Impact of serum estradiol decline before hCG-triggering on IVF outcomes


A recent study delves into how serum estradiol decline preceding human chorionic gonadotropin administration affects in vitro fertilization outcomes, particularly among patients without oral contraceptive pretreatment, shedding light on the importance of monitoring during controlled ovarian hyperstimulation.

Impact of serum estradiol decline before hCG-triggering on IVF outcomes | Image Credit: © - © -

Impact of serum estradiol decline before hCG-triggering on IVF outcomes | Image Credit: © - © -

Serum estradiol (E2) decline before human chorionic gonadotropin (hCG)-triggering leads to adverse in vitro fertilization (IVF) and clinical outcomes among patients without oral contraceptive (OC) pretreatment, according to a recent study published in the International Journal of Women’s Health.


  1. Patients experiencing a reduction in estradiol (E2) levels before human chorionic gonadotropin (hCG)-triggering exhibited inferior in vitro fertilization (IVF) indexes, leading to decreased fertilization, pregnancy, and live birth rates.
  2. E2 levels serve as vital indicators during COH, with declining levels potentially signaling adverse outcomes in IVF cycles.
  3. The study highlights differences in outcomes between patients with and without oral contraceptive (OC) pretreatment, suggesting a potential role of OCs in mitigating the adverse effects of E2 decline.
  4. Factors such as age, body mass index, and basal FSH levels differed between groups, indicating the importance of considering patient-specific variables in IVF treatment planning.
  5. While this retrospective study provides valuable insights, researchers advocate for randomized controlled trials to corroborate findings and inform clinical practice regarding the management of E2 levels in IVF cycles.

E2 has been recognized as a vital component of follicle monitoring during controlled ovarian hyperstimulation (COH) among patients experiencing IVF cycles. Additionally, E2 may be an indicator of ovarian hyperstimulation syndrome risk because of the association between high E2 serum levels and multiple follicle development.

Reduced E2 levels the day before hCG administration is associated with inferior IVF indexes prior to the development of GnRH protocols. Data has also indicated a link to declining E2 and lower fertilization and clinical pregnancy rates, leading E2 monitoring to be closely related to drug adjustment during COH.

Investigators conducted a retrospective study to evaluate the impact of OC pretreatment on the role of E2 decline before hCG-triggering. IVF and intracytoplasmic sperm injection was administered to patients during their first cycle and were reviewed between 2013 and 2019.

Participants included women aged 40 years or less with a body mass index (BMI) of 28 or lower, antral follicle number from 5 to 10, and basal FSH below 15 IU/L on day 2 to 3 of the menstrual cycle. Patients with adenomyosis, endometriosis, recurrent spontaneous abortion, hyperprolactinemia, cycle cancellation, or recurrent implantation failure were excluded from the analysis.

The test group included patients with a drop in serum E2 during COH cycle while the control group included patients with continuous increases in E2 until the day of hCG. These groups were divided into OC and non-OC subgroups.

Ovarian stimulation protocols applied include GnRH agonist ultra-short protocol, short protocol, long protocol, and GnRH antagonist protocol. The GnRH agonist ultra-short protocol involved administration of the GnRH agonist on day 2 or 3 of the menstrual cycle for 3 days and gonadotropin (Gn) on day 3 or 4 until triggering day.

The short protocol involved GnRH agonist administration on day 2 and exogenous Gn on day 3 until the day of hCG administration. The long protocol involved agonist administration on the 21st day of the last cycle and Gn administration on day 3 of the next cycle until the triggering day.

The antagonist protocol involved starting Gn on day 2 and administering GnRH antagonist based on follicle size and E2 level until the day of hCG administration. Individual ultrasound follicular monitoring and blood testing were performed during the COH.

Embryo developement was measured on the third day following fertilization based on number of blastomeres, regularity, and embryonic fragmentation. Additional data collected included BMI, basal FSH, age, anti-Mullerian hormone (AMH), and stimulation parameters.

Age, proportion of infertility indications, AMH, treatment protocols, hCG dosage, and Gn dosage during COH did not differ between groups. However, a lower BMI and higher basal FSH level were reported in the E2 decline group compared to the control group.

Peak E2 value, E2, LH, and FSH levels were also significantly reduced in the E2 decline group vs the control group, at 11,065.1 ± 8292.1pmol/L vs 13,048.9 ± 7883.1pmol/L, 9614.0 ± 7457.3pmol/L vs 13,048.9 ± 7883.1pmol/L, 1.7 ± 1.9IU/L vs 2.8 ± 2.3IU/L, and 11.0 ± 3.7IU/L vs 11.6 ± 3.6IU/L, respectively.

The number of number of follicles on hCG day and normally fertilized zygote were 11.1 ± 6.2 and 7.5 ± 5.3 in the E2 decline group. These numbers were significantly lower than those in the control group, at 12.1 ± 5.9, and 8.3 ± 4.8, respectively. The E2 group had a significantly decreased live birth rate, indicating and adverse impact on IVF and clinical outcomes.

Live birth rates were 48.7% in the E2 decline group vs 55.1% in the control group. Pregnancy rates were 56% and 61.6%, respectively, mplantation rates 43.1% vs 46.2%, respectively, and miscarriage rates 12.3% vs 10.3%, respectively.

A significant reduction in fertilization and pregnancy rates were observed in E2 decline patients without OC pretreatment vs those with OC pretreatment, at 59.8% and 56.3% vs 63.3% and 68%. Live birth rates were also decreased at 50.8% vs 63.5%, respectively.

These results indicated E2 decline before the day of hCG administration in patients without OC pretreatment is associated with reduced fertilization, pregnancy, and live birth rates. Investigators recommended a randomized controlled trial be conducted to support these findings.


Zhu Y, Zheng Z, Fan B, Sun Y, Zhai J, Du Y. Estradiol decline before hCG administration in COH has a negative effect on IVF outcomes in patients without OC pretreatment. Int J Womens Health. 2024;16:411-419. doi:10.2147/IJWH.S423089

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