Random start natural progesterone-primed ovarian stimulation (NPPOS) enables maximal flexibility: analysis of 1202...

Can a random start natural micronized progestin-primed ovarian stimulation (NPPOS) protocol provide an equivalent and flexible alternative strategy for elective freeze-all stimulation cycles compared with a conventional start gonadotrophin-releasing hormone (GnRH) antagonist protocol?

This retrospective cohort study included 1202 elective freeze-all cycles between 2022 and 2024. Four groups were compared: GnRH-antagonist early follicular (n = 503), NPPOS early follicular (n = 319), NPPOS late follicular (n = 163) and NPPOS luteal (n = 217) starts. The primary endpoint was the number of metaphase II (MII) oocytes retrieved. The secondary endpoints included the follicular output rate (FORT), follicle-oocyte index (FOI) and the duration of stimulation. A predefined subgroup analysis was conducted in poor ovarian responders.

The concentration of anti-Müllerian hormone was comparable across groups, and the median number of MII oocytes retrieved was similar: NPPOS late follicular group, 8 (IQR 5-15); GnRH-antagonist group, 10 (IQR 6-16); NPPOS early follicular group, 10 (IQR 6-16); and NPPOS luteal group, 10 (IQR 5-16) (P = 0.20). A generalized estimating equation Poisson regression model analysis confirmed equivalence. FORT and FOI-MII remained stable across the NPPOS early and late follicular, and luteal groups: estimated marginal mean ± SD FORT, 37.1 ± 9.9%, 40.4 ± 24.8% and 39.8 ± 24.9 (P = 0.30); and FOI-MOI, 70.8 ± 38.7%, 73.5 ± 44.2% and 75.0 ± 43.6% (P = 0.60), respectively. The NPPOS luteal group required a longer mean ± SD duration of stimulation (11 ± 2 days) compared with the NPPOS early follicular group (9 ± 2 days; P < 0.001), NPPOS late follicular group (10 ± 3 days; P = 0.004) and GnRH-antagonist group (10 ± 2 days; P < 0.001). In poor ovarian responders, the MII yield was comparable across all groups.

Random start NPPOS using micronized progesterone is an effective and flexible alternative to a conventional GnRH-antagonist protocol in freeze-all cycles. The ability to initiate stimulation irrespective of menstrual phase combined with the use of oral progesterone may reduce treatment delays and improve convenience without compromising ovarian response.