A novel two-injection ovarian stimulation strategy yielded a comparable number of mature (MII) oocytes to that of a conventional protocol but did not demonstrate noninferiority, according to a recent study presented at ESHRE 2026.
This phase III, single-centre, noninferiority clinical trial was conducted at a university-affiliated fertility unit between December 2023 and July 2025. The study enrolled 194 women (aged ≤40 years) undergoing elective fertility preservation, all with an antral follicle count <20 and anti-Müllerian hormone ≤3 ng/mL.
Participants were randomized 1:1 to receive two sequential injections of corifollitropin alfa (CFA) 150 mcg on day 1 and 100 mcg on day 5 (two-shot protocol group; n=97) or a single injection of CFA 150 mcg on day 1, followed by daily rFSH* at 200 IU/day from day 8 (conventional protocol group; n=97). Both groups received daily oral desogestrel 75 mcg to suppress the LH** surge, and final oocyte maturation was triggered with a GnRH*** agonist (triptorelin 0.2 mg).
In the intention-to-treat analysis, the mean number of MII oocytes did not differ between the two-shot and conventional protocol groups (6.14 vs 7.19; estimated mean difference [EMD], –1.04, 95 percent confidence interval, –2.27 to 0.18). [ESHRE 2026, abstract L26/O-198]
“However, the lower bound of the confidence interval (–2.27) falls below the noninferiority margin of –1.5, indicating that the study could not demonstrate the noninferiority of the two-shot protocol compared with the conventional protocol,” said lead author Dr Valeria Donno from Dexeus Fertility in Barcelona, Spain.
Additionally, other ovarian stimulation outcomes, including the mean duration of ovarian stimulation (10.3 vs 10.2 days), the number of follicles ≥14 mm on the trigger day (10.7 vs 11.1), and the number of oocytes retrieved (8.1 vs 9.1), showed no differences between the two-shot and conventional protocol groups.
During stimulation, a hormonal profile assessment was performed. The findings revealed no clinically meaningful differences in LH, oestradiol, and progesterone levels, except that FSH concentrations were markedly higher in the two-shot protocol group compared with the control group on day 8 (53.43 vs 24.60 IU/L) and remained higher on the day of the ovulation trigger (31.28 vs 24.46 IU/L).
“Overall, this study shows that we can achieve ovarian stimulation with just two injections … The two-shot protocol seems a viable alternative to conventional stimulation, offering a more patient-friendly strategy,” said Donno.
“Although formal noninferiority was not demonstrated, the two-shot protocol may still be clinically reasonable in selected patients, particularly when reducing treatment burden is a relevant priority and when a small potential reduction in MII oocyte yield would be acceptable,” she noted.
“However, further confirmation is warranted before broader adoption overall,” Donno added.