Elevated Estradiol on Day of Progesterone Initiation Is Detrimental After Frozen Embryo Transfer

Close up of green tray with researcher removing embryo frozen in liquid nitrogen for IVF procedure

Evidence is mixed, but some studies suggest that elevated estradiol levels resulting from ovarian hyperstimulation can negatively affect conception and live birth rates after fresh embryo transfers. Many in vitro fertilization (IVF) programs now freeze all embryos and transfer them later to mitigate this risk.

However, researchers at Brigham and Women’s Hospital determined that elevated estradiol thresholds at the time of progesterone initiation have similarly negative effects on outcomes after frozen embryo transfer cycles. Mark D. Hornstein, MD, director of the Brigham’s Center for Infertility and Reproductive Surgery, and colleagues report the findings in the Journal of Assisted Reproduction and Genetics.


The researchers reviewed all first autologous single or double frozen blastocyst transfer cycles performed between June 1, 2012, and June 30, 2018, at the Brigham. Cycles were eligible only if all of the following criteria were met:

  • Only oral estradiol was used for endometrial preparation
  • Serum estradiol was measured on the day of progesterone initiation
  • A blastocyst was transferred
  • Progesterone replacement was administered intramuscularly

363 eligible cycles were stratified by quartile of serum estradiol on the day of progesterone initiation.

IVF Outcomes

In the lowest quartile, the mean serum estradiol level was 212 pg/mL, and in the highest quartile, it was 528 pg/mL. In the top decile of estradiol, the mean was extremely high at 697 pg/mL.

Outcomes of patients in the lowest and highest quartiles were compared in models adjusted for maternal age and body mass index. The poorest outcomes were associated with the highest estradiol values:

  • Implantation—RR, 0.66 for highest vs. lowest quartile (P=0.01)
  • Ongoing pregnancy—RR, 0.66 (P=0.03)
  • Live birth—RR, 0.70 (P=0.04)
  • Miscarriage—No significant difference between groups

Analyses that considered only single embryo transfers showed similar results.

Continued Scrutiny Needed

There was no direct, linear relationship in this study between IVF outcomes and estradiol level on the day of progesterone initiation. Still, further research is needed to find whether a “threshold” estradiol level may exist above which outcomes are poorer, as these findings suggest.

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