Comparison of clinical outcomes between use of estradiol transdermal gel and oral estradiol valerate in patients undergoing frozen-thaw embryo transfer: an observational study.

Totally 251 cycles were recruited, with 7 participants canceling their cycles due to personal reasons. Therefore, this study included 121 and 123 cycles using oral estrogen tablets and transdermal gel, respectively. The baseline characteristics of both groups are shown in Table  1 , including patient age, duration of infertility, BMI, total cholesterol (TC), total triglycerides and basal FSH, LH and E 2 . There were no significant differences between the two groups except for basal FSH levels (4.96 ± 1.77 versus 5.47 ± 1.65, p  = 0.020). Table 1 Baseline patient characteristics Gel group N  = 121 Oral group N  = 123 t p value Age (years) 29.62 ± 3.26 29.90 ± 3.07 − 0.680 0.497 Duration of infertility (years) 4.39 ± 2.97 4.58 ± 3.00 − 0.494 0.622 BMI (kg/m 2 ) 21.30 ± 2.25 21.20 ± 2.27 0.321 0.748 Basal FSH (IU/L) 4.96 ± 1.77 5.47 ± 1.65 − 2.351 0.020* Basal LH (IU/L) 4.31 ± 5.00 3.73 ± 1.74 1.215 0.221 Basal E 2 (pg/ml) 32.36 ± 13.64 29.98 ± 12.81 1.411 0.159 AMH (ng/mL) 5.09 ± 3.37 4.65 ± 2.90 1.173 0.242 ALT (U/L) 16.31 ± 6.83 16.64 ± 7.32 − 0.357 0.721 AST (U/L) 18.69 ± 4.13 19.24 ± 4.05 − 1.047 0.296 TC (mmol /L) 4.57 ± 0.61 4.33 ± 0.68 2.797 0.060 TG (mmol /L) 1.19 ± 0.68 1.17 ± 0.62 0.304 0.761 * p  < 0.05 was considered statistically significant Baseline patient characteristics * p  < 0.05 was considered statistically significant Cycle characteristics and clinical pregnancy outcomes in both groups are shown in Table  2 . There were no significant differences in estrogen duration and E 2 levels on the day of embryo transfer. Endometrial thickness on the day of embryo transfer was reduced in the gel group compared with the oral group (0.88 ± 0.13 versus 0.91 ± 0.12, p  = 0.026). Additionally, the oral group had higher ALT (16.58 ± 6.13 versus 23.78 ± 7.17, p  < 0.001) and AST (19.70 ± 3.58 versus 23.78 ± 7.17, p  = 0.001) levels at 12 weeks of gestation. Table 2 Clinical pregnancy outcomes in both groups Gel group N  = 121 Oral group N  = 123 t /X 2 p value E 2 on the day of ET (pg /ml) 289.05 ± 232.35 272.39 ± 237.59 0.554 0.290 Duration of E 2 administration (days) 17.52 ± 2.52 17.15 ± 2.04 1.270 0.205 Endometrial thickness on the day of ET (cm) 0.88 ± 0.13 0.91 ± 0.12 − 2.247 0.026* ALT at 12 weeks of gestation (U/L) 16.58 ± 6.13 (N = 74) 23.78 ± 7.17 (N = 74) − 6.57 0.000* AST at 12 weeks of gestation (U/L) 19.70 ± 3.58 ( N  = 74) 22.42 ± 5.13 ( N  = 74) − 3.740 0.001* Implantation rate (%) 41.73% (101/242) 42.68% (105/246) 0.0449 0.832 Ectopic pregnancy rate (%) 4.96% (6/121) 4.88% (6/123) 0.0008 0.977 Clinical pregnancy rate (%) 61.16% (74/121) 60.16% (74/123) 0.0253 0.874 Miscarriage rate (%) 5.79% (7/121) 10.57% (13/123) 1.8552 0.173 Live birth rate (%) 55.37% (67/121) 51.20% (61/125) 1.0639 0.302 * p  < 0.05 was considered statistically significant Clinical pregnancy outcomes in both groups * p  < 0.05 was considered statistically significant Implantation, ectopic pregnancy, and clinical pregnancy rates exhibited no significant differences between the two groups. The gel group showed a higher live birth rate (55.37% versus 51.20%, p  = 0.302) and a lower miscarriage rate (5.79% versus 10.57%, p  = 0.173), but statistical significance was not reached. No adverse drug reactions were observed in this study. To remove the effects of various potential confounders (age, BMI, AMH, basal FSH, E 2 levels and endometrial thickness on the day of embryo transfer) on clinical pregnancy outcomes, including live birth rate, logistic regression analysis was performed (Table  3 ). Intervention (gel), age, BMI, AMH, basal FSH, E 2 levels and endometrial thickness on the day of embryo transfer had no significant effects on live birth rate. Table 3 Univariate binary logistic regression of live birth rate OR 95.0% CI p value Gel group 1.161 (0.495–2.726) 0.731 Age (years) 1.125 (0.926–1.367) 0.235 BMI (kg/m 2 ) 0.945 (0.816–1.095) 0.435 AMH (ng/mL) 0.994 (0.910–1.085) 0.889 Basal FSH (IU/L) 0.838 (0.618–1.136) 0.255 Endometrial thickness on the day of ET (cm) 1.096 (0.766–1.568) 0.615 Univariate binary logistic regression of live birth rate

Patients who underwent FET at the Reproductive Center of Chongqing Maternal and Child Health Hospital from March 1, 2017 to October 30, 2019 were recruited in the present study. The study was approved by the Ethics Committee of Women and Children’s Hospital of Chongqing Medical University (Number: 2017-RGI-06). Women aged between 20 and 37 years with a healthy endometrial environment, evaluated by routine transvaginal ultrasound, and expected to transfer double D3 cleavage-stage embryos, were recruited for hormone replacement therapy. Exclusion criteria included: (1) poor ovarian reserve; (2) PGT cycles; (3) hydrosalpinx; (4) > 2 failed transfers; (5) abnormal renal or hepatic function; (6) uterine abnormalities, including adenomyosis, intrauterine adhesions, endometrial polyps, uterine malformations, submucosal uterine and intramural fibroids > 3 cm; (7) major congenital diseases, chromosomal abnormalities, autoimmune diseases, thromboembolic disorders, hypertension, diabetes mellitus and cancers. All individuals were assessed on days 2–5 of the menstrual cycle, measuring estradiol (E 2 ), follicle-stimulating hormone (FSH), luteinizing hormone (LH), serum glutamic oxaloacetic transaminase (AST), glutamic pyruvic transaminase (ALT) levels, lipid profile and coagulation function. Patients started treatment with estradiol transdermal gel or oral estradiol valerate tablets per their preference once they met the testing criteria. The numbers of patients in both groups had a ratio of 1:1. The gel group was administered estradiol transdermal gel (17β estradiol 0.06%; Oestrogel, Besins, Belgium), at an initial dose of 4.5 mg per application (7.5 g gel), administered twice daily. The oral group was treated with oral estradiol valerate tablets (Progynova, Bayer), starting at 2 mg per dose, also twice daily. After 7 days of continuous treatment, the thickness and growth rate of the endometrium were assessed by ultrasonography. Dose adjustments were based on serum estradiol levels and endometrial thickness. After 14 days of E 2 administration, when endometrial thickness reached ≥ 8 mm, vaginal progesterone (Utrogestan, micronized progesterone, Besins, Belgium) at a dose of 200 mg, thrice daily, was administered to induce the endometrium from proliferative to secretive state and luteal support. If after 21 days of endometrial preparation endometrial thickness remains below 8 mm with P > 1 ng/ml, the transplantation cycle was terminated. All participants continued treatment with estrogen and progesterone until 14 days after embryo transfer, when blood hCG levels were assessed. Individuals with positive results were examined by ultrasound 35 days post-embryo transfer (7 weeks of gestation) for confirming the presence of an intrauterine gestational sac and detecting cardiac pulsations, indicating clinical pregnancy. Ultrasound examination, liver function testing, coagulation function assessment, and blood lipid analysis were conducted at 8 weeks of gestation. A continued pregnancy was confirmed by the presence of at least one live intrauterine fetus at 12 weeks of gestation. SPSS 9.1.3 was used for data analysis. Demographic data and other baseline features in each treatment group were summarized by descriptive statistics. Continuous variables were presented as mean, median, standard deviation, maximum, and minimum. Categorical variables were described as frequency and percentage. Univariate binary logistic regression was utilized to determine the predictors of clinical pregnancy outcome. Two-sided p  < 0.05 was considered statistically significant.

Recent advances in cryopreservation techniques have indeed increased the number of FET cycles. In FET cycles, endometrial preparation is crucial as it significantly impacts the success rate of the FET procedure. Data are inconclusive regarding whether combining a depot GnRH agonist with an HRT cycle improves or worsens reproductive outcomes in FET cycles compared to using the natural cycle or HRT protocols [ 14 , 15 ]. Consequently, more patients select the HRT cycle for its higher convenience. Estrogens can be administered orally, vaginally, or via transdermal application. While oral treatment is straightforward and well-tolerated, transdermal and vaginal administrations confer notable benefits. These routes have higher bioavailability since they bypass intestinal and hepatic metabolism, decreasing estradiol conversion into estrone and estrone sulfate, resulting in more stable level of estradiol [ 16 ]. Based on its established pharmacological safety profile, transdermal estradiol gel may be considered the regimen of choice for patients at increased risk of venous thromboembolism. The transdermal route represents a safer and well-tolerated alternative for patients with contraindications to oral estrogen [ 17 , 18 ]. Multiple reports have demonstrated a correlation between endometrial thickness and clinical pregnancy outcome in FET cycles, with a general consensus that a thin endometrium is associated with a low pregnancy rate [ 19 , 20 ]. A thin endometrium in assisted reproduction is often defined as endometrial thickness < 7 mm or < 8 mm [ 21 ]. Therefore, in this study, patients whose endometrial thickness was 8 mm or greater were recruited. In a randomized controlled trial involving 100 patients with 50 per group, clinical pregnancy rates were similar in both groups ( p  = 0.384), which corroborates the current study. This study reported significantly lower miscarriage (p = 0.035) and higher live birth ( p  = 0.035) rates in the estradiol transdermal gel group compared with the oral estradiol valerate group [ 10 ]. Sita Garimella et al. found no significant differences in clinical pregnancy and miscarriage rates between these two groups, which is consistent with our study [ 22 ]. Although the duration of endometrial preparation prior to embryo transfer were similar in both groups, endometrial thickness on the day of embryo transfer was reduced in the gel group compared with the oral group (0.88 ± 0.13 versus 0.91 ± 0.12, p = 0.026). This might be due to the patient's selection bias. The gel group exhibited a lower abortion rate and a higher live birth rate in comparison with the oral group. These results could be attributed to elevated blood estradiol levels, which occur because transdermal application bypasses the liver, decreasing physiological fluctuations in estrogen content. Another putative mechanism is that estradiol transdermal gel reduces the risk of thrombosis [ 17 , 18 ]. Additionally, the gel group had lower ALT and AST levels at 12 weeks of gestation compared with the oral group. However, large randomized controlled studies are required to confirm the above findings and to define the role of estradiol transdermal gel in FET. The primary limitation of this study is its non-randomized design, with treatment allocation based on patient preference. Although this approach is pragmatic, it introduces a risk of selection bias. We employed multivariate regression and a supplementary propensity score analysis to minimize the impact of measured confounders; however, residual confounding from unobserved variables (e.g., patient motivation or subtle differences in endometrial receptivity) cannot be entirely excluded. To definitively establish efficacy, future large-scale randomized trials are needed, and employing more transfer protocols and rigorously control for confounding factors. In summary, this study demonstrates that transdermal estradiol gel is a safe and feasible alternative for endometrial preparation in frozen embryo transfer cycles, yielding comparable ongoing pregnancy rates to the standard oral regimen. Although trends suggested lower ALT and AST levels at 12 weeks of gestation in the gel group, these differences were not statistically significant. Hence, future large-scale, randomized trials are needed to provide a definitive comparison of efficacy and safety.

Frozen embryo transfer (FET) applies elective freezing of all high-quality embryos in IVF (in vitro fertilization) cycles and transfer in subsequent cycles. In recent years, FET constitutes approximately 30% of all assisted reproductive technology (ART) cycles worldwide [ 1 , 2 ]. Initially, FET was applied for individuals at high risk of developing ovarian hyperstimulation syndrome (OHSS) [ 3 , 4 ]. Later, several reports have demonstrated that the complex molecular and morphological alterations in the endometrium during the window of implantation resulting from excessive supraphysiological hormone levels after controlled ovarian hyperstimulation (COH) may exert detrimental effects on the implantation potential of embryos [ 5 , 6 ]. Therefore, FET not only reduces the risk of OHSS, but also optimizes endometrial receptivity in IVF [ 7 ]. Several tools are available for endometrial preparation in FET cycles, including natural cycle with spontaneous ovulation or incorporating human chorionic gonadotrophin (hCG) to trigger ovulation, hormone replacement therapy (HRT) cycle with or without gonadotropin-releasing hormone agonist (GnRH-a) downregulation, and ovarian stimulation cycle with or without letrozole [ 8 ]. Compared with the natural cycle, HRT cycles provide enhanced flexibility and convenience, streamlining scheduled transplantation and resulting in a lower cancelation rate. Therefore, HRT cycles are broadly utilized in clinical practice [ 9 ]. In HRT cycles, the main administration tools for estradiol supplementation include oral tablets and transdermal gels [ 10 ]. In HRT cycles, evidence suggests that estradiol transdermal gel and oral estradiol valerate have comparable clinical pregnancy outcomes [ 11 , 12 ]. However, estradiol transdermal gel yields steadier serum estradiol levels and improved patient comfort, with less side effects and better safety profile, compared with oral tablets [ 5 ], These pharmacological and patient-centered advantages, observed alongside similar reproductive outcomes, suggest that transdermal gel is a valuable option within the portfolio of endometrial preparation protocols [ 13 ]. Its potential to improve the patient experience warrants consideration, and future studies should aim to confirm these benefits in a larger population. Therefore, this study aimed to comparatively assess the efficacy and safety of estradiol gel versus oral estradiol valerate for HRT in patients undergoing FET.