 27.8 ng/mL) on ET day and chemical pregnancy rates, suggesting that high P4 levels may adversely affect embryo transfer success. However, no significant differences in other pregnancy outcomes were observed across quartiles, implying that serum P4 levels may not be a reliable predictor of ET success. The CPR, OPR, and MR in our study were reported as 18.18%, 14.05%, and 4.96%, respectively. In a prior study, Alyasin and colleagues estimated a CPR of 35.6% in the group that received IM P4. They demonstrated a significant correlation between serum P4 levels and CPR as well as the LBR ( 10 ). Gaggiotti-Marre et al. demonstrated that women with lower quartile P4 levels have a higher MR compared to women with higher quartile levels ( 13 ). The findings of Álvarez et al.'s study indicated that individualized LPS led to higher OPR in patients receiving HRT one day before ET ( 25 ). Results from several previous studies also showed that serum P4 level is a significant factor in predicting independent LBR ( 26 , 27 ), which contradicts our study's results. Possible reasons for this difference include the variations in P4 route and dose of administration, timing of measurement, the baseline P4 levels, and individual metabolic characteristics of participants. Nevertheless, some studies support our findings. In line with our results, Volovsky et al. in their study showed that P4 levels > 10 ng/mL on the day of FET are not a significant factor in predicting CPR and LBR ( 12 ). Alyasin et al. did not find any correlation between serum P4 levels and miscarriage ( 10 ). Polat and colleagues, in a retrospective cohort study, demonstrated that while examining the impact of VP4 compared to IM P4 on OPR, the prescription of P4 is not an independent predictor of OPR ( 14 ). The findings of the study by Cédrin-Durnerin et al. indicated that doubling the dose of VP4 on the ET day has no effect on fertility outcomes ( 27 ). In the study by Chen and colleagues, serum P4 levels on ET day showed no significant association with LBR or CPR in artificial cycles with IM P4, while D5 blastocysts and good-quality embryos were independently linked to higher LBR ( 28 ). The findings of this study indicated that there is no significant difference in serum P4 levels across age and BMI quartiles. However, González-Foruria et al. found that a woman's age can influence the absorption of P4 ( 26 ), which contrasts with our study's results. The potential reason for this difference may be the variation in the method of VP4 administration compared to IM P4. The researchers in that study also attributed the potential increase in drug absorption to vaginal atrophy and thin vaginal mucosa in older women. The optimal timing of P4 testing and the ideal P4 blood concentrations have not been definitively established, and treatment strategies based on serum P4 are still under investigation. Findings from Kofinas et al.’s study indicate that maintaining P4 levels within the range of 10–20 ng/ml is essential ( 6 ). Furthermore, the results of this study showed that P4 levels higher than 30 ng/ml have an adverse effect on the cycle. In interpreting the findings of this study, it can be said that low P4 levels hinder endometrial growth. On the other hand, significantly higher P4 levels accelerate endometrial growth, potentially delaying the window of implantation. The main source of P4 in the early stages of NC is the corpus luteum, which persists until approximately the first 8 weeks of pregnancy. After that, placental P4 synthesis takes over. After the luteal phase declines, infertility treatment necessitates P4 supplementation ( 29 ). In our study, we examined P4 levels during cycles controlled by IM exogenous hormone therapy. While the IM method presented notable challenges in patient tolerance, its potential clinical advantages warrant careful consideration in assisted reproductive techniques. The results of a study by Devine et al. demonstrated that women who received only VP4 for LPS, without any IM administration of P4, had significantly poorer OPR ( 18 ). Kaser et al. found that women who received Crinone vaginal gel, had 44% lower odds of CPR and 49% lower odds of LBR, compared with women who received IM P4 ( 19 ). In a randomized clinical trial by Tehraninejad et al., IM P4 administration for LPS demonstrated superior chemical pregnancy rates compared to vaginal and subcutaneous routes, despite patients reporting higher discomfort related to pain and swelling ( 17 ). However, some other research appeared that endometrial P4 levels play a more significant role in the success of FET cycles compared to serum levels. In a study by Miles, it was shown that although serum P4 concentration following IM P4 injection is more than double that of vaginal administration, the average endometrial concentration of P4 in the vaginal method is approximately 8 times higher ( 30 ). According to Klement et al.'s study, the P4 serum concentration was significantly higher in patients using the IM P4 compared to VP4 administration, but this did not translate into a lower sub-endometrial contractility ( 16 ). In total, due to the lack of strong randomized controlled trials, a consensus on the best P4 administration method during FET cycles has not been reached. There is a prevailing belief among a proportion of Iranian reproductive endocrinology and infertility specialists that administering 50 mg/day of IM P4 for endometrial preparation in FET cycles is considered insufficient. Consequently, they routinely prescribe 100 mg/day of IM P4 (Fertigest, Aburaihan Pharmaceutical Co., Tehran, Iran) ( 22 , 31 – 33 ), 800 mg/day of VP4 (Cyclogest®, Actoverco, Iran) ( 22 , 34 – 37 ), or a combination of IM P4 and VP4 ( 10 , 24 ), despite increased patient discomfort. In the present study, administration of 50 mg/day IM P4 alone not only resulted in achieving substantial serum P4 levels (> 10 ng/mL) on the ET day in about 96% of women but also yielded comparable pregnancy outcomes to other similar studies that utilized higher P4 doses. In prior studies by Arabian et al. and Lorillon et al., oral DYD was found to be as effective as IM P4 ( 24 ) and VP4 ( 21 ) in maintaining pregnancy, as measured by CPR, OPR, and MR. Also, Rashidi et al. evaluated the pregnancy outcomes of oral, IM, and vaginal P4 administration for LPS during HRT-FET ( 22 ). According to their results, the pregnancy rates, abortion, and LBR were not significantly different among groups. Consequently, these findings positioned DYD as a compelling hormonal support protocol, characterized by reduced local complications, lower treatment costs, and enhanced patient satisfaction. In our current study, among 5 women receiving DYD combined with IM P4 according to the specified protocol, the OPR and MR were 20% and 0%. Interestingly, despite observing lower serum P4 levels on the ET day in this cohort, the pregnancy outcomes were superior compared to the group receiving IM P4 alone, although this difference did not reach statistical significance. However, it is crucial to acknowledge the limitation of our study's small sample size, which substantially constrains the potential for robust statistical analysis and broader result generalization. This study had several limitations. One limitation is the relatively short follow-up period, which only extended to the first 12 weeks of pregnancy. Additionally, the study did not investigate the outcomes of IM P4 administration after childbirth and the LBR. Given the limited sample size and the potential variability in individual responses to P4, further research is necessary to explore the potential benefits of individualized LPS. Future studies should aim to include larger, multicenter cohorts, assess the impact of different P4 administration routes and dosages, and evaluate outcomes, especially LBR and neonatal health rate during FET cycles. Conclusion Daily administration of 50 mg IM P4 remains a promising approach for endometrial preparation in FET cycles, offering accessibility and effective elevation of serum P4 levels to optimal ranges. However, monitoring serum P4 levels on ET day is recommended to ensure adequate LPS. The addition of DYD can serve as a supplementary measure in these cases. This study identified a significant negative association between elevated serum P4 levels (> 27.8 ng/mL) on the ET day and chemical pregnancy rates. However, the absence of significant correlations with other pregnancy outcomes highlights the multifactorial nature of embryo implantation success. These findings emphasize the need for further research to refine P4 thresholds and identify additional predictive factors influencing pregnancy outcomes in FET cycles. Abbreviations FET Frozen Embryo Transfer ART Assisted Reproductive Technology NC Natural Cycle MNC Modified Natural Cycle AC-HRT Artificial Cycle with Hormone Replacement Therapy LPS Luteal Phase Support P4 Progesterone DYD Dydrogesterone IM P4 Intramuscular Progesterone VP4 Vaginal Progesterone TV-USG Transvaginal Ultrasonography ICSI Intracytoplasmic Sperm Injection OPR Ongoing Pregnancy Rate CPR Clinical Pregnancy Rate MR Miscarriage Rates LBR Live Birth Rate Declarations Acknowledgements The authors would like to thank the participating women, for providing consent, without which the study would not have been possible. Author contributions The conception and study design was developed by Dr. Batool Hossein Rashidi. This manuscript was derived from Dr. Robabeh Hatami's infertility fellowship thesis research. Dr. Ensieh Shahrokh Tehraninejad, Dr. Batool Hossein Rashidi, Dr. Fatemeh Keikha, and Dr. Azadeh Tarafdari were involved in clinical investigation and patient care at the infertility clinic. Dr. Masoumeh Masoumi was responsible for data collection and patient follow-up procedures. Dr. Azadeh Tarafdari and Dr. Amirali Barkhordarioon contributed to data analysis and finalization of the manuscript. All authors have read and agreed to the published version of the manuscript. The authors declare no conflicts of interest, and this research received no external funding. Written informed consent was obtained from all subjects involved in the study. The data that support the findings of this study are available from the corresponding author upon reasonable request. Funding No funding or sponsorship was received for this study. Data availability The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. All relevant data are presented within the manuscript and summary statistics of the analyzed variables are included in the tables. Ethics approval and consent to participate This study was approved by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.IKHC.REC.1401.204). Informed consent was obtained from legal guardians of the subjects enrolled in the study for study participation. This study was performed in accordance with the Declaration of Helsinki. Clinical trial number is not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References De Geyter C, Wyns C, Calhaz-Jorge C, de Mouzon J, Ferraretti AP, Kupka M, et al. 20 years of the European IVF-monitoring Consortium registry: what have we learned? A comparison with registries from two other regions. Hum Reprod. 2020;35(12):2832-49. Mumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, et al. 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Melo P, Chung Y, Pickering O, Price MJ, Fishel S, Khairy M, et al. Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis. Fertil Steril. 2021;116(6):1534-56. Hershko Klement A, Samara N, Weintraub A, Mitri F, Bentov Y, Chang P, et al. Intramuscular versus Vaginal Progesterone Administration in Medicated Frozen Embryo Transfer Cycles: A Randomized Clinical Trial Assessing Sub-Endometrial Contractions. Gynecol Obstet Invest. 2018;83(1):40-4. Tehraninejad ES, Alizadeh S, Nekoo EA, Zargarzadeh N, Shariat M, Haghollahi F, et al. Comparing the outcomes of in-vitro fertilization in patients receiving vaginal, subcutaneous, and intramuscular progesterone for luteal phase support: a three-armed randomized controlled trial. BMC Womens Health. 2024;24(1):481. Devine K, Richter KS, Widra EA, McKeeby JL. Vitrified blastocyst transfer cycles with the use of only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: results from the planned interim analysis of a three-arm randomized controlled noninferiority trial. Fertil Steril. 2018;109(2):266-75. Kaser DJ, Ginsburg ES, Missmer SA, Correia KF, Racowsky C. Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support for day 3 cryopreserved embryo transfer. Fertil Steril. 2012;98(6):1464-9. Delcour C, Robin G, Delesalle AS, Drumez E, Plouvier P, Dewailly D, et al. Weekly intramuscular progesterone for luteal phase support in women receiving oocyte donation is associated with a decreased miscarriage rate. Reprod Biomed Online. 2019;39(3):446-51. Lorillon M, Robin G, Keller L, Cailliau E, Delcourt C, Simon V, et al. Is oral dydrogesterone equivalent to vaginal micronized progesterone for luteal phase support in women receiving oocyte donation? Reprod Biol Endocrinol. 2024;22(1):154. Rashidi BH, Ghazizadeh M, Tehrani Nejad ES, Bagheri M, Gorginzadeh M. Oral dydrogesterone for luteal support in frozen-thawed embryo transfer artificial cycles: A pilot randomized controlled trial. Asian Pacific Journal of Reproduction. 2016;5(6):490-4. Neumann K, Masuch A, Vonthein R, Depenbusch M, Schultze-Mosgau A, Eggersmann TK, et al. Dydrogesterone and 20α-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study. Hum Reprod. 2022;37(6):1183-93. Sahereh A, Maryam E, Saeideh D, Nahid H, Elham N. Comparison of pregnancy outcome after adding oral or intramuscular progesterone to vaginal progesterone in frozen embryo transfer: A cross-sectional study. International Journal of Reproductive BioMedicine (IJRM). 2024;22(10). Alvarez M, Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Gonzalez-Foruria I, et al. Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study. Hum Reprod. 2021;36(6):1552-60. González-Foruria I, Gaggiotti-Marre S, Álvarez M, Martínez F, García S, Rodríguez I, et al. Factors associated with serum progesterone concentrations the day before cryopreserved embryo transfer in artificial cycles. Reproductive BioMedicine Online. 2020;40(6):797-804. Cédrin-Durnerin I, Isnard T, Mahdjoub S, Sonigo C, Seroka A, Comtet M, et al. Serum progesterone concentration and live birth rate in frozen-thawed embryo transfers with hormonally prepared endometrium. Reprod Biomed Online. 2019;38(3):472-80. Chen W, Xu Y, Liu X, Pan J, Cai B, Zhou C, et al. Serum Progesterone Level on the Day of Embryo Transfer Is Not a Reliable Predictor for Frozen-Thawed Embryo Transfer Outcomes With Euploid Blastocyst Transfer: A Retrospective Cohort Study. Bjog. 2024. Ovarian Stimulation T, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI(†). Hum Reprod Open. 2020;2020(2):hoaa009. Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril. 1994;62(3):485-90. Akbari Asbagh F, Ghasemzadeh F, Ebrahimi M, Davari-Tanha F, Feizabad E, Akbari Asbagh P, et al. Effect of intramuscular injection of human chorionic gonadotropin on endometrium preparation in frozen-thawed embryo transfer cycle: A randomized clinical trial. Caspian J Intern Med. 2023;14(2):185-91. Eftekhar M, Rahsepar M, Rahmani E. Effect of progesterone supplementation on natural frozen-thawed embryo transfer cycles: a randomized controlled trial. Int J Fertil Steril. 2013;7(1):13-20. Eslami Moayed M, Moini A, Kashani L, Farid Mojtahedi M, Rezaee T, Tabasizadeh H, et al. Pregnancy outcomes in women with adenomyosis, undergoing artificial endometrial preparation with and without gonadotropin-releasing hormone agonist pretreatment in frozen embryo transfer cycles: An RCT. Int J Reprod Biomed. 2023;21(6):481-90. Agha-Hosseini M, Hashemi L, Aleyasin A, Ghasemi M, Sarvi F, Shabani Nashtaei M, et al. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: A randomized prospective trial. Turk J Obstet Gynecol. 2018;15(1):12-7. Farid Mojtahedi M, Aref S, Moini A, Maleki-Hajiagha A, Kashani L. Natural cycle versus modified natural cycle for endometrial preparation in women undergoing frozen-thawed embryo transfer: An RCT. Int J Reprod Biomed. 2022;20(11):923-30. Aflatoonian A, Mohammadi B. Subcutaneous progesterone versus vaginal progesterone for luteal-phase support in frozen-thawed embryo transfer: A cross-sectional study. Int J Reprod Biomed. 2021;19(2):115-20. Omidi M, Halvaei I, Akyash F, Khalili MA, Agha-Rahimi A, Heydari L. The exact synchronization timing between the cleavage embryo stage and duration of progesterone therapy-improved pregnancy rates in frozen embryo transfer cycles: A cross-sectional study. Int J Reprod Biomed. 2021;19(3):227-34. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5875677","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":405321757,"identity":"dcbcdc8b-e579-4c1d-a6d1-1e9a9d64f101","order_by":0,"name":"Robabeh Hatami","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Zanjan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Robabeh","middleName":"","lastName":"Hatami","suffix":""},{"id":405321758,"identity":"393be702-5ab9-4e4e-a3ad-566ba650d688","order_by":1,"name":"Ensieh Shahrokh Tehraninejad","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ensieh","middleName":"Shahrokh","lastName":"Tehraninejad","suffix":""},{"id":405321759,"identity":"9506ed2a-9bd9-421f-abdd-21bb4c94bfb1","order_by":2,"name":"Batool Hossein Rashidi","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Batool","middleName":"Hossein","lastName":"Rashidi","suffix":""},{"id":405321760,"identity":"b03ccd34-de13-4b5c-9182-773bef3ff00e","order_by":3,"name":"Fatemeh Keikha","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Fatemeh","middleName":"","lastName":"Keikha","suffix":""},{"id":405321761,"identity":"6cb166e7-c39f-4851-bd29-891b76af975d","order_by":4,"name":"Masoumeh Masoumi","email":"","orcid":"","institution":"Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Masoumeh","middleName":"","lastName":"Masoumi","suffix":""},{"id":405321762,"identity":"36e70e36-5a43-4eb1-b792-77790d31adad","order_by":5,"name":"Amirali Barkhordarioon","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Amirali","middleName":"","lastName":"Barkhordarioon","suffix":""},{"id":405321763,"identity":"870b269c-2f8c-48d2-91dd-9bbdf6fb834d","order_by":6,"name":"Azadeh Tarafdari","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYLCCCjYGBjb2BhiXsQG3UiDgARFnQFp4DpOqhUEimUg32bOfffjhQJldPp/k+2NSN/4wyPM3MLd9wGsLT7qxxIFzyZZt0sls0rltDIYzDjA2z8DvsDQG6Y9tzAZsYC0NDIwbGBib8fuF/xnzj4Nt9QZskofZpHP+MNgT1iKRxiZxsO2wAZsEM1ALG0MiYS03nrFZHDh33ICNJ9nYOrdNInnGYQJa2PvTmG8cKKs2kG8/+PB2zh8b2/729sd4taADCQYGZpI0jIJRMApGwSjABgCA+z2QSzWzIwAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Obstetrics and Gynecology, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Azadeh","middleName":"","lastName":"Tarafdari","suffix":""}],"badges":[],"createdAt":"2025-01-21 19:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5875677/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5875677/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":74680060,"identity":"dbd15123-b0ab-43d9-a5de-81f944090707","added_by":"auto","created_at":"2025-01-24 15:42:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":28892,"visible":true,"origin":"","legend":"\u003cp\u003ePregnancy outcomes according to serum P4 levels on the ET day split in Q1 \u0026amp; Q2 vs. Q3 \u0026amp; Q4\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5875677/v1/a9cfab0b7b2236ffa9aef8ba.png"},{"id":75383385,"identity":"cc72a59b-2611-40b9-a036-918a6017f46c","added_by":"auto","created_at":"2025-02-04 03:23:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1047334,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5875677/v1/1ad7ebe3-9ac9-40fd-b05d-40d68643809f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of Daily 50 mg Intramuscular Progesterone for Luteal Phase Support in Frozen Embryo Transfer Cycles: Analysis of Serum Levels and Pregnancy Outcomes","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFrozen embryo transfer (FET) has undergone remarkable transformation with advancements in vitrification techniques, revolutionizing assisted reproductive technology (ART) by offering enhanced pregnancy rates and improved clinical outcomes (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). By optimizing embryo transfer conditions, FET provides clinicians and patients with a more flexible and potentially more successful approach to assisted reproduction.\u003c/p\u003e \u003cp\u003eEndometrial preparation represents a critical determinant of reproductive success, with multiple protocols available, including natural cycle (NC), modified natural cycle (MNC), artificial cycle with hormone replacement therapy (AC-HRT), and mild ovarian stimulation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). There is no sufficient evidence that shows which endometrium preparation protocol is the best. While natural menstrual cycles involve corpus luteum production of approximately 25\u0026ndash;50 mg of progesterone daily, ART cycles require exogenous supplementation to support endometrial gland formation and successful trophoblast invasion (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLuteal phase support (LPS) in FET cycles has predominantly been studied through retrospective research, revealing significant knowledge gaps (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Recent studies have highlighted the critical importance of serum progesterone (P4) levels on the day of embryo transfer (ET) (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Emerging evidence suggests remarkable variability in serum P4 levels among patients receiving identical hormonal protocols, with these variations potentially correlating with differential live birth rates. Most research identifies a threshold range between 10\u0026ndash;20 ng/mL as pivotal for successful pregnancy, with levels below 5\u0026ndash;12 ng/mL or above 30-32.5 ng/mL associated with reduced clinical pregnancy rates and increased miscarriage risks (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients have traditionally received P4 supplementation uniformly, adopting a \"one size fits all\" approach that ignores potential inter-individual physiological variations that could impact reproductive success (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Factors such as patient age, body mass index (BMI), metabolic characteristics, and individual hormonal profiles contribute to these complex interactions (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Multiple administration routes exist for P4 supplementation, including intramuscular, vaginal, oral, subcutaneous, and trans-rectal, each associated with distinct serum and endometrial tissue responses (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Comparative studies have revealed potential differences in outcomes between various P4 administration routes, with some research suggesting that combined or IM approaches might offer superior results compared to vaginal administration alone (\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Additionally, Dydrogesterone (DYD), a stereoisomer of P4, seems to be a good alternative for the treatment of LPS in an artificial cycle, especially in combination with a high dose of IM P4 during the course of oocyte donation (\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven the intricate relationship between P4 levels and reproductive outcomes, this prospective cohort study aims to comprehensively investigate two primary objectives: first, to determine whether IM P4 administration can effectively elevate serum P4 concentrations to the optimal range during endometrial preparation; and second, to examine the correlation between these serum P4 levels on embryo transfer day and subsequent fertility outcomes in HRT-FET protocols. By elucidating these nuanced relationships, we seek to advance personalized approaches in assisted reproductive interventions and challenge the conventional uniform approach to LPS.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and Setting\u003c/h2\u003e \u003cp\u003eThis prospective cohort study was conducted at the Infertility Clinic of Imam Khomeini Hospital Complex (IKHC), a teaching center affiliated with Tehran University of Medical Sciences (TUMS) in Tehran, Iran, from December 2022 to January 2024. The study protocol received approval from the Institutional Review Board and Ethics Committee of Tehran University of Medical Sciences, with a comprehensive informed consent process implemented for all participants (approval code: IR.TUMS.IKHC.REC.1401.204).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eThe study included 121 eligible women aged 22 to 45 years who were candidates for frozen embryo transfer (FET) using hormone replacement therapy (HRT). Participants were carefully selected based on specific inclusion and exclusion criteria. Inclusion criteria comprised willingness to participate, normal uterine anatomy, and infertility requiring FET. Patients with recurrent miscarriage, repeated implantation failure, uterine abnormalities, metabolic disorders, antiphospholipid syndrome, severe male factor infertility, or the presence of hydrosalpinx were excluded.\u003c/p\u003e\n\u003ch3\u003eEmbryo Morphology Assessment\u003c/h3\u003e\n\u003cp\u003eAbout 55% of the patients were undergoing their first FET cycle. Embryos were derived from intracytoplasmic sperm injection (ICSI) cycles. Embryo quality assessment utilized the standardized Gardner classification system (Gardner and Schoolcraft, 1999) and categorized as excellent, good, average, or poor. In the present, study patients who had poor-level embryos, according to the Gardner classification, were excluded.\u003c/p\u003e\n\u003ch3\u003eEndometrial preparation and Progesterone administration protocol\u003c/h3\u003e\n\u003cp\u003eEndometrial preparation commenced on the second day of the menstrual cycle through oral estradiol valerate administration (6 mg/day, Aburaihan Pharmaceutical Co., Tehran, Iran). Transvaginal ultrasonography (TV-USG) (Philips Healthcare, Netherlands, Model; Affiniti 70) was performed periodically by an expert infertility fellowship to measure endometrial thickness and to confirm a triple layer pattern. Once the endometrial thickness reached\u0026thinsp;\u0026ge;\u0026thinsp;8 mm, 50 mg of IM progesterone (Fertigest, Aburaihan Pharmaceutical Co., Tehran, Iran) was administered daily for LPS.\u003c/p\u003e \u003cp\u003eEmbryo transfers were conducted at two distinct time points following the initiation of progesterone (P4) administration: at day 4 for embryos at the cleavage stage and at day 6 for those that had reached the blastocyst stage. Blood sampling occurred between 7:00 and 10:00 AM on the ET day to measure serum P4 concentrations. The biochemical analysis was performed using chemiluminescent microparticle immunoassay (CMIA) (ARCHITECT Progesterone, Abbott Laboratories, Illinois, USA). For patients receiving routine LPS and having serum P4 levels\u0026thinsp;\u0026lt;\u0026thinsp;10.0 ng/ml on the FET day, we added oral DYD (20 mg/day, Duphaston, Abbott Healthcare Co., Netherlands) to salvage the FET cycles.\u003c/p\u003e \u003cp\u003eE2 and P4 supplementation were continued until the 10th week of pregnancy in patients with confirmed pregnancies. Participants were followed up until the 12th week to monitor miscarriage or ongoing pregnancy status.\u003c/p\u003e\n\u003ch3\u003eOutcome Measures\u003c/h3\u003e\n\u003cp\u003eSerum β-HCG levels were measured two weeks after ET day. Patients who demonstrated positive β-HCG tests (\u0026gt;\u0026thinsp;50 IU/L) were scheduled for their initial TV-USG two weeks later to verify the presence of a gestational sac. Chemical pregnancy (positive β-HCG test), clinical pregnancy (visualization of a gestational sac with fetal heartbeat on ultrasound), miscarriage (pregnancy loss before 12 weeks), and ongoing pregnancy (presence of fetal heartbeat beyond 12 weeks) were examined.\u003c/p\u003e \u003cp\u003eRecognizing the optimum range of serum P4 levels on ET day (10-32.5 ng/mL) to improve pregnancy outcomes based on prior research, the primary objective of the study was to determine the efficacy of daily 50 mg intramuscular P4 administration in achieving these optimal serum P4 levels, and the second objective was to comprehensively evaluate pregnancy outcomes between participants whose serum P4 levels fall within this target range and those whose levels remain outside it.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eP4 levels above 10 ng/mL (including women who received only IM P4) were stratified into four quartiles to facilitate more analysis. Descriptive statistics were used to summarize patient demographic characteristics, including age, BMI, infertility type (primary or secondary), and duration of infertility. Quantitative variables were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), and categorical variables were presented as frequency and percentage. Quartiles of serum P4 levels were compared using analysis of variance (ANOVA) and chi-square tests for continuous and categorical variables, respectively. The relationships between serum P levels and pregnancy outcomes were evaluated using logistic regression analysis. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were conducted using SPSS version 20 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 121 eligible women were included in the final analysis. The mean age of participants was 35.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 years (range: 22\u0026ndash;45), and the mean duration of infertility was 6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0 years. Most participants (70.3%) experienced primary infertility, while 29.7% had secondary infertility. Male factor infertility accounted for 22.3% of cases, with the remainder attributed to ovulatory disorders, tubal factor, unexplained, or multifactorial causes. The mean serum progesterone (P4) level on the day of embryo transfer (ET) was 22.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1 ng/mL, ranging from 7.5 to 60.8 ng/mL (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Following the administration of 50 mg/day IM P4, a significant proportion of participants (n\u0026thinsp;=\u0026thinsp;95, 78.5%) achieved the target optimal serum P4 concentration. Specifically, these patients demonstrated P4 levels within the clinically favorable range of 10-32.5 ng/mL. Conversely, 5 cases (4.1%) exhibited persistently low P4 concentrations, with serum levels remaining\u0026thinsp;\u0026lt;\u0026thinsp;10 ng/mL threshold on the ET day and 21 patients (17.4%) experienced P4 levels\u0026thinsp;\u0026gt;\u0026thinsp;32.5 ng/mL.\u003c/p\u003e\n\u003ch3\u003eSerum Progesterone Quartiles and Baseline Characteristics\u003c/h3\u003e\n\u003cp\u003eParticipants receiving IM P4 for luteal phase support (LPS) were stratified into quartiles based on serum P4 levels on ET day: Q1 (10.0\u0026ndash;16.2 ng/mL), Q2 (16.3\u0026ndash;20.9 ng/mL), Q3 (21.0\u0026ndash;27.8 ng/mL), and Q4 (\u0026gt;\u0026thinsp;27.8 ng/mL). No statistically significant differences in demographic or clinical characteristics\u0026mdash;including age, BMI, duration of infertility, endometrial thickness, and number of transferred embryos\u0026mdash;were observed across quartiles (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePregnancy Outcomes\u003c/h2\u003e \u003cp\u003eThe overall chemical pregnancy rate was 23.1%, the clinical pregnancy rate was 18.2%, and the ongoing pregnancy rate was 14.1%, with a miscarriage rate of 5.0%. Pregnancy outcomes did not significantly differ between P4 administration protocols (IM P4 vs. IM P4\u0026thinsp;+\u0026thinsp;DYD) (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Although higher chemical and clinical pregnancy rates were observed in Q4 compared to other quartiles, these differences did not reach statistical significance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMultivariate Analysis\u003c/h2\u003e \u003cp\u003eMultivariate logistic regression analysis revealed that higher serum P4 levels on ET day (Q4: \u0026gt;27.8 ng/mL) were significantly associated with reduced odds of chemical pregnancy compared to Q1 (OR\u0026thinsp;=\u0026thinsp;0.22; 95% CI: 0.05\u0026ndash;0.92; p\u0026thinsp;=\u0026thinsp;0.04) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Other variables, including age, BMI, duration of infertility, endometrial thickness, duration of E2 consumption, and number of transferred embryos, were not significantly associated with pregnancy outcomes (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCombined Quartile Analysis\u003c/h2\u003e \u003cp\u003eTo further assess the relationship between serum P4 levels and pregnancy outcomes, quartiles were grouped into two categories: Q1 \u0026amp; Q2 (10.0\u0026ndash;20.9 ng/mL) and Q3 \u0026amp; Q4 (\u0026gt;\u0026thinsp;21.0 ng/mL). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the comparison of pregnancy outcomes between these groups. Patients in Q3 \u0026amp; Q4 demonstrated numerically higher rates of pregnancy outcomes, but these findings lacked statistical significance.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of the patients in the study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eContinuous Variables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22, 45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.1, 45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDuration of infertility (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1, 20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7, 19.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDuration of E2 consumption (day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11, 24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eP4 level on ET day (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.5, 60.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCategorical Variables\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFrequency\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003ePercentage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSecondary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCause of infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOvulatory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTubal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUn-explained\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMultifactorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrequency of embryo transferred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFirst\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSecond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThird\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of transferred embryo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOne\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTwo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e94.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays of embryo transferred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 Days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 Days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eBMI: Body mass index, E2: Estradiol, P4: Progesterone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of variables according to serum progesterone quartiles\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"2\" nameend=\"c2\" namest=\"c1\" rowspan=\"3\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c7\" namest=\"c3\"\u003e \u003cp\u003eSerum P4 levels (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ep-value between quartiles\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIM P4\u0026thinsp;+\u0026thinsp;DYD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c7\" namest=\"c4\"\u003e \u003cp\u003eIM P4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP4\u0026thinsp;\u0026lt;\u0026thinsp;10\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQ1\u003c/p\u003e \u003cp\u003e(10.0-16.2)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ2\u003c/p\u003e \u003cp\u003e(16.3\u0026ndash;20.9)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eQ3\u003c/p\u003e \u003cp\u003e(21.0-27.8)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eQ4\u003c/p\u003e \u003cp\u003e(\u0026gt;\u0026thinsp;27.8)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e35.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDuration of infertility (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDuration of E2 consumption (day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN. of transferred embryos (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOne\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTwo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25 (86.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26 (89.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmbryo quality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExcellent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (34.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (51.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (27.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9 (31.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (62.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17 (58.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e17 (58.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAverage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eChemical pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (27.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10 (34.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eClinical pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8 (27.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMiscarriage rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eOngoing pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (17.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (6.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (20.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTwin pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (6.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eQ: Quartile, BMI: Body mass index, E2: Estradiol, P4: Progesterone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePregnancy outcomes based on serum progesterone levels on ET day\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTotal (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eSerum P4 levels (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;10 (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10 (n\u0026thinsp;=\u0026thinsp;116)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemical pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (23.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (22.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (18.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (18.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiscarriage rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOngoing pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (14.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (13.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwin pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate logistic regression analysis of factors associated with chemical pregnancy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.07 (0.99\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96 (0.87\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDuration of infertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 (0.89\u0026ndash;1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEndometrial thickness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.87 (0.67\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDuration of E2 consumption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.17 (0.90\u0026ndash;1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNumber of transferred embryos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.67 (0.06\u0026ndash;7.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum P4 levels (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQ1 (10.0-16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eReference group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQ2 (16.3\u0026ndash;20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.36 (0.09\u0026ndash;1.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQ3 (21.0-27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.70 (0.14\u0026ndash;3.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQ4 (\u0026gt;\u0026thinsp;27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.22 (0.05\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eOR: Odds ratio, CI: Confidence interval, BMI: Body mass index, E2: Estradiol, P4: Progesterone, Q: Quartile\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis prospective cohort study aimed to investigate the potency of IM P4 administration to reach serum P4 levels on the day of ET to the favorable range in the HRT-FET cycles. Additionally, the study sought to comparatively assess pregnancy outcomes between two therapeutic protocols during endometrial preparation: IM P4 (50 mg/day) alone and IM P4 (50 mg/day)\u0026thinsp;+\u0026thinsp;oral DYD (20 mg/day). In cases where serum P4 levels were low (\u0026lt;\u0026thinsp;10 ng/mL), DYD was administered. According to the study results, the IM P4 protocol was identified as an effective treatment strategy. Notably, it successfully achieved the optimal P4 range of 10-31.5 ng/mL in 78.51% of participants. Statistical analysis revealed that despite the lower P4 levels on ET day, there was no statistically significant difference in clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), or miscarriage rates (MR) between this group and the group with P4 levels\u0026thinsp;\u0026gt;\u0026thinsp;10 ng/mL using the IM P4 protocol. Importantly, the study findings demonstrated no significant correlation between serum P4 levels and pregnancy outcomes, suggesting that serum P4 levels measured on the day of ET may not be a reliable predictor of embryo transfer success in patients receiving IM P4 for LPS. Importantly, the study findings indicate a significant negative association between elevated serum P4 levels (\u0026gt;\u0026thinsp;27.8 ng/mL) on ET day and chemical pregnancy rates, suggesting that high P4 levels may adversely affect embryo transfer success. However, no significant differences in other pregnancy outcomes were observed across quartiles, implying that serum P4 levels may not be a reliable predictor of ET success.\u003c/p\u003e \u003cp\u003eThe CPR, OPR, and MR in our study were reported as 18.18%, 14.05%, and 4.96%, respectively. In a prior study, Alyasin and colleagues estimated a CPR of 35.6% in the group that received IM P4. They demonstrated a significant correlation between serum P4 levels and CPR as well as the LBR (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Gaggiotti-Marre et al. demonstrated that women with lower quartile P4 levels have a higher MR compared to women with higher quartile levels (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The findings of \u0026Aacute;lvarez et al.'s study indicated that individualized LPS led to higher OPR in patients receiving HRT one day before ET (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Results from several previous studies also showed that serum P4 level is a significant factor in predicting independent LBR (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), which contradicts our study's results. Possible reasons for this difference include the variations in P4 route and dose of administration, timing of measurement, the baseline P4 levels, and individual metabolic characteristics of participants. Nevertheless, some studies support our findings. In line with our results, Volovsky et al. in their study showed that P4 levels\u0026thinsp;\u0026gt;\u0026thinsp;10 ng/mL on the day of FET are not a significant factor in predicting CPR and LBR (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Alyasin et al. did not find any correlation between serum P4 levels and miscarriage (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Polat and colleagues, in a retrospective cohort study, demonstrated that while examining the impact of VP4 compared to IM P4 on OPR, the prescription of P4 is not an independent predictor of OPR (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The findings of the study by C\u0026eacute;drin-Durnerin et al. indicated that doubling the dose of VP4 on the ET day has no effect on fertility outcomes (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In the study by Chen and colleagues, serum P4 levels on ET day showed no significant association with LBR or CPR in artificial cycles with IM P4, while D5 blastocysts and good-quality embryos were independently linked to higher LBR (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe findings of this study indicated that there is no significant difference in serum P4 levels across age and BMI quartiles. However, Gonz\u0026aacute;lez-Foruria et al. found that a woman's age can influence the absorption of P4 (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), which contrasts with our study's results. The potential reason for this difference may be the variation in the method of VP4 administration compared to IM P4. The researchers in that study also attributed the potential increase in drug absorption to vaginal atrophy and thin vaginal mucosa in older women.\u003c/p\u003e \u003cp\u003eThe optimal timing of P4 testing and the ideal P4 blood concentrations have not been definitively established, and treatment strategies based on serum P4 are still under investigation. Findings from Kofinas et al.\u0026rsquo;s study indicate that maintaining P4 levels within the range of 10\u0026ndash;20 ng/ml is essential (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Furthermore, the results of this study showed that P4 levels higher than 30 ng/ml have an adverse effect on the cycle. In interpreting the findings of this study, it can be said that low P4 levels hinder endometrial growth. On the other hand, significantly higher P4 levels accelerate endometrial growth, potentially delaying the window of implantation.\u003c/p\u003e \u003cp\u003eThe main source of P4 in the early stages of NC is the corpus luteum, which persists until approximately the first 8 weeks of pregnancy. After that, placental P4 synthesis takes over. After the luteal phase declines, infertility treatment necessitates P4 supplementation (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In our study, we examined P4 levels during cycles controlled by IM exogenous hormone therapy. While the IM method presented notable challenges in patient tolerance, its potential clinical advantages warrant careful consideration in assisted reproductive techniques. The results of a study by Devine et al. demonstrated that women who received only VP4 for LPS, without any IM administration of P4, had significantly poorer OPR (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Kaser et al. found that women who received Crinone vaginal gel, had 44% lower odds of CPR and 49% lower odds of LBR, compared with women who received IM P4 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In a randomized clinical trial by Tehraninejad et al., IM P4 administration for LPS demonstrated superior chemical pregnancy rates compared to vaginal and subcutaneous routes, despite patients reporting higher discomfort related to pain and swelling (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, some other research appeared that endometrial P4 levels play a more significant role in the success of FET cycles compared to serum levels. In a study by Miles, it was shown that although serum P4 concentration following IM P4 injection is more than double that of vaginal administration, the average endometrial concentration of P4 in the vaginal method is approximately 8 times higher (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). According to Klement et al.'s study, the P4 serum concentration was significantly higher in patients using the IM P4 compared to VP4 administration, but this did not translate into a lower sub-endometrial contractility (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In total, due to the lack of strong randomized controlled trials, a consensus on the best P4 administration method during FET cycles has not been reached.\u003c/p\u003e \u003cp\u003eThere is a prevailing belief among a proportion of Iranian reproductive endocrinology and infertility specialists that administering 50 mg/day of IM P4 for endometrial preparation in FET cycles is considered insufficient. Consequently, they routinely prescribe 100 mg/day of IM P4 (Fertigest, Aburaihan Pharmaceutical Co., Tehran, Iran) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), 800 mg/day of VP4 (Cyclogest\u0026reg;, Actoverco, Iran) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR35 CR36\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), or a combination of IM P4 and VP4 (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), despite increased patient discomfort. In the present study, administration of 50 mg/day IM P4 alone not only resulted in achieving substantial serum P4 levels (\u0026gt;\u0026thinsp;10 ng/mL) on the ET day in about 96% of women but also yielded comparable pregnancy outcomes to other similar studies that utilized higher P4 doses.\u003c/p\u003e \u003cp\u003eIn prior studies by Arabian et al. and Lorillon et al., oral DYD was found to be as effective as IM P4 (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) and VP4 (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) in maintaining pregnancy, as measured by CPR, OPR, and MR. Also, Rashidi et al. evaluated the pregnancy outcomes of oral, IM, and vaginal P4 administration for LPS during HRT-FET (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). According to their results, the pregnancy rates, abortion, and LBR were not significantly different among groups. Consequently, these findings positioned DYD as a compelling hormonal support protocol, characterized by reduced local complications, lower treatment costs, and enhanced patient satisfaction. In our current study, among 5 women receiving DYD combined with IM P4 according to the specified protocol, the OPR and MR were 20% and 0%. Interestingly, despite observing lower serum P4 levels on the ET day in this cohort, the pregnancy outcomes were superior compared to the group receiving IM P4 alone, although this difference did not reach statistical significance. However, it is crucial to acknowledge the limitation of our study's small sample size, which substantially constrains the potential for robust statistical analysis and broader result generalization.\u003c/p\u003e \u003cp\u003eThis study had several limitations. One limitation is the relatively short follow-up period, which only extended to the first 12 weeks of pregnancy. Additionally, the study did not investigate the outcomes of IM P4 administration after childbirth and the LBR. Given the limited sample size and the potential variability in individual responses to P4, further research is necessary to explore the potential benefits of individualized LPS. Future studies should aim to include larger, multicenter cohorts, assess the impact of different P4 administration routes and dosages, and evaluate outcomes, especially LBR and neonatal health rate during FET cycles.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDaily administration of 50 mg IM P4 remains a promising approach for endometrial preparation in FET cycles, offering accessibility and effective elevation of serum P4 levels to optimal ranges. However, monitoring serum P4 levels on ET day is recommended to ensure adequate LPS. The addition of DYD can serve as a supplementary measure in these cases. This study identified a significant negative association between elevated serum P4 levels (\u0026gt;\u0026thinsp;27.8 ng/mL) on the ET day and chemical pregnancy rates. However, the absence of significant correlations with other pregnancy outcomes highlights the multifactorial nature of embryo implantation success. These findings emphasize the need for further research to refine P4 thresholds and identify additional predictive factors influencing pregnancy outcomes in FET cycles.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eFET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eFrozen Embryo Transfer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eAssisted Reproductive Technology\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eNatural Cycle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eMNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eModified Natural Cycle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eAC-HRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eArtificial Cycle with Hormone Replacement Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eLPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eLuteal Phase Support\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eP4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eProgesterone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eDYD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eDydrogesterone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eIM P4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eIntramuscular Progesterone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eVP4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eVaginal Progesterone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eTV-USG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eTransvaginal Ultrasonography\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eIntracytoplasmic Sperm Injection\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eOPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eOngoing Pregnancy Rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eCPR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eClinical Pregnancy Rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eMiscarriage Rates\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13.4126%;\"\u003e\n \u003cp\u003eLBR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86.5874%;\"\u003e\n \u003cp\u003eLive Birth Rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the participating women, for providing consent, without which the study would not have been possible.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe conception and study design was developed by Dr. Batool Hossein Rashidi. This manuscript was derived from Dr. Robabeh Hatami\u0026apos;s infertility fellowship thesis research. Dr. Ensieh Shahrokh Tehraninejad, Dr. Batool Hossein Rashidi, Dr. Fatemeh Keikha, and Dr. Azadeh Tarafdari were involved in clinical investigation and patient care at the infertility clinic. Dr. Masoumeh Masoumi was responsible for data collection and patient follow-up procedures. Dr. Azadeh Tarafdari and Dr. Amirali Barkhordarioon contributed to data analysis and finalization of the manuscript. All authors have read and agreed to the published version of the manuscript. The authors declare no conflicts of interest, and this research received no external funding. Written informed consent was obtained from all subjects involved in the study. The data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding or sponsorship was received for this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. All relevant data are presented within the manuscript and summary statistics of the analyzed variables are included in the tables.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.IKHC.REC.1401.204). Informed consent was obtained from legal guardians of the subjects enrolled in the study for study participation. This study was performed in accordance with the Declaration of Helsinki. Clinical trial number is not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDe Geyter C, Wyns C, Calhaz-Jorge C, de Mouzon J, Ferraretti AP, Kupka M, et al. 20 years of the European IVF-monitoring Consortium registry: what have we learned? A comparison with registries from two other regions. Hum Reprod. 2020;35(12):2832-49.\u003c/li\u003e\n\u003cli\u003eMumusoglu S, Polat M, Ozbek IY, Bozdag G, Papanikolaou EG, Esteves SC, et al. 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Bjog. 2024.\u003c/li\u003e\n\u003cli\u003eOvarian Stimulation T, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI(\u0026dagger;). Hum Reprod Open. 2020;2020(2):hoaa009.\u003c/li\u003e\n\u003cli\u003eMiles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril. 1994;62(3):485-90.\u003c/li\u003e\n\u003cli\u003eAkbari Asbagh F, Ghasemzadeh F, Ebrahimi M, Davari-Tanha F, Feizabad E, Akbari Asbagh P, et al. Effect of intramuscular injection of human chorionic gonadotropin on endometrium preparation in frozen-thawed embryo transfer cycle: A randomized clinical trial. Caspian J Intern Med. 2023;14(2):185-91.\u003c/li\u003e\n\u003cli\u003eEftekhar M, Rahsepar M, Rahmani E. Effect of progesterone supplementation on natural frozen-thawed embryo transfer cycles: a randomized controlled trial. Int J Fertil Steril. 2013;7(1):13-20.\u003c/li\u003e\n\u003cli\u003eEslami Moayed M, Moini A, Kashani L, Farid Mojtahedi M, Rezaee T, Tabasizadeh H, et al. Pregnancy outcomes in women with adenomyosis, undergoing artificial endometrial preparation with and without gonadotropin-releasing hormone agonist pretreatment in frozen embryo transfer cycles: An RCT. Int J Reprod Biomed. 2023;21(6):481-90.\u003c/li\u003e\n\u003cli\u003eAgha-Hosseini M, Hashemi L, Aleyasin A, Ghasemi M, Sarvi F, Shabani Nashtaei M, et al. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: A randomized prospective trial. Turk J Obstet Gynecol. 2018;15(1):12-7.\u003c/li\u003e\n\u003cli\u003eFarid Mojtahedi M, Aref S, Moini A, Maleki-Hajiagha A, Kashani L. Natural cycle versus modified natural cycle for endometrial preparation in women undergoing frozen-thawed embryo transfer: An RCT. Int J Reprod Biomed. 2022;20(11):923-30.\u003c/li\u003e\n\u003cli\u003eAflatoonian A, Mohammadi B. Subcutaneous progesterone versus vaginal progesterone for luteal-phase support in frozen-thawed embryo transfer: A cross-sectional study. Int J Reprod Biomed. 2021;19(2):115-20.\u003c/li\u003e\n\u003cli\u003eOmidi M, Halvaei I, Akyash F, Khalili MA, Agha-Rahimi A, Heydari L. The exact synchronization timing between the cleavage embryo stage and duration of progesterone therapy-improved pregnancy rates in frozen embryo transfer cycles: A cross-sectional study. Int J Reprod Biomed. 2021;19(3):227-34.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Frozen Embryo Transfer, Luteal Phase Support, Progesterone, Pregnancy Outcomes, Hormone Replacement Therapy","lastPublishedDoi":"10.21203/rs.3.rs-5875677/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5875677/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eFrozen embryo transfer (FET) success depends on adequate luteal phase support (LPS), with serum progesterone (P4) levels on embryo transfer (ET) day being a critical factor. While serum P4 levels have been probably associated with improved outcomes, there is ongoing debate regarding the most effective route and dosage of P4 supplementation. This prospective cohort study aimed to (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) evaluate the efficacy of 50 mg/day intramuscular (IM) progesterone in achieving optimal serum P4 levels during endometrial preparation and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) investigate the association between serum P4 levels on ET day and subsequent fertility outcomes in hormone replacement therapy (HRT) FET cycles.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe study included 121 women (aged 22\u0026ndash;45 years) undergoing HRT-FET at Imam Khomeini Hospital Complex from December 2022 to January 2024. Endometrial preparation began with oral estradiol valerate (6 mg/day) on cycle day 2, followed by daily IM P4 (50 mg) upon achieving endometrial thickness\u0026thinsp;\u0026ge;\u0026thinsp;8 mm. Serum P4 levels were measured on ET day, and oral dydrogesterone (20 mg/day) was added for patients with P4 levels\u0026thinsp;\u0026lt;\u0026thinsp;10.0 ng/mL. Primary outcomes included chemical pregnancy, clinical pregnancy, miscarriage, and ongoing pregnancy rates.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe mean serum P4 level on ET day was 22.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1 ng/mL, with 78.5% of participants achieving the target range (10-32.5 ng/mL) following IM P4 administration. Overall chemical pregnancy, clinical pregnancy, and ongoing pregnancy rates were 23.1%, 18.2%, and 14.1%, respectively, with a miscarriage rate of 5.0%. Multivariate analysis revealed that P4 levels\u0026thinsp;\u0026gt;\u0026thinsp;27.8 ng/mL were associated with reduced odds of chemical pregnancy (OR\u0026thinsp;=\u0026thinsp;0.22; 95% CI: 0.05\u0026ndash;0.92; p\u0026thinsp;=\u0026thinsp;0.04), while no significant differences were observed in other pregnancy outcomes across P4 quartiles.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eDaily administration of 50 mg IM P4 effectively achieved optimal serum P4 levels in most patients. While higher P4 levels (\u0026gt;\u0026thinsp;27.8 ng/mL) were associated with reduced chemical pregnancy rates, the absence of significant correlations with other pregnancy outcomes highlights the multifactorial nature of embryo implantation success. These findings emphasize the need for further research to refine P4 thresholds and identify additional predictive factors influencing pregnancy outcomes in FET cycles.\u003c/p\u003e","manuscriptTitle":"Efficacy of Daily 50 mg Intramuscular Progesterone for Luteal Phase Support in Frozen Embryo Transfer Cycles: Analysis of Serum Levels and Pregnancy Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-24 15:41:55","doi":"10.21203/rs.3.rs-5875677/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f426234e-e3fe-4543-a47a-ac43d921e615","owner":[],"postedDate":"January 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-04T03:23:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-24 15:41:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5875677","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5875677","identity":"rs-5875677","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}