The goal of this observational study is to compare two commonly used vaginal progesterone formulations - soft capsules versus pessaries - in women undergoing frozen embryo transfer (FET). The main question it aims to answer is:

- Do soft vaginal progesterone capsules provide similar or better patient satisfaction, convenience, and tolerability compared with vaginal progesterone pessaries during preparation for frozen embryo transfer?

Participants undergoing FET who are prescribed vaginal progesterone as part of their endometrial preparation and luteal phase support will use one of the two formulations and complete patient-reported assessments regarding satisfaction, convenience, and tolerability. The study will also measure serum progesterone levels on the day of embryo transfer and evaluate pregnancy outcomes, including clinical pregnancy and live birth rates.

Over the past few decades, assisted reproductive technology (ART) treatments have seen their protocols updated by advances in cryopreservation methods, leading to the mainstream use of the frozen embryo transfer (FET) strategy (Nagy, Shapiro, & Chang, 2020). FET protocols are generally subdivided in either natural cycle (NC-FET) or artificial cycle (AC-FET), with several centers preferring the latter due to its flexibility in scheduling and ease of monitoring. Nonetheless, previous reports positing that AC-FET may be associated with an increased risk of miscarriage and hypertensive disorders during pregnancy have put this preference into question (Roelens, et al., 2022). Having said that, the natural proliferative phase frozen embryo transfer protocol (NPP-FET) has recently be proposed as a strategy which potentially allows for easier cycle scheduling while potentially maintaining the benefits of the natural cycle in terms of safer pregnancy outcomes (Godinho, Soares, & Ribeiro, 2021). Both AC-FET and NPP-FET protocols rely immensely on the use exogenous progesterone for luteal phase support (LPS), with the vaginal route being the most common in Europe due to its ease of use compared to intramuscular or subcutaneous alternatives.

Progesterone is a natural hormone produced mainly by the theca cells of the corpus luteum. When supplemented vaginally, endometrial progesterone concentrations reach a steady-state within 5 hours after administration, while serum progesterone levels remain elevated for about 48 hours with prolonged bioavailability (Bulletti, et al., 1997). In a systematic review of 18 randomized clinical trials comparing vaginal preparations for LPS, all tested preparations seemed to be equally effective and safe for assisted reproductive technology cycles (Child, Leonard, Evans, & Lass, 2018). However, studies assessing patient satisfaction are lacking (Beltsos, et al., 2014). Hence, the main objective of this study is to assess the level of satisfaction as well as understand the convenience and tolerability of two of the most common vaginal LPS formulations (soft capsules versus pessaries). The study will compare satisfaction levels, convenience and tolerability, serum progesterone levels on the FET day and pregnancy rates between the two therapeutic formulations.

Inclusion Criteria:

• Age: ≥18 and <49 years old;
• Body Mass Index (BMI) ≥18.5 Kg/m2 and <30 Kg/m2;
• Planned for single blastocyst stage transfer;
• Has been prescribed two vaginal 200mg soft capsules or one 400mg pessary of progesterone, each 12hours before and after FET;
• Either AC-FET or NPP-FET.

Exclusion Criteria:

• Women who have previously enrolled in this study;
• Those unable to comprehend the investigational nature of the proposed study;
• Rank of FET>3;
• Use of oral/injectable corticoids.

The study population consists of women aged 18 to 48 years undergoing frozen embryo transfer (FET) at IVI Lisboa. Eligible participants must have a BMI between 18.5 and <30 kg/m², be scheduled for a single blastocyst-stage transfer, and be prescribed vaginal progesterone for luteal phase support, either soft capsules (400 mg every 12 hours) or pessaries (400 mg every 12 hours). Both artificial cycle (AC-FET) and natural proliferative phase (NPP-FET) protocols are included. The study population reflects real-world patients receiving routine clinical care.