The rising utilization and success of in vitro fertilization (IVF) can be attributed to the optimization of several clinical and laboratory protocols [1]. One such example is the optimization of controlled ovarian stimulation (COS) by incorporating gonadotropin-releasing hormone antagonist (GnRH-ant)-based COS protocols [2,3]. These COS protocols have several advantages over traditional long GnRH-agonist protocols, including lower utilization of gonadotropins [2,3], a lower risk of ovarian hyperstimulation syndrome [2,3], and a lower rate of ovarian cyst formation [4]. COS with GnRH-ant based protocols can be preceded by pretreatment with oral contraceptive pills (OCPs) or estrogen, with the goal of synchronizing follicular growth [5,6]. Most of these findings have been reported in studies comparing OCPs [7,8,9,10,11,12] or estrogen [5,13,14,15,16] to no pretreatment. However, scarce data are available comparing transdermal pretreatment modalities to standard pretreatment modalities in terms of COS, embryological, or pregnancy outcomes. Thus, the primary objective of this study was to compare the impact of pretreatment with transdermal estradiol (E₂) to OCPs on COS response in normal responders undergoing fresh IVF-embryo transfer (ET) cycles with GnRH-ant based protocols.

A total of 2,092 patients met the inclusion criteria: 1,057 patients in the E₂ group and 1,035 patients in the OCP group. As shown in Table 1, the demographics and baseline characteristics were similar across both groups. Most patients had roughly two unsuccessful IVF-ET cycles elsewhere prior to pursuing treatment at our center. Table 2 summarizes the COS outcomes of the study cohort. Patients in the OCP group had a longer duration of COS (10.7±1.63 days) than the transdermal E₂ group (9.92±1.94 days). Furthermore, patients in the OCP group required higher cumulative doses of gonadotropins (2,657.3±1,187.9 IU) than the E₂ group (2,550.1±1,270.2 IU, p=0.002). Overall, no difference was noted in the total days of GnRH-ant administration, E₂ level on the day of trigger, peak endometrial thickness, number of total or mature oocytes retrieved, and the fertilization rate. No difference in IVF-ET cycle cancelation was observed in the E₂ and OCP pretreatment groups.

Table 3 presents the pregnancy outcomes of the study cohort. No significant difference was found in the mean age of patients or the number of embryos transferred. The number of surplus embryos cryopreserved at the blastocyst stage was also comparable among the pretreatment groups. Overall, no statistically significant differences were found in the rates of biochemical pregnancy, clinical pregnancy, spontaneous miscarriage, or live birth when comparing both groups. These findings remained unchanged even after adjusting for duration of COS, gonadotropin dose, and E₂ level on the day of the trigger.

Hormonal pretreatment modalities are used to suppress a patient's endogenous gonadotropin secretion, thereby promoting the coordinated growth of early antral follicles in response to exogenous gonadotropins [5,6]. The resulting synchronization of follicles has shown to increase oocyte and embryo yield and therefore, the overall chances of pregnancy [6,7]. OCPs are perhaps the most frequently used pretreatment modality and their impact on IVF-ET cycles have been well studied in normal responders [7,8,9,10,11], poor responders [12,21] and hyper-responders [22]. Conflicting data have been reported regarding the impact of OCP pretreatment on IVF-ET outcomes in normal responders, with some studies suggesting lower oocyte yield, clinical pregnancy, and live birth rates [10,11] than observed in patients receiving no pretreatment, while other studies have not replicated these findings [7,14]. The variation in results may be attributed to the use of different OCPs with varying durations [7,14]. The large majority of studies do, however, emphasize that OCP pretreatment was associated with a longer duration of COS and higher gonadotropin utilization [9,10,11].

The use of E₂ for pretreatment in normal responders was proposed as an alternative to OCPs given its shorter duration [5,14]. Administration of E₂, which is generally 17-β-E₂, during the luteal phase of the preceding cycle exerts negative feedback on FSH during the late luteal-early follicular phase transition, thereby suppressing follicular growth until the administration of exogenous gonadotropins [14]. In a randomized controlled trial of 100 patients comparing oral E₂ to OCPs for pretreatment, Hauzman et al. [14] found no significant differences in stimulation, embryological, implantation, clinical pregnancy, spontaneous miscarriage, or live birth outcomes in fresh IVF-ET cycles. The same study also suggested that oral E₂ could be used as an alternative to OCPs for scheduling or timing fresh IVF-ET cycles. It must be noted that the E₂ utilized in all the aforementioned studies was E₂ valerate (i.e., [17β]-3-hydroxyestra-1,3,5[10]-trien-17-yl valerate, which is the 17-pentanoyl ester of 17-β-E₂).

Our center has previously described the use of another form of E₂ (17-β-E₂, i.e., estra-1,3,5 [10]-triene-3,17β-diol) for pretreatment in poor responder patients [23]. In order to broaden the use of this regimen, we retrospectively evaluated its utility for the pretreatment of normal responder patients. In addition to its large sample size, the current study uniquely compares transdermal E₂ to OCPs. The outcomes of the OCP group are consistent with previously published findings. However, unlike the study of Hauzman et al. [14], which showed no difference in stimulation outcomes between the E₂ valerate and OCP groups, our findings revealed a shorter duration of COS and lower utilization of gonadotropins in the transdermal E₂ group than in the OCP group. These contrasting results may be due to the difference in sample sizes and the E₂ and OCP products utilized in the two studies. For example, patients using estrane-derived and gonane-derived OCPs, with higher androgenic properties, prior to COS have been shown to have lower oocyte yield than those using anti-androgenic OCPs or those not using OCPs [24].

Despite its strengths, the current study is limited by two main shortcomings. First, the sample size calculation was based on the gonadotropin dosage difference reported by Hauzman et al. [14]. If clinical pregnancy or live birth was considered as the primary outcome of interest, then post-hoc calculations based on the same reference would suggest a sample size of at least 9,804 patients per pretreatment group. Thus, the current study is underpowered to detect a difference in clinical pregnancy or live birth rates. Second, the assignment of patients to transdermal E₂ or OCP pretreatment was based on physician preference, thus introducing some selection bias to the study methodology.

In conclusion, our findings suggest that compared to OCPs, pretreatment with transdermal E₂ was associated with shorter duration of COS and lower gonadotropin utilization in normal responder patients undergoing IVF-ET with GnRH-ant based protocols. The overall yield of oocytes and embryos, as well as the clinical pregnancy and live birth rates, remain unaffected by E₂ or OCP pretreatment. As pretreatment with E₂ begins in the preceding luteal phase, the overall length of pretreatment may also be shorter than for OCPs. While pretreatment with OCPs and oral E₂ has previously been described for prospective scheduling of IVF-ET cycles, the current study presents reasonable data to suggest that OCP or E₂ pretreatment may not be required in normal responders because they do not improve the overall pregnancy outcomes of fresh IVF-ET cycles. However, these suppositions need prospective validation in studies with adequate sample sizes.