Luteal Phase Estradiol Support for In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles: a Randomized, Controlled Study

Background:

It is well established that the luteal phase is compromised in IVF cycles using GnRH analogues. Use of GnRH agonists or antagonists results in decreased production of estrogen and progesterone, a decrease in luteal phase length, and impaired endogenous gonadotropin secretion caused by persistent pituitary suppression. While the benefits of progesterone support during the luteal phase of an IVF cycle are well established, the role of estrogen support during the luteal phase is less clear.

The corpus luteum produces both progesterone and estradiol in support of the endometrium for implantation. Estrogen produced during the luteal phase modulates the concentration of progesterone receptors within the secretory endometrium in an effort to maintain sufficient receptor concentrations for progesterone stimulation. Stewart et al. highlighted the importance of luteal phase serum estradiol concentration after observing a significant difference in midluteal serum estradiol concentration between conception and non-conception cycles. This observation appears to hold true in patients undergoing IVF as well. Shahara et al. demonstrated that, not only the absolute estradiol level, but also the magnitude of estradiol decline (as measured by the ratio of peak estradiol at the time of hCG administration to midluteal estradiol) was predictive of IVF success. These studies support the idea that luteal phase estradiol supplementation may be important to implantation and IVF success.

Studies investigating the effect of luteal phase estradiol supplementation have produced conflicting results. In a small randomized, controlled trial (RCT) by Farhi et al., IVF patients receiving both oral estradiol and vaginal progesterone luteal phase support achieved higher clinical pregnancy and implantation rates than patients received vaginal progesterone alone. Lukaszuk et al. confirmed these findings and found that the most significant benefit occurred at the highest dose of estradiol administered (6mg). Elgindy et al. observed a correlation between mid-luteal serum estradiol concentration and clinical pregnancy rates in patients receiving 6mg of oral estradiol15. Similar benefits of luteal phase estradiol support have been demonstrated in both vaginal and transdermal formulations.

Conversely, multiple older studies have failed to demonstrate a benefit of luteal phase estradiol support in IVF cycles. Lin et al., in a RCT of 402 patients undergoing IVF, found no benefit of luteal phase oral estradiol. This finding was supported by studies investigating both vaginal and transdermal formulations of luteal phase estradiol support. A recent meta-analysis also did not demonstrate a statistically significant benefit of luteal phase estradiol administration to IVF outcomes, though the common odds ratio was 1.18 (95% CI: 0.98, 1.41) with a p value of 0.07. Significant heterogeneity was observed between the included studies and the authors admit that more large-scale RCTs are needed to appropriately address this question.