Effectiveness of vaginal pessaries versus soft capsules for delivery of progesterone during luteal phase support in frozen embryo transfer cycles: An observational study

Supplementation with estrogens and progestins during the luteal phase is a standard procedure in freeze–thaw embryo transfer treatments.1, 2 However, the precise threshold for optimal serum progesterone during luteal phase support remains unclear. A systematic review and meta-analysis of 21 cohort studies showed that serum progesterone levels >10 ng/mL on the day of frozen embryo transfer were associated with increased rates of ongoing pregnancy or live birth, higher chance of clinical pregnancy, and lower risk of miscarriage in cycles.3 In patients with suboptimal progesterone levels, rescue with a single subcutaneous injection of progesterone on the day of embryo transfer is sufficient to normalize the pregnancy outcomes.4 It is uncertain if the suboptimal progesterone levels on the day of embryo transfer are due to patient factors or to the route of administration and posology. Differences between treatments with the various pharmacological formulations available could be relevant, as this variable could determine the rate of absorption and bioavailability.5 In the present observational retrospective study, we compared serum levels of progesterone at three points during luteal phase support (1 day before embryo transfer, the day of transfer, and 14 days after transfer). We conducted the study on two cohorts of patients using two formulations of vaginal micronized progesterone: one 400 mg pessary (Cyclogest®; Gedeon Richter, Spain) twice daily or two 200 mg soft gel capsules (Progeffik®; Laboratoire Effik, France) twice daily. As a secondary objective, the proportion of ongoing pregnancies (>12 weeks) as a function of treatment was evaluated. The study was conducted at the Assisted Human Reproduction Unit of Valme University Hospital (Seville, Spain) between October 1, 2021 and September 30, 2023. The Ethics Review Board of Valme University Hospital approved the study (0388-N-22). Detailed methods can be found in Data S1. The baseline demographic and clinical characteristics of the women included (N = 582; pessaries, n = 433; soft capsules, n = 149) are shown in Table S1. The mean ages (± SD) of the cohorts treated with pessaries and soft capsules were 34.9 (± 3.8) and 34.5 (± 3.9) years, respectively. Women treated with pessaries had a lower body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) than those treated with soft capsules (P = 0.012). The serum progesterone levels before, during, and after transfer are shown in Figure 1. At the three time points, the women treated with pessaries had significantly higher levels than those treated with soft capsules (P < 0.01). On the day of transfer, women treated with pessaries presented a mean (SD) serum progesterone of 16.8 (5.8) ng/mL versus 12.0 (3.0) ng/mL of those treated with soft capsules (P < 0.001). The proportion of ongoing pregnancy (>12 weeks) was 273/433 (63.0%) in the group treated with pessaries and 72/149 (48.3%) among those treated with soft capsules (P = 0.004) (Figure S1). There were no statistically significant differences in BMI between women who achieved pregnancy compared and those who did not (mean BMI [SD] = 24.5 [3.5] vs. 24.6 [3.5], respectively, P = 0.771). The analysis of the beta-human chorionic gonadotropin levels in women who did not achieve a continuing pregnancy (160 [36.9%] in the pessaries group, 77 [51.7%] in the soft capsules group) is shown in Table S2. Two recent retrospective studies of a similar design compared the effectiveness of 400 mg pessaries of micronized vaginal progesterone (Cyclogest®) twice daily with two 200 mg capsules twice daily (Progeffik® or Utrogestan®) during luteal phase support.6, 7 In the first study, no statistically significant differences were found in the serum progesterone concentration between the two groups on the day of embryo transfer.6 In the second study,7 the mean serum progesterone levels on the day of embryo transfer were significantly higher in the group of patients using pessaries than in the group using capsules (14.5 ± 5.1 vs. 13.0 ± 4.8 ng/mL, P < 0.0001), as shown in the present study. It has been suggested that variations in the vaginal absorption rate or bioavailability may account for the differences, despite the same dose of micronized progesterone in the two formulations.5 The progesterone released from the pessaries may be absorbed more gradually and continuously than that from the soft capsules, some of which could be lost in the form of vaginal discharge before absorption.7, 8 Although, in the present study, the number of patients requiring rescue with subcutaneous progesterone on the day of embryo transfer was not included as a variable, it could be expected that fewer patients would require rescue in the group treated with pessaries than in the group treated with soft capsules. This study's results are generally consistent with previous reports showing that 400 mg pessaries are more effective than 200 mg soft capsules in achieving optimal serum concentrations of progesterone during luteal phase support in hormone replacement cycles. Our results also suggest that a higher progesterone concentration could improve rates of ongoing pregnancies. AAS: conceived and conducted the research and wrote the manuscript; CF-CdP: data collection and editing of the manuscript; ESL: data collection and editing of the manuscript; JBL: performed the analysis; MPTC: data collection; MDGM: data collection. EMB: conceived and designed the analysis. All authors read and approved the final version of the manuscript. We want to express our gratitude to the entire Assisted Human Reproduction Unit of Valme University Hospital: nurses, auxiliary nurses, embryologists, and other professionals. A special thank you goes to the Biochemistry Laboratory for their collaboration. We did not receive any external funding for the development of this study. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.