The Link Between Serum Estradiol Level on the Day of Human Chorionic Gonadotrophin Administration and Clinical Outcomes
In the realm of assisted reproductive technology (ART), in vitro fertilization-embryo transfer (IVF-ET) is a crucial method for helping infertile patients. Estradiol (E2), a key hormone in follicular development and endometrial receptivity, has a significant impact on the clinical outcomes of fresh IVF-ET cycles. This article delves into a retrospective study that aimed to evaluate the association between elevated serum E2 levels on the day of human chorionic gonadotrophin (hCG) administration and IVF-ET pregnancy and birth outcomes.
Introduction
IVF-ET is the mainstay of ART. Controlled ovarian hyper-stimulation (COH) is used to retrieve more oocytes, which is positively correlated with a high live birth rate. However, the effect of high E2 levels on the day of hCG administration in IVF treatment is still a matter of debate. Some studies suggest a concentration-dependent effect on pregnancy and delivery rates, while others report no alteration in the pregnancy rate.
Theoretical Considerations
High E2 concentrations at implantation can impair endometrial receptivity, leading to abnormal placentation. Previous research has shown that exposure to high E2 during implantation in infertility treatment may have a negative impact on endometrial receptivity. Additionally, supraphysiologic serum E2 in COH during ART increases the risk of abnormal placentation and adverse outcomes like miscarriages, preeclampsia (PreE), and small fetuses.
Methods
Ethical Approval and Patient Selection
This retrospective cohort study was approved by the Institutional Ethics Committee of Peking University First Hospital. A total of 2998 patients undergoing their first IVF cycles from January 2011 to January 2016 were reviewed. After excluding patients with incomplete cycles, non-top-quality embryos, fibroid uterus, adenomyosis, abnormal pregnancy history, or congenital uterine anomalies, 1771 patients were included. They were categorized into six groups based on serum E2 levels on the day of hCG administration: group 1 (E2 ≤ 1000 pg/mL), group 2 (1001–2000 pg/mL), group 3 (2001–3000 pg/mL), group 4 (3001–4000 pg/mL), group 5 (4001–5000 pg/mL), and group 6 (E2 > 5000 pg/mL).
Controlled Hyper-stimulation Induction and Embryo Transfer
The GnRH agonist long protocol and the GnRH antagonist protocol were used. The GnRH agonist long protocol involved daily injections of short-acting and long-acting GnRH-a at different doses. The GnRH antagonist protocol consisted of daily gonadotrophin stimulation followed by daily injections of Cetrotide once the leading follicle reached 14 mm. After retrieval, oocytes were fertilized by standard insemination, and embryos were transferred on day 2 or 3. The luteal phase was supported by progesterone.
Data Collection and Statistical Analysis
Patient clinical parameters (age, day 3 follicle-stimulating hormone [FSH], LH, E2 concentration, duration of infertility, type of protocol) were collected. The outcomes of IVF (number of retrieved oocytes, number of MII oocytes, implantation rate, clinical pregnancy rate) and pregnancy outcomes (pre-term delivery [PT], birth weight, presence of PreE) were analyzed. Statistical analysis was performed using SPSS, including unpaired Student’s t test, Chi-squared test, odds ratios (ORs), and receiver operating characteristic (ROC) curve analysis.
Results
General Information of Patients
The mean age of the 1771 patients was 32.69 years. Patients in group 1 had a higher average age and baseline FSH. Binary logistic regression analysis showed that serum E2 levels on hCG administration day were an independent risk factor for clinical pregnancy rate.
Ovulation-promoting and Clinical Results
The retrieved oocyte and MII oocyte numbers and implantation and clinical pregnancy rates gradually increased from groups 1 to 5 but decreased in group 6. Group 1 had statistically worse parameters than the other groups. For example, the number of retrieved oocytes, MII oocytes, implantation rate, and clinical pregnancy rate were significantly lower in group 1 compared to the other groups.
Pregnancy Outcomes
Among the 360 women with singleton births, the mean age was 31.8 years, and the median serum E2 level was 2559 pg/mL. The prevalence rates of PT, PreE, and LBW were 14.1%, 5.3%, and 9.7%, respectively. The odds of LBW were higher in the top E2 group. ROC analysis revealed that a serum peak E2 of 3148 pg/mL was associated with LBW.
Discussion
IVF Outcomes
The study showed that as serum E2 levels increased up to 5000 pg/mL, the number of oocytes and MII oocytes received and the implantation and clinical pregnancy rates increased. However, these parameters declined at concentrations above 5000 pg/mL. This is in line with previous studies that suggest an optimal range of E2 levels for IVF outcomes. For example, Joo et al. reported an optimum range of 3000 to 4000 pg/mL for women <38 years and 2000 to 3000 pg/mL for women ≥38 years.
Pregnancy Outcomes
The study also found that peri-implantation maternal hormonal milieu in fresh ET cycles was associated with a higher risk of delivering LBW infants. The odds of delivering LBW infants were 16.8-fold greater in patients with higher E2 levels. This may be due to abnormal placentation caused by high E2 concentrations. Previous studies have shown that elevated E2 levels can impair the expression of implantation-associated genes, leading to aberrant placentation.
Limitations and Future Directions
The study had some limitations, such as the retrospective design and small sample size from a single institution. However, it provides valuable insights into the relationship between E2 levels and IVF-ET outcomes. Future research should include larger prospective studies to confirm these findings and explore the impact of the hyper-estrogenic milieu during COH on implantation and placentation.
Conclusion
In conclusion, serum E2 levels on the day of hCG administration influence the IVF and pregnancy outcomes in a concentration-dependent manner. The optimal range of E2 levels during a fresh IVF-ET cycle is 1000 to 3148 pg/mL. Insufficient or excessive E2 levels may have negative effects on clinical outcomes. ART providers should be aware of the possible adverse pregnancy outcomes associated with supraphysiologic E2 levels on the hCG trigger day.
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