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Objective: To evaluate methodologies to establish abnormal progesterone (P) levels on the day of trigger for recommending freeze only cycles., Design: Threshold analysis and cost analysis., Setting: Private ART practice., Patient(s): Fresh autologous ART., Interventions(s): None., Main Outcome Measure(s): Live birth., Result(s): Fourteen established statistical methodologies for generating clinical thresholds were evaluated. These methods were applied to 7,608 fresh ART transfer cycles to generate various P thresholds which ranged widely from 0.4 to 3.0 ng/mL. Lower thresholds ranged from 0.4 to 1 ng/mL and classified the majority of cycles as abnormal as well as required very large number needed to treat (NNT) to increase one live birth. Frozen embryo transfer was cost-effective when P was ≥1.5 ng/mL, with 12% of the population having an abnormal test result and an NNT of 13. Statistical and cost-effective thresholds clustered between 1.5 and 2.0 ng/mL., Conclusion(s): Statistically significant thresholds for P were demonstrated as low as 0.4 ng/mL but resulted in a very large NNT to increase one live birth. A clinical benefit to a freeze-only approach was demonstrated above P thresholds ranging from 1.5 to 2.0 ng/dL. At these thresholds, elevated P has a demonstrable and clinically significant negative effect and captures a smaller percentage of the patient population at higher risk for fresh transfer failure, thus making freeze-only a cost-effective option., (Copyright © 2018 American Society for Reproductive Medicine. All rights reserved.)

Premature progesterone (P) elevation was commonly seen in IVF prior to the utilization of GnRH analogues for suppression of endogenous gonadotropin release. The cause and effect of premature P elevation has finally been better elucidated in the past decade. Although still occurring in 5-38% of all IVF cycles, the adverse effects of premature P elevation on pregnancy outcomes are now well known.

Context: Adequate luteal phase progesterone exposure is necessary to induce endometrial changes required for a successful pregnancy outcome. The relationship between low midluteal progesterone concentration and the outcome of live birth in ovarian stimulation with intrauterine insemination (OS-IUI) treatments is not defined., Objective: To determine the level of midluteal progesterone portending a low chance of live birth after OS-IUI in couples with unexplained infertility., Design and Setting: Secondary analyses of data from a prospective, randomized, multicenter clinical trial that determined pregnancy outcomes following OS-IUI with clomiphene citrate, letrozole, or gonadotropins for couples with unexplained infertility., Participants: Couples (n = 900) underwent 2376 OS-IUI cycles during the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial., Main Outcome Measures: Live birth as it relates to midluteal progesterone level and thresholds below which no live births occur by treatment group., Results: Thresholds for non-live birth cycles were similar for clomiphene (14.4 ng/mL) and letrozole (13.1 ng/mL) yet were lower for gonadotropin (4.3 ng/mL) treatments. A midluteal progesterone level >10th percentile specific for each treatment group independently was associated with greater odds for a live birth in all OS-IUI cycles (adjusted OR: 2.17; 95% CI: 1.05, 4.48)., Conclusions: During OS-IUI, a low midluteal progesterone level was associated with a low probability of live birth. Thresholds differed by medication, with the lowest threshold for gonadotropin. Several pathophysiologic mechanisms may account for low progesterone levels. Refinement of the predictive range associated with particular ovarian stimulation medications during treatment of unexplained infertility may improve accuracy.

Recent evidence has shown elevated progesterone (P) advances the endometrium in fresh ART cycles, creating asynchrony with the embryo and thus implantation failure and decreased live birth rates. If the window of implantation is closing as the embryo attempts to implant, there may be difficulty with trophoblastic invasion, leading to failure of early pregnancies. Our objective was to evaluate if P on the day of trigger was associated with spontaneous abortion (SAB) rates in fresh ART transfers. This was a retrospective cohort study involving fresh autologous and FET cycles from 2011 to 2013. The main outcome was spontaneous abortion rates. About 4123 fresh and FET transfer cycles were included which resulted in 1547 fresh and 491 FET pregnancies. The overall SAB rate was 20% among fresh cycles and 19% in FET cycles. P on the day of trigger, as a continuous variable or when > 2 ng/mL, was not associated with SAB in fresh cycles. Similar results were found after adjusting for age, embryo quality, and embryo stage. Despite elevated P likely advancing the window of implantation, once implantation occurs, pregnancies were no longer negatively impacted by progesterone.

Objective: To evaluate the effect of progesterone (P) for luteal phase support after ovulation induction (OI) and intrauterine insemination (IUI)., Design: An updated systematic review and meta-analysis., Setting: Not applicable., Patient(s): Patients undergoing OI-IUI for infertility., Intervention(s): Exogenous P luteal support after OI-IUI., Main Outcome Measure(s): Live birth., Result(s): Eleven trials were identified that met inclusion criteria and constituted 2,842 patients undergoing 4,065 cycles, more than doubling the sample size from the previous meta-analysis. In patients receiving gonadotropins for OI, clinical pregnancy (relative risk [RR] 1.56, 95% confidence interval [CI] 1.21-2.02) and live birth (RR 1.77, 95% CI 1.30-2.42) were more likely in P supplemented patients. These findings persisted in analysis of live birth per IUI cycle (RR 1.59, 95% CI 1.24-2.04). There were no data on live birth in clomiphene citrate or clomiphene plus gonadotropin cycles. There was no benefit on clinical pregnancy with P support for patients who underwent OI with clomiphene (RR 0.85, 95% CI 0.52-1.41) or clomiphene plus gonadotropins (RR 1.26, 95% CI 0.90-1.76)., Conclusion(s): Progesterone luteal phase support is beneficial to patients undergoing ovulation induction with gonadotropins in IUI cycles. The number needed to treat is 11 patients to have one additional live birth. Progesterone support did not benefit patients undergoing ovulation induction with clomiphene citrate or clomiphene plus gonadotropins., (Published by Elsevier Inc.)

Objective: To critically evaluate the P to oocyte (O) ratio (P/O) in the prediction of live birth in assisted reproductive technology (ART) cycles., Design: Retrospective cohort study., Setting: Not applicable., Patient(s): A total of 7,608 fresh autologous ART ET cycles., Intervention(s): None., Main Outcome Measure(s): Live birth., Result(s): Generalized estimating equation (GEE) models and receiver operating characteristic curves assessed the ability of P, O, and the P/O ratio to predict live birth. In univariate GEE models, P, O, and P/O were each associated with live birth. However, in multivariate GEE models, the P/O ratio was not associated with live birth, but P alone was. This suggested that converting P and O into a ratio of P/O was not more helpful than the two independent variables themselves. Measures of overall model fit further suggested that P/O did not increase the predictive ability of the model over P and O alone. Receiver operating characteristic curves using incremental predictors further demonstrated that the P/O provided no incremental improvement in predicting live birth over P and O separately., Conclusion(s): These data suggest that P and O have utility in prediction modeling but demonstrate that additional oocytes were not protective from the negative association of P with live birth. There was no incremental improvement related to the P/O ratio specifically for predicting live birth over each variable independently., (Published by Elsevier Inc.)

The aim of this study was to evaluate if premature progesterone elevation on the last day of assisted reproduction technique stimulation contributes to racial disparities in IVF outcome. A total of 3289 assisted reproduction technique cycles were evaluated in Latino, Asian, African American, and white women. Live birth was more likely in white women (42.6%) compared with Asian (34.8%) and African American women (36.3%), but was similar to Latino women (40.7%). In all racial groups, progesterone was negatively associated with live birth and the negative effect of progesterone persisted when adjusting for confounders. Although the effect of elevated progesterone was similar in all racial groups, the prevalence of elevated progesterone differed. Progesterone > 1.5 ng/ml occurred in only 10.6% of cycles in white women compared with 18.0% in Latino and 20.2% in Asian women. Progesterone > 2 ng/ml occurred in only 2.3% of cycles in white women compared with 6.3% in Latino, 5.9% in Asian and 4.4% in African American women. The increased prevalence of premature elevated progesterone persisted when controlling for IVF stimulation parameters. In conclusion, premature progesterone elevation had a negative effect on live birth in all racial groups studied. The prevalence of elevated progesterone was higher in racial minorities., (Published by Elsevier Ltd.)

Study Question: Is there an association of progesterone (P 4 ) on the day of trigger with live birth in autologous ART transfer cycles on day 5 versus day 6?, Summary Answer: P 4 had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers., What Is Known Already: Premature P 4 elevation is associated with lower live birth rates in fresh autologous ART cycles, likely due to worsened endometrial-embryo asynchrony. Few studies have evaluated whether the effect of an elevated P 4 on the day of trigger is different on live birth rates with a day 5 compared to a day 6 embryo transfer., Study Design Size, Duration: This was a retrospective cohort study with autologous IVF cycles with fresh embryo transfers on day 5 and day 6 from 2011 to 2014. A total of 4120 day 5 and 230 day 6 fresh autologous embryo transfers were included. The primary outcome was live birth, defined as a live born baby at 24 weeks gestation or later., Participants/materials, Setting, Methods: Patients from a large private ART practice were included. Analysis was performed with generalized estimating equations (GEE) modeling and receiver operating characteristic (ROC) curves., Main Results and the Role of Chance: Day 6 transfers were less likely to have good quality embryos (73% versus 83%, P < 0.001) but the cohorts had similar rates of blastocyst stage transfer (92% versus 91%, P = 0.92). Live birth was less likely in fresh day 6 versus day 5 embryo transfers (34% versus 46%, P = 0.01) even when controlling for embryo confounders. In adjusted GEE models, the effect of P 4 as a continuous variable on live birth was more pronounced on day 6 (P < 0.001). Similarly, the effect of P 4 > 1.5 ng/ml on day of trigger was more pronounced on day 6 than day 5 (P < 0.001). Day 6 live birth rates were 8% lower than day 5 when P 4 was in the normal range (P = 0.04), but became 17% lower when P 4 was > 1.5 ng/ml (P < 0.01). ROC curves for P 4 predicting live birth demonstrated a greater AUC in day 6 transfers (AUC 0.59, 95% CI 0.51-0.66) than day 5 (AUC 0.54, 95% CI 0.52-0.55). Interaction testing of P 4 × day of embryo transfer was highly significant (P < 0.001), further suggesting that the effect of P 4 was more pronounced on day 6 embryo transfer. In fresh oocyte retrieval cycles with elevated P 4 , a subsequent 760 frozen-thaw transfers did not demonstrate a difference between embryos that were frozen after blastulation on day 5 versus 6., Limitations Reasons for Caution: Limitations include the retrospective design and the inability to control for certain confounding variables, such as thaw survival rates between day 5 and day 6 blastocysts. Also, the data set lacks the known ploidy status of the embryos and the progesterone assay is not currently optimized to discriminate between patients with a P 4 of 1.5 versus 1.8 ng/ml., Wider Implications of the Findings: This study suggests further endometrial-embryo asynchrony when a slow growing embryo is combined with an advanced endometrium, ultimately leading to decreased live births. This suggests that premature elevated P 4 may be a factor in the lower live birth rates in day 6 fresh embryo transfers. Further studies are needed to evaluate if a frozen embryo transfer cycle can ameliorate the effect of elevated P 4 on the day of trigger among these slower growing embryos that reach blastocyst staging on day 6., Study Funding/competing Interests: No external funding was received for this study. There are no conflicts of interest to declare., Trial Registration Number: Not applicable., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: To compare the effect of P on live birth rate between hCG and GnRH agonist (GnRH-a) trigger cycles., Design: Retrospective cohort study., Setting: Large private assisted reproductive technology (ART) practice., Patient(s): A total of 3,326 fresh autologous ART cycles., Intervention(s): None., Main Outcome Measure(s): Live birth., Result(s): A total of 647 GnRH-a trigger cycles were compared with 2,679 hCG trigger cycles. Live birth was negatively associated with P in both the hCG trigger (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52-0.76) and the agonist trigger cohorts (OR 0.56, 95% CI 0.45-0.69). Interaction testing evaluating P and trigger medication was not significant, indicating that P had a similar negative effect on live birth rates in both cohorts. Progesterone ≥2 ng/mL occurred more commonly in GnRH-a trigger cycles compared with hCG trigger cycles (5.5% vs. 3.1%) and was negatively associated with live birth in both the hCG trigger (OR 0.28, 95% CI 0.11-0.73) and agonist trigger cohorts (OR 0.35, 95% CI 0.14-0.90). When P ≥2 ng/mL, the live birth rates were poor and similar in the hCG and GnRH-a cohorts (5.9% vs. 14.2%), indicating that P ≥2 ng/mL had a similar negative effect on live birth in both cohorts., Conclusion(s): Elevated serum P on the day of hCG was negatively associated with live birth rates in both hCG and GnRH-a trigger cycles., (Published by Elsevier Inc.)

Objective: To compare the effect of progesterone (P) on the day of trigger in fresh assisted reproduction technology (ART) transfer cycles versus its effect on subsequent frozen embryo transfer (FET) cycles., Design: Retrospective cohort study., Setting: Large private ART practice., Patient(s): Fresh autologous and FET cycles from 2011-2013., Intervention(s): None., Main Outcome Measure(s): Live birth., Result(s): A paired analysis of patients who underwent both a fresh transfer and subsequent FET cycle and an unpaired analysis of data from all fresh transfer cycles and all FET cycles were performed. We analyzed 1,216 paired and 4,124 unpaired cycles, and P was negatively associated with birth in fresh but not FET cycles in all analyses. Interaction testing of P and cycle type indicated P had a different association with birth in fresh versus FET cycles. When P was ≥ 2 ng/mL at the time of trigger, live birth was more likely in FET versus fresh cycles in the paired analysis (47% vs. 10%), in the unpaired analysis (51% vs. 14%), and in unpaired, good blastocyst only transfer subgroup (51% vs. 29%). Live birth was similar in FET cycles, with P ≥ 2 ng/mL versus P < 2 ng/mL (51% vs. 49%). Conversely, live birth was lower in fresh cycles, with P ≥ 2 ng/mL versus P <2 ng/mL (15% vs. 45%)., Conclusion(s): Elevated P levels on the day of trigger during the initial fresh cycle were negatively associated with live birth in the fresh transfer cycles but not in subsequent FET cycles. Freezing embryos and performing a subsequent FET cycle ameliorates the effect of elevated P on live-birth rates., (Published by Elsevier Inc.)

Objective: To evaluate if an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration is associated with a decrease in live-birth rate in patients with a good prognosis., Design: Retrospective cohort study., Setting: Large, private, assisted reproductive technology (ART) practice., Patient(s): One thousand six hundred twenty fresh autologous ART cycles., Intervention(s): None., Main Outcome Measure(s): Live-birth rate., Result(s): A total of 934 blastocyst and 686 cleavage-stage embryo transfer (ET) cycles were evaluated. Serum P levels were not associated with markers of oocyte or embryo quality, including fertilization, embryo stage at transfer, and embryos available for cryopreservation. Patient age, stage of ET, embryo quality, the number of embryos transferred, and P level on the day of hCG administration were all significantly associated with live birth. Higher P levels were associated with decreased odds of live birth for cleavage- and blastocyst-stage embryos, poor-fair and good-quality embryos, and poor- and high-responder patients. The nonsignificance of interaction tests of P levels with embryo stage, embryo quality, patient age, and ovarian response indicated that the relationship between P level and live birth was similar regardless of these factors., Conclusion(s): An elevated serum P level on the day of hCG administration was negatively associated with live birth, even in ETs with a good prognosis., (Published by Elsevier Inc.)

Objective: To summarize the available published randomized controlled trial data regarding timing of P supplementation during the luteal phase of patients undergoing assisted reproductive technology (ART)., Design: A systematic review., Setting: Not applicable., Patient(s): Undergoing IVF., Intervention(s): Different starting times of P for luteal support., Main Outcome Measure(s): Clinical pregnancy (PR) and live birth rates., Result(s): Five randomized controlled trials were identified that met inclusion criteria with a total of 872 patients. A planned meta-analysis was not performed because of a high degree of clinical heterogeneity with regard to the timing, dose, and route of P. Two studies compared P initiated before oocyte retrieval versus the day of oocyte retrieval and PRs were 5%-12% higher when starting P on the day of oocyte retrieval. One study compared starting P on day 6 after retrieval versus day 3, reporting a 16% decrease in pregnancy in the day 6 group. Trials comparing P start times on the day of oocyte retrieval versus 2 or 3 days after retrieval showed no significant differences in pregnancy., Conclusion(s): There appears to be a window for P start time between the evening of oocyte retrieval and day 3 after oocyte retrieval. Although some studies have suggested a potential benefit in delaying vaginal P start time to 2 days after oocyte retrieval, this review could not find randomized controlled trials to adequately assess this. Further randomized clinical trials are needed to better define P start time for luteal support after ART., (Published by Elsevier Inc.)

Objective: To evaluate the effect of luteal phase P support after ovulation induction IUI., Design: A systematic review and meta-analysis., Setting: Not applicable., Patient(s): Undergoing ovulation induction IUI., Intervention(s): Any form of exogenous P in ovulation induction IUI cycles., Main Outcome Measure(s): Clinical pregnancy and live birth., Result(s): Five trials were identified that met inclusion criteria and comprised 1,298 patients undergoing 1,938 cycles. Clinical pregnancy (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.15-1.98) and live birth (OR 2.11, 95% CI 1.21-3.67) were more likely in P-supplemented patients. These findings persisted in analyses evaluating per IUI cycle, per patient, and first cycle only data. In subgroup analysis, patients receiving gonadotropins for ovulation induction had the most increase in clinical pregnancy with P support (OR 1.77, 95% CI 1.20-2.6). Conversely, patients receiving clomiphene citrate (CC) for ovulation induction showed no difference in clinical pregnancy with P support (OR 0.89, 95% CI 0.47-1.67)., Conclusion(s): Progesterone luteal phase support may be of benefit to patients undergoing ovulation induction with gonadotropins in IUI cycles. Progesterone support did not benefit patients undergoing ovulation induction with CC, suggesting a potential difference in endogenous luteal phase function depending on the method of ovulation induction., (Published by Elsevier Inc.)

Purpose: To prospectively evaluate serum and follicular fluid leptin, estradiol, and progesterone levels during in vitro fertilization., Methods: Prospective observational study measuring serum levels at six points during the IVF cycle and follicular fluid at the time of retrieval., Results: Serum leptin and estradiol levels both significantly increased for the individual patients during the IVF stimulation process. None of the leptin levels differed based on pregnancy outcome. BMI significantly correlated with all leptin levels. Follicular fluid estradiol correlated with serum estradiol only in pregnant patients (r = 0.97, p<0.01) and was unrelated in non-pregnant patients (r=-0.15, p=0.81)., Conclusion: Serum and follicular leptin levels are highly correlated. Leptin levels increase during the IVF cycle and vary between patients based on maternal BMI, but do not correlate with other serum hormone levels or pregnancy outcome. Pregnancy outcome success was reflected in the relationship between follicular fluid and serum levels of estradiol, independent of leptin levels.