Progestogen‐primed ovarian stimulation vs GnRH antagonists and/or agonists for women undergoing assisted reproduction: systematic review and meta‐analysis

ABSTRACT Objective To compare the effectiveness and safety of progestogen‐primed ovarian stimulation (PPOS) vs gonadotropin‐releasing hormone (GnRH) antagonists and/or agonists for women undergoing assisted reproduction. Methods PubMed, Scopus, Web of Science and major clinical trial registries were searched from inception until 11 November 2025 for randomized controlled trials (RCTs) comparing PPOS (e.g. medroxyprogesterone acetate, dydrogesterone, micronized progesterone) with GnRH antagonists and/or GnRH agonists in women undergoing ovarian stimulation for in‐vitro fertilization or intracytoplasmic sperm injection using their own oocytes, for oocyte donation or for fertility preservation. The primary outcome was the live‐birth rate per woman randomized. Secondary outcomes included rates of clinical pregnancy, premature luteinizing hormone (LH) surge, moderate/severe ovarian hyperstimulation syndrome (OHSS) and oocyte pick‐up (OPU) cancelation, and the number of oocytes retrieved. Risk of bias was assessed using the Cochrane revised Risk of Bias (RoB 2) tool and trustworthiness was evaluated using the INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT‐SR) tool. We performed random‐effects meta‐analyses to calculate relative risk (RR) and mean difference (MD) with 95% CI, as appropriate. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Twenty RCTs involving 4430 participants were included. No study was at low overall risk of bias; 13 had some concerns and seven were at high risk. INSPECT‐SR identified serious trustworthiness concerns in five studies. PPOS was compared with GnRH antagonists in 17 studies, GnRH agonists in two studies and a combined GnRH agonist + antagonist regimen in one study. Compared with GnRH antagonists, PPOS was associated with a significantly higher live‐birth rate (RR, 1.13 (95% CI, 1.02–1.25); P = 0.02; moderate certainty). This finding remained robust on sensitivity analysis excluding the study with a high risk of bias (RR, 1.11 (95% CI, 1.00–1.23); P = 0.05). PPOS was also associated with a higher number of oocytes retrieved compared with GnRH antagonists (MD, 0.88 (95% CI, 0.27–1.50); P = 0.005; low certainty). There were no significant differences in the rates of OPU cancelation (RR, 0.82 (95% CI, 0.42–1.57); P = 0.55; low certainty) or premature LH surge (RR, 0.49 (95% CI, 0.05–4.94); P = 0.54) between groups. No moderate/severe OHSS events were reported in either group across 10 studies. For the comparison of PPOS vs GnRH agonists, there were no significant differences in live‐birth rate (RR, 0.97 (95% CI, 0.74–1.26); P = 0.80; low certainty), moderate/severe OHSS (RR, 0.14 (95% CI, 0.01–2.74); P = 0.20; very low certainty) or number of oocytes retrieved (MD, 0.91 (95% CI, –0.55 to 2.37); P = 0.22; low certainty), with zero events reported for premature LH surge and OPU cancelation in both groups. In the comparison of PPOS vs combined GnRH agonist + antagonist regimen, there were no significant differences in live‐birth rate (RR, 1.01 (95% CI, 0.80–1.27); P = 0.93; very low certainty) or OPU cancelation (RR, 0.79 (95% CI, 0.38–1.67); P = 0.54; very low certainty), with no premature LH surges reported. Conclusions Current evidence of moderate‐to‐low certainty suggests that PPOS results in a higher number of oocytes and a higher live‐birth rate in the first embryo‐transfer cycle compared with a GnRH antagonist protocol. PPOS appears safe, with no case of severe OHSS observed across the analyzed cohorts. Given its oral administration, lower drug cost and demonstrated efficacy, PPOS represents a viable and potentially superior alternative to GnRH analogs for women undergoing ovarian stimulation for whom fresh‐embryo transfer is not intended. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.