Randomized controlled trial to evaluate the impact of follicle priming on IVM outcomes in women with polycystic ovaries: CFA versus FSH-B.

Abstract

Study question: Do corifollitropin alfa (CFA) and follitropin beta (FSH-B) have different effects on oocyte yield and live birth rates (LBRs) after IVM in women with polycystic ovaries?

Summary answer: In patients who underwent IVM, one injection of CFA resulted in lower oocyte retrieval rates, but similar cumulative LBRs compared to three injections of FSH-B.

What is known already: IVM involves the maturation of cumulus-oocyte complexes (COCs) from antral follicles and has been offered to women with polycystic ovaries as an alternative for conventional ovarian stimulation (OS). A short course of exogenous FSH is typically administered in IVM cycles to enhance meiotic and developmental competence of immature oocytes in vivo. Previous studies have shown that the number of COCs is associated with pregnancy rates after IVM. Because one injection of CFA yields more oocytes compared to daily FSH-B injections in conventional OS protocols, CFA has the potential to combine patient-friendliness and maximum COC yield in IVM cycles.

Study design, size, duration: We conducted a randomized controlled superiority trial from November 2017 to December 2022. The primary endpoint was the number of COCs at oocyte retrieval. We randomized 145 patients to either one injection of 100 μg CFA or three daily injections of 150 IU FSH-B. Laboratory and safety parameters, and pregnancy outcomes after frozen embryo transfer (FET) were analysed on an intention-to-treat (ITT) basis. All cycles were scheduled using oral contraceptive pre-treatment.

Participants/materials, settings, methods: Eligible patients were <37 years, had ≥24 antral follicles and an anti-Müllerian hormone ≥3.25 ng/ml, and BMI 18-30 kg/m2. We analysed serum oestradiol, progesterone, LH, and FSH on stimulation days 1 and 3, at oocyte retrieval, and at 6 days after oocyte retrieval. No ovulation trigger was given. Oocyte retrieval was performed 5 days after the start of OS. COCs were incubated in monophasic IVM media for 30 h. After ICSI, an elective freeze-only strategy was performed. Data were analysed using STATA 13.0.

Main results and the role of chance: After randomization, 70 patients underwent oocyte retrieval after FSH-B and 72 had oocyte retrieval after CFA. According to the ITT analysis, hormone levels at oocyte retrieval were significantly different between FSH-B-treated and CFA-treated patients (FSH 6.4 ± 3.1 IU/l vs 22.6 ± 9.8 IU/l, P < 0.001; LH 3.1 ± 2.7 IU/l vs 1.6 ± 1.6 IU/l, P = 0.002; E2 100.8 ± 144.9 ng/l vs 536.2 ± 519.0 ng/l, P < 001; Prog 0.17 ± 0.16 μg/l vs 0.26 ± 0.21 μg/l, P < 0.001, respectively). On average, 37.7 ± 24.8 (FSH-B) versus 45.9 ± 31.5 (CFA) follicles, all <10 mm, were punctured during oocyte retrieval (P = 0.06). More COCs per follicle were retrieved after FSH-B (59.8 ± 37.2% vs 46.1 ± 27.9%, P = 0.02), resulting in more COCs after FSH-B (30.5 ± 23.5), compared to CFA (23.1 ± 11.9, P = 0.11, difference -7.4, 95% CI (-13.5 to -1.3)). Maturation rates after IVM were similar (48.3 ± 16.6% vs 48.3 ± 20.0%, P = 0.88). In spite of more mature oocytes after FSH-B (15.5 ± 14.6 vs 11.5 ± 7.9, P = 0.13), the number of good-quality cryopreserved embryos was similar (3.8 ± 2.9 (FSH-B) vs 3.5 ± 2.7 (CFA), P = 0.53). LBR after the first FET (25.0% (FSH-B) vs 34.2% (CFA), P = 0.31) and cumulative LBR 6 months after oocyte retrieval (38.9% (FSH-B) vs 45.2% (CFA), P = 0.44) were comparable. None of the patients developed ovarian hyperstimulation syndrome.

Limitations, reasons for caution: Results are only valid for patients with high antral follicle count (AFC) who are treated using a monophasic IVM culture system. The sample size was too small to draw significant conclusions for LBR.

Wider implications of the findings: While follicle priming for IVM using one injection of CFA in subfertile patients with high AFC results in a trend towards lower oocyte retrieval rates compared to daily injections of FSH-B, the use of CFA in IVM cycles is safe, convenient, and as efficacious as priming with FSH-B.

Study funding/competing interest(s): Supported in part by a research grant from the Investigator Initiated Studies Program of Organon. The opinions expressed in this abstract are those of the authors and do not necessarily represent those of Organon. M.D.V. declares honoraria for lecturing from Cooper Surgical, Ferring, Gedeon Richter, and IBSA in the past 2 years. He also declares support from Ferring for attending ESHRE 2024 and ASRM 2024. He is also a member of the Scientific Advisory Board of Gameto Inc. and is a past chair of the IVM SIG of ASRM. C.B. declares honoraria from Abbott, IBSA, Organon, Gedeon Richter, Merck A/S, and Ferring. C.B. has also received grants from Gedeon Richter and Ferring which were paid to his institution. P.D. has received payment from Ferring Pharmaceuticals, Merck A/S, and Organon for lectures/presentations. S.M. Declares consulting fees from Oxolife and payment or honoraria from IBSA, Ferring, and Gedeon-Richter. J.S. has received royalties or licenses from Lavima Fertility and is an unpaid treasurer for ISIVF. J.S. also holds stock for Lavima Fertility. The other authors declare no conflict of interest related to this study.

Trial registration number: EudraCT 2017-002571-25.

Trial register date: 16th June 2017.

Date of first patient’s enrolment: 1st November 2017.