Impact of hgh preovulatory estradiol on reproductive outcomes in gonadotropin-releasing hormone agonist-triggered cycles with fresh embryo transfer: a retrospective study

The study investigated an independent association between elevated preovulatory serum estradiol (E2) levels and pregnancy outcomes in women triggered by gonadotropin-releasing hormone agonist (GnRH-a), followed by fresh embryo transfer (ET) and modified luteal phase support (LPS). This study is based on data acquired from a previous randomized controlled trial. A total of 328 consecutive participants, ages 18-40 years old, with normal to high responses to controlled ovarian hyper-stimulation (COH) were included. Patients were stratified into two groups based on preovulatory E2 levels (low E2 level < 3000 pg/ml and high E2 level ≥ 3000 pg/ml). The primary outcome was live birth (LB).The unpaired t-test and chi-square test were used as appropriate. Logistic regression was performed to determine the association between preovulatory E2 and LB as well as early pregnancy loss (EPL) after adjusting for confounders. The potential confounders included in the models were chosen a priori based on a Directed Acyclic Graph (DAG). An exploratory analysis was performed to examine which variables could impact serum E2 levels on the day of GnRH-a trigger. In the entire cohort, high preovulatory E2 levels were associated with lower LB rates and a trend towards higher EPL rates; (88/238 [36.97%]) vs. 22/90 [24.4 %]); P<0.03, 19/238 [7.98%]) vs. 13/90 [14.4 %]); P<0.09 respectively. Multivariate regression revealed that preovulatory E2 level was an independent factor associated with both LB and EPL; Odds Ratio (OR) were 0.55 (0.32-0.95); P< 0.03 and 6.8 (1.90-24.25); P< 0.003 for LB and EPL respectively. None of the patients in the low E2 group developed any form of ovarian hyper-stimulation syndrome (OHSS) compared with 0.8% (2/90) of patients in the high E2 group. Multiple linear regression showed that number of follicles (> 14 mm) and progesterone levels on the trigger day were positively correlated with preovulatory E2 levels (p < 0.0001), while body mass index (BMI) showed a negative correlation (p <0.01). The study demonstrates that elevated preovulatory serum E2 levels in women undergoing fresh IVF-ET cycles using a GnRH-a trigger decrease the odds of LB and increase the odds of EPL, presumably due to impaired endometrial receptivity despite modifications to LPS and thus, could be the elephant in the room.