By offering a shorter duration of treatment and fewer clinic visits, the transdermal route might be more attractive for patients than the vaginal route. This difference was expected and can be explained by the different metabolism of these two routes: Both bypass the first pass hepatic metabolism, and vaginal results in very high serum levels because of an important absorption through the vaginal mucosa while transdermal produces the most stable steady-state levels 12 , High estradiol levels are associated with many drawbacks: a higher vascular risk 25 , 26 , lower LBR in FET, and higher risk of small for gestational age, abnormal placentation and preeclampsia in the ensuing pregnancy after fresh embryo transfers 27 , 28 , Moreover, the more physiologic hormonal milieu found in FET cycles is one of the main arguments in favor of frozen over fresh embryo transfers.
Therefore, the lower plasma estradiol levels with transdermal estrogen could be an added advantage over the vaginal route. It seems contradictory to have a significantly lower serum estradiol levels in the T group with a significantly shorter duration of treatment.
One possible explanation is that very high levels of serum estradiol, as those obtained with the vaginal route, could have an antiproliferative effect.
There were more cycle cancelations because of spontaneous ovulation in the T group compared to the V group 7. This can be explained by the lower serum estradiol levels with transdermal treatment, leading to less efficient inhibition of the hypothalamic-pituitary axis HPO.
Indeed, the serum LH levels were significantly higher on the day of ultrasound assessment in the T group This drawback of transdermal estrogen could be overcome with pre-treatment pituitary down-regulation using a Gonadotropin releasing hormone agonist GnRHa.
Indeed, down-regulation with GnRHa is commonly used in artificial FET cycles, no matter the type of estrogen used and without any negative impact on endometrial thickness 18 , However, results have not shown any added benefits when using oral or vaginal estradiol, where the rates of spontaneous ovulation are already low However, it could be beneficial when using transdermal estrogen for FET since spontaneous ovulation seems to be higher.
We did not find any difference in CPR, clinical pregnancy loss, biochemical pregnancy loss and LBR between the transdermal and vaginal groups. Several studies have already shown that the type of estrogen treatment does not influence the pregnancy outcomes in FET 21 , 34 , 37 , but our study is the first to directly compare the transdermal and vaginal route, and confirm the lack of difference between the two.
Our study has shown a better tolerance of transdermal estrogen compared to vaginal estrogen. Indeed, the global satisfaction score was significantly higher and the rate of undesirable side effects was significantly lower in the T group. Moreover, The higher rate of undesirable side effects could be explained by the higher serum estradiol levels in the vaginal group. Patient tolerance is an essential factor to be taken into consideration when choosing a treatment for FET, considering patients have to be highly compliant for a period of 8 weeks when pregnant.
To the best of our knowledge, our study is the first to compare endometrial thickness and cycles outcomes, as well as patient satisfaction and tolerability, between transdermal and vaginal estradiol for endometrial preparation in FET cycles. Moreover, our clinical findings were corroborated by biologic data, further validating our conclusions.
Our main limitations were the lack of randomization and the monocentric design. Finally, it would have been interesting to add the oral route to the comparison, but we do not use oral estrogen for endometrial preparation in our center. In conclusion, our study has shown that transdermal estrogen was associated with higher endometrial thickness and shorter treatment duration when compared with vaginal estrogen for endometrial preparation before FET, but higher cycle cancelation because of spontaneous ovulation.
Moreover, transdermal estrogen was better tolerated by patients with significantly fewer side effects. Finally, pregnancy outcomes were comparable between the two. These findings suggest that transdermal estrogen should be offered first for endometrial preparation before FET.
A pretreatment injection of GnRH agonist could be added to decrease the rate of spontaneous ovulation and cycle cancelation. We performed a unicentric prospective cohort study at the department of reproductive medicine of the Angers university hospital, between January 1 st and December 31 st The study was registered in the clinical trial database at Clinicaltrials. All patients were briefed on the study and signed an informed consent before inclusion. All methods were performed in accordance with the relevant guidelines and regulations.
We excluded from the study all patients: 1 who refused to sign the consent form; 2 who were given a specific treatment without being given the option between the two routes; 3 who had a FET performed in natural or stimulated cycles; 4 who had a FET following oocyte donation; 5 under legal guardianship; 6 non beneficiaries of a social security scheme; 7 non-French speaking.
Estrogen was started on day 2 of the menstrual cycle and continued at the same dose until the serum human Chorionic Gonadotropin hCG testing, and until 8 weeks of pregnancy when positive.
The patches were changed every 4 days, and treatment continued until the serum hCG test and until 8 weeks of pregnancy when positive. The patients were instructed to apply the patches on a clean and dry skin, in the lower abdomen region or on the hips, based on their preference.
Having received the information, the choice between the vaginal route V group and the transdermal route T group was left to the patient, and the drug prescriptions were handed accordingly. The distance was measured between the two calipers placed at the outer lining of the endometrial—myometrial interface from the anterior to the posterior wall of the uterus. The measurements were performed by three attending physicians and two senior fellows. Progesterone was started on the night of the theoretical day of oocyte retrieval, meaning day 3 embryos were transferred on day 4 of progesterone, and blastocysts transferred on day 6 of progesterone.
Cycle cancelation was defined as a cycle abandoned before the embryo transfer. Cycles could also be canceled even after progesterone supplementation was started, such as cases where the embryos did not survive the thaw procedure. At our center, we transfer embryos on day 2, 3 or 5, depending on the case. All embryos had been cryopreserved by vitrification, and were thawed the morning of the planned transfer and transferred on the same day they had been cryopreserved.
Blastocysts were classified according to the Gardner and Schoolcraft criteria On the day of embryo transfer, an anonymous questionnaire was handed to all included patients, depending on the treatment they received. Patients who had vaginal estrogen were asked to: quote their satisfaction from 0 not satisfied at all to 10 totally satisfied , describe if they had any undesirable side effects and what were they, and specify if there were any drawbacks related to the treatment Supplementary material 1.
Patients who received the transdermal route were asked the same questions, with extra questions reserved for patients who had already received vaginal estrogen for another FET prior to this one.
These patients were asked to state their preference between the two routes, and which one had more side effects Supplementary material 2. Each patient received only one questionnaire and was only included once if she received the same protocol twice, but twice if she received the two protocols one for each group. When positive, the test was repeated seven days later. Our secondary outcomes were the clinical pregnancy rate CPR , live birth rate LBR , clinical miscarriage loss, biochemical pregnancy loss, the hormonal profile serum estradiol, progesterone and LH on the first ultrasound, the cancelation rate, the number of days of treatment before the FET, and the satisfaction rate as measured by our survey.
We performed an intention to treat analysis by including all started cycles and a per protocol analysis by including only cycles where the FET was performed. The dataset generated during the current study can be made available upon request to the corresponding author. McLernon, D. Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials.
BMJ , c Shapiro, B. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfers in high responders.
Fertility and Sterility 96 , — Article Google Scholar. Yarali, H. Preparation of endometrium for frozen embryo replacement cycles: a systematic review and meta-analysis. Mackens, S. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Wright, K. Artificial versus stimulated cycles for endometrial preparation prior to frozen-thawed embryo transfer. Online 13 , — Groenewoud, E. A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer.
Ziegler, W. High success with gestational carriers and oocyte donors using synchronized cycles. Abu-Musa, A. Artificial endometrial preparation for oocyte donation using synthetic estrogen and progestogen.
Clin Exp Obstet Gynecol 25 , 83—85 Devroey, P. Preparation of endometrium for egg donation. Update 4 , — Paulson, R. It is important that you start estrogen therapy on the first day of your period. This is a pill containing 2 mg of estradiol, the same hormone produced by the ovaries. We will have you take one pill twice a day for about 14 days.
This may be administered vaginally or as an intramuscular injection. If the test is positive, these medications may be continued for several weeks. Embryo transfer is usually performed on the third to fifth day of progesterone therapy. As with natural cycle FET, embryos are thawed on the morning of the scheduled frozen embryo transfer. In our laboratory, approximately percent of embryos survive cryopreservation and thawing. We usually transfer 1 to 2 embryos during each FET cycle.
However, this number is flexible, and your physician will discuss this issue with you. Excellent FET pregnancy rates occur in most cases with the transfer of one to two embryos, which also minimizes the risk of multiples. The transfer of more embryos may increase the likelihood of a multiple pregnancy, which increases the pregnancy risks for the woman and the fetuses. The actual embryo transfer itself is identical to the embryo transfer following in vitro fertilization-embryo transfer.
A small plastic catheter is passed gently through the cervix into the uterus. The same artificial protocol was applied to all cycles. Supplementation started on cycle day 2 after confirmation of basal serum hormonal values for E2, P, and LH. Routinely, a dose of 2 mg was prescribed twice daily during the first 6 days, followed by 2 mg three times daily during the following 7 days.
Serum P assessments were used to detect escape ovulation and the cycle was canceled when progesterone was 1. If the endometrial thickness was below 6.
If following the step-up protocol endometrial thickness did not reach 6. Once P supplementation was started, the estradiol valerate dose was decreased to 2 mg twice daily to mimic the natural cycle. Luteal phase support was continued until the time of the hCG pregnancy test and prolonged until 8 weeks of gestation whenever positive. Cleavage stage day 3 embryos were warmed the day before FET and transferred as a day 4 embryo on the fifth day of P supplementation.
Blastocysts were warmed and transferred that same day on the seventh day of P supplementation. In accordance with the Belgian legislation, one or maximum two embryos were transferred. Morphological survival was assessed by counting the number of intact cells on the number of cells present at warming. Further cleavage was assessed the next morning and defined as the percentage of embryos with at least division of 2 cells after overnight culture on the total number of transferred embryos Blastocysts were vitrified on day 5 or 6 of embryo culture if they reached at least the full blastocyst stage with good quality inner cell mass and trophectoderm, i.
Blastocysts were warmed in the morning of the day of transfer and immediately evaluated for morphological survival. The morphological quality of the blastocyst was scored at the moment of transfer. To account for embryo quality in the statistical analysis, we attributed a quality score from 1 to 4 to each transferred embryo Supplementary Table 1. Blood samples were drawn by venipuncture, allowed to coagulate at least 30 min followed by a centrifugation for 10 min at 1, g, after which serum was decanted, avoiding erythrocytes.
The same assay was used during the entire study and regularly calibration was performed to minimize variation related to time and reagent batch renewal. Serum E2 levels were measured in all patients 1 or 2 days before the start of P supplementation for the induction of the luteal phase.
Comparisons between these groups for relevant patient background, fresh and frozen cycle characteristics were performed using mixed-effects regression in order to account for clustering of patients who performed more than one fresh cycle and, within these, more than one FET cycle, followed by pairwise comparisons whenever statistically significant.
LBR was the main outcome of the study. Stata Statistical Software: Release A total of patients were included in the analysis having performed 1, artificial autologous FET cycles. The baseline characteristics of the included patients and their fresh cycles are summarized in Table 2. Table 2. Baseline patient and fresh cycle characteristics according to late-proliferative phase serum estradiol level percentiles of the FET cycle. The FET cycle characteristics can be found in Table 3.
Table 3. FET cycle characteristics according to late-proliferative phase serum estradiol level percentiles. LBRs were To assess further a possible relationship between the late-proliferative serum E2 level and the FET cycle outcome, the crude clinical pregnancy rate, clinical miscarriage rate and LBR are depicted in Figure 1 according to each 10th percentile. No statistically significant relationship was found. Figure 1. Artificial frozen embryo transfer cycle outcomes according to each 10th percentile of the late-proliferative serum estradiol level.
No statistically significant relationship could be withheld. The only significant p -value 0. The predicted LBR for the p11—p90 reference group was This single-center retrospective analysis did not detect a correlation between the serum E2 level prior to the induction of the luteal phase and the subsequent LBR in artificial FET cycles. To the best of our knowledge, this is the largest dataset addressing this particular question, consisting of more than double the size of the previously performed studies in terms of the included number of artificial FET cycles.
Its conclusion is in line with the majority of formerly published work 8 — 11 , however, it is for the first time confirmed at the level of the LBR. Considerably, Fritz et al. In this study, patients supplemented with E2 via the transdermal route were excluded, not because the administration route is thought to affect FET success rate 20 , but as a different pharmacokinetic profile has been described In our center, the above-mentioned artificial protocol using oral estradiol valerate is used routinely, while transdermal administration is applied mainly in second line or on specific patient's or treating physician's request.
To avoid a possible bias, we chose to not include these cycles in the current analysis. As the experimental results above show, few patients in an artificial FET cycle where the endometrium reaches 6. Indeed, a potential negative impact of even more extreme ranges of the spectrum is theoretically interesting and could not be excluded, however, the low prevalence of these events limits the importance for clinical practice.
Besides this, another limitation of the study is the non-fixed time interval between the last estradiol dose intake and the harvesting of the blood sample to determine the circulating serum E2 level, which could have caused variation in the measurements.
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