Progestin-primed ovarian stimulation has become an established alternative to antagonist protocols, offering comparable suppression at lower cost and with convenient oral administration. Yet a fundamental question has remained unanswered: when exactly should the progestin start? Most clinics use a fixed regimen, beginning medroxyprogesterone acetate on day two or three of the menstrual cycle, before stimulation drugs begin. A flexible approach would instead delay the progestin until follicles reach a certain size or estradiol crosses a threshold, potentially reducing the total progestin exposure each patient receives. The idea is appealing, but comparative evidence between the two approaches has been scarce, particularly for women whose ovarian reserves are less than ideal.

A team of researchers at Khon Kaen University in Thailand has now provided the first randomized controlled trial data addressing this question in a specific and clinically important population. Their study, published in the Journal of Ovarian Research, enrolled 98 infertile women belonging to POSEIDON groups 1 and 2, a classification system that identifies women with normal or suboptimal ovarian reserve who have previously experienced an unexpected poor response to stimulation. These patients represent a challenging middle ground in fertility medicine: their ovaries are not depleted, but they have a documented history of responding less well than expected to gonadotropin drugs. All participants were undergoing intracytoplasmic sperm injection, a technique in which a single sperm is injected directly into each mature egg.

Participants were randomly assigned in equal numbers to one of two protocols. In the flexible group, medroxyprogesterone acetate was initiated only when follicular size or estradiol levels met predefined criteria, allowing clinicians to individualize the timing based on each patient’s response. In the fixed group, the progestin began on day two or three of the cycle, before any stimulation drugs were given. The researchers designed the study as a non-inferiority trial, meaning their goal was not to prove that the flexible approach was better, but to determine whether it was at least as effective as the fixed regimen at preventing a premature luteinizing hormone surge on the day of the final maturation trigger.

The results were striking in their simplicity. A premature luteinizing hormone surge occurred in just one of 49 women in the flexible group, an incidence of 2.04 percent, while none of the 49 women in the fixed group experienced one. The absolute difference between the groups was 2.04 percent, with a 95 percent confidence interval ranging from negative 1.92 to 6.00 percent, and the p-value exceeded 0.999. According to the predefined non-inferiority margin, this outcome demonstrated that the flexible protocol was indeed non-inferior to the fixed approach. Notably, premature ovulation was not observed in either group, confirming that both strategies successfully protected the cycles from the most damaging consequence of an early surge.

Beyond the primary outcome, the researchers examined a battery of secondary measures that reflect the quality of the stimulation and the potential for successful fertilization. The number of oocytes retrieved, the number of mature metaphase II oocytes, the fertilization rate, the cleavage rate, and the blastocyst rate were all statistically comparable between the two groups. Even the proportion of good-quality blastocysts, the embryos most likely to lead to a successful pregnancy, showed no meaningful difference. One patient in each group developed moderate to severe ovarian hyperstimulation syndrome, a potentially serious complication of stimulation, with an identical incidence of 2.04 percent in both arms.

Perhaps the most clinically meaningful finding was the difference in progestin exposure itself. The duration of medroxyprogesterone acetate administration was significantly shorter in the flexible group, which is exactly what the flexible approach was designed to achieve. Reducing the total progestin exposure matters for several reasons. Progestins can influence the endometrium, the uterine lining that must be receptive for embryo implantation in subsequent frozen embryo transfer cycles. Shorter exposure may also reduce side effects and align better with a growing movement in reproductive medicine toward patient-centered, individualized treatment rather than one-size-fits-all protocols.

The significance of this trial extends beyond the immediate question of progestin timing. The POSEIDON classification system, which stands for Patient-Oriented Strategies Encompassing Individualized Oocyte Number, was developed to help clinicians tailor stimulation strategies to specific patient profiles. Women in groups 1 and 2 have normal or suboptimal ovarian reserve but a history of unexpected poor response, making them a particularly vulnerable population for cycle failure. Demonstrating that a flexible progestin-primed approach works as well as a fixed one in this group gives fertility specialists a new tool for individualizing care without compromising outcomes.

The trial was registered with the Thai Clinical Trials Registry and received ethics approval from the Khon Kaen University Ethics Committee for Human Research. The researchers analyzed their data using an intention-to-treat approach, which includes all randomized participants regardless of whether they completed the protocol exactly as assigned. This method is considered the gold standard for randomized controlled trials because it preserves the benefits of randomization and avoids bias that can arise from excluding patients after assignment. The study was supported by the Research and Development Fund of the Faculty of Medicine at Khon Kaen University.

For patients and clinicians alike, the message from this trial is one of reassurance and expanded choice. Women with suboptimal to normal ovarian reserve who have previously responded poorly to stimulation can now be offered a flexible progestin-primed protocol with confidence that it will suppress the premature luteinizing hormone surge just as effectively as the traditional fixed regimen. The shorter progestin exposure, combined with equivalent oocyte yield, fertilization rates, and embryo development, suggests that individualized timing is not only safe but potentially preferable. As fertility medicine continues to evolve toward more personalized approaches, this randomized controlled trial provides solid evidence that flexibility in progestin priming is a viable and patient-centered strategy.

Subject of Research: Reproductive Medicine

Article Title: Flexible versus fixed progestin-primed ovarian stimulation for preventing premature luteinizing hormone surge in POSEIDON groups 1–2: a non-inferiority randomized controlled trial

Article References: Tangterdchanakit, R., Sothornwit, J., Aupongkaroon, P., Pongsritasana, T., Sukkasame, S., & Salang, L. (2026). Flexible versus fixed progestin-primed ovarian stimulation for preventing premature luteinizing hormone surge in POSEIDON groups 1–2: a non-inferiority randomized controlled trial. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02312-6

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02312-6

Keywords: Flexible, versus, fixed, progestin-primed, ovarian, stimulation, preventing, premature, luteinizing, hormone, surge, POSEIDON