Comparison of art outcome in frozen embryo transfer cycle using oral estradiol valerate and estradiol transdermal gel
Authors: Patil Madhuri , Venkatappa Kavya G. , Patil Milind 
Published: December 2021

Aim:
Endometrial preparation with exogenous estrogen is a common practice in frozen embryo transfer (FET) cycles. The aim of this study was to compare the clinical outcome of oral estradiol valerate versus transdermal estrogen (17-β estradiol) gel in FET cycles.

Materials and Methods:
A prospective pilot study was carried out at a tertiary fertility clinic after Ethics Committee approval from January 2018 to December 2018. It included 103 infertile women who underwent FET cycles. Either oral estradiol valerate or transdermal 17-beta estradiol was used for endometrial preparation. Combination was used in case of breakthrough bleeding or if optimal endometrial thickness was not achieved. Baseline demographic parameters and details of the stimulation protocol and embryogenesis in fresh cycle were noted. In the FET cycle, the patient was seen on day 2 of menstrual cycle, where baseline ultrasound (USG), estradiol, and progesterone levels were done. If normal, the patients were given either oral or dermal preparation. The patient was seen again on day 9 for endometrial thickness and if required again after 2 days till endometrial thickness was 9 mm. If optimal endometrial thickness was not achieved or there was breakthrough bleeding, combination of both oral and dermal preparation was used. Once the endometrial thickness was 9 mm or more, progesterone was started, and ET was done on day 5. On the day of progesterone initiation, endometrial thickness, endometrial volume by 3D, and Doppler indices [pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV)] were noted. The primary outcome of the study was clinical pregnancy rate (CPR) and live birth rate (LBR).

Results:
There was no statistical difference in any of the demographic parameters in groups A and B. In group C, the pregnant patients were younger with higher body mass index and follicle-stimulating hormone and lower anti-Mullerian hormone and antral follicle count when compared with those who did not conceive. Demographics of the fresh cycle did not show any significant difference in dose and duration of stimulation, fertilization, cleavage, and blastulation rate in group A. In group B, the fertilization rate was significantly higher in the pregnant group (0.001), whereas the other parameters were similar. In group C, the pregnant group required more dose and days of stimulation and had lower oocytes retrieved but had a higher blastulation rate. In the hormone replacement therapy (HRT) cycle, there was no difference in the mean duration of HRT in groups A and B but was significantly higher in group C when compared with group A. The CPR with oral estradiol valerate, transdermal gel, and combination therapy was 34.85%, 35%, and 52.94%, respectively. The LBR with oral estradiol valerate, transdermal gel, and combination therapy was 25.76%, 30%, and 47.06%, respectively. Though the CPR and LBR were higher in group C, it did not reach statistical significance and this could be due to small sample size. There was no difference in the abortion rate (oral 7.58%, gel 5%, combination 5.88%) between the three groups. The implantation rate (oral 26%, gel 25.8%, combination 29.03%) in the three groups was also similar. There was also no statistical difference in the endometrial thickness, volume, and blood flow between the three groups. The cut-off values for Doppler indices for a positive pregnancy were as follows: Group A—PSV: >8.7, RI: <0.99, PI: >1.54; Group B—PSV: >5, RI: <0.72, PI: >2.1; Group C—PSV: >5.6, RI: <0.64, PI: >1.29.

Conclusion:
Both the oral estradiol valerate and transdermal 17-beta estradiol were equally effective for optimal outcome in an FET cycle in HRT. Those not responding to single preparation may benefit from combination therapy. Transdermal 17-beta estradiol gel may be of use in those patients who have breakthrough bleeding with oral preparation which may be due to hepatic bypass effect.