Feasibility and efficacy of random-start progestin-primed ovarian stimulation: a multicenter pilot randomized controlled trial in oocyte donation

We aimed to assess the impact of the timing of ovarian stimulation initiation on the number of oocytes retrieved in a progestin-primed ovarian stimulation (PPOS) protocol for oocyte donors. A total of 110 oocyte donors were randomized in a multicenter, open-label, pilot randomized controlled trial conducted across four centers in France. Of these, 102 donors completed ovarian stimulation and underwent oocyte retrieval. Donors were assigned to start stimulation with corifollitropin alfa and oral desogestrel during one of five menstrual cycle phases: early follicular (EFP, Days 1–3), mid-follicular (MFP, Days 4–7), late follicular (LFP, Days 8–11), ovulatory (OP, Days 12–15), or luteal (LP, Days 16–30). Final oocyte maturation was triggered with triptorelin acetate. The primary endpoint was the total number of oocytes retrieved, with secondary outcomes including mature oocytes, premature LH surge, and ovarian hyperstimulation syndrome (OHSS). The median age of donors was 33 years, with a mean BMI of 23.4 kg/m². The median number of retrieved oocytes was 11.5, with no significant differences between groups (p = 0.314). The median number of mature oocytes was 10, with no significant differences across groups. Given the limited statistical power inherent to pilot studies, an additional non-inferiority study was conducted. This subsequent analysis confirmed that the number of oocytes retrieved in the less previously studied and more challenging groups — the late follicular and ovulatory phases — was non-inferior to that observed in the reference group, defined as the early follicular phase. One donor in the mid-follicular phase had a premature LH surge (0.98%), and four cases of mild OHSS were reported (3.9%). According to this pilot study, initiating PPOS with corifollitropin alfa at any phase of the menstrual cycle resulted in similar oocyte retrieval outcomes. This flexible approach is safe, effective, and offers potential benefits for donor management, patient convenience, and clinical workflow. Larger, adequately powered studies are required to validate these preliminary findings. ClinicalTrials.gov Identifier: NCT03895099. Date of registration: March 28, 2019. First participant enrolled: September 4, 2020.