The true natural cycle frozen embryo transfer - impact of patient and follicular phase characteristics on serum progesterone levels one day prior to warmed blastocyst transfer

BACKGROUND: In a true-natural cycle (t-NC), optimal progesterone (P(4)) output from the corpus luteum is crucial for establishing and maintaining an intrauterine pregnancy. In a previous retrospective study, low P(4) levels (< 10 ng/mL) measured one day before warmed blastocyst transfer in t-NC were associated with significantly lower live-birth rates. In the current study, we aim to examine the relationship between patient, follicular-phase endocrine and ultrasonographic characteristics, and serum P(4) levels one day prior to warmed blastocyst transfer in t-NC. METHOD: 178 consecutive women undergoing their first t-NC frozen embryo transfer (FET) between July 2017-August 2022 were included. Following serial ultrasonographic and endocrine monitoring, ovulation was documented by follicular collapse. Luteinized unruptured follicle (LUF) was diagnosed when there was no follicular collapse despite luteinizing-hormone surge (> 17 IU/L) and increased serum P(4) (> 1.5 ng/mL). FET was scheduled on follicular collapse + 5 or LH surge + 6 in LUF cycles. Primary outcome was serum P(4) on FET − 1. RESULTS: Among the 178 patients, 86% (n = 153) experienced follicular collapse, while 14% (n = 25) had LUF. On FET-1, the median serum luteal P(4) level was 12.9 ng/mL (IQR: 9.3–17.2), ranging from 1.8 to 34.4 ng/mL. Linear stepwise regression revealed a negative correlation between body mass index (BMI) and LUF, and a positive correlation between follicular phase peak-E(2) and peak-P(4) levels with P(4) levels on FET-1. The ROC curve analyses to predict < 9.3 ng/mL (< 25th percentile) P(4) levels on FET-1 day showed AUC of 0.70 (95%CI 0.61–0.79) for BMI (cut-off: 23.85 kg/m(2)), 0.71 (95%CI 0.61–0.80) for follicular phase peak-P(4) levels (cut-off: 0.87 ng/mL), and 0.68 (95%CI 0.59–0.77) for follicular phase peak-E(2) levels (cut-off: 290.5 pg/mL). Combining all four independent parameters yielded an AUC of 0.80 (95%CI 0.72–0.88). The adjusted-odds ratio for having < 9.3 ng/mL P(4) levels on FET-1 day for patients with LUF compared to those with follicle collapse was 4.97 (95%CI 1.66–14.94). CONCLUSION: The BMI, LUF, peak-E(2,) and peak-P(4) levels are independent predictors of low serum P(4) levels on FET-1 (< 25th percentile; <9.3 ng/ml) in t-NC FET cycles. Recognition of risk factors for low serum P(4) on FET-1 may permit a personalized approach for LPS in t-NC FET to maximize reproductive outcomes.