Luteal phase stimulation versus follicular phase stimulation in poor ovarian responders: A systematic review and a...

Poor ovarian response (POR) complicates a substantial proportion of in vitro fertilization (IVF) cycles, frequently causing cycle cancellation and suboptimal reproductive outcomes. Conventional follicular-phase ovarian stimulation (FPOS) protocols often yield limited results, prompting the evaluation of alternative strategies such as luteal-phase ovarian stimulation (LPOS).

This study assesses whether LPOS presents similar efficacy in terms of assisted reproductive technology (ART) outcomes compared with stimulation in the conventional follicular phase in women with POR according to Bologna criteria.

Comprehensive electronic searches were performed up to July 2024 across MEDLINE (via PubMed), EMBASE, SCOPUS, LILACS, SciELO, CINAHL, PsycINFO, AMED, Clinicaltrials.gov, WHO ICTRP, and Cochrane databases, with additional hand-searching of reference lists and gray literature. Inclusion criteria were comparative studies evaluating LPOS versus FPOS in poor ovarian responders undergoing IVF/intracytoplasmic sperm injection. Studies involving DuoStim protocols, lacking control groups, or with incomplete data were excluded. Study selection, data extraction, and quality assessments (RoB 2 for randomized clinical trial (RCTs); ROBINS-I for observational studies) were conducted independently by multiple reviewers. Meta-analysis utilized random-effects models to generate pooled mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI). Certainty of evidence was assessed using the GRADE methodology.

Five studies (312 patients; 114 LPOS vs. 198 FPOS) met the inclusion criteria. LPOS resulted in a non-significant increase in cumulus-oocyte complexes retrieved (MD 0.56; 95% CI -0.12 to 1.23) and mature (MII) oocytes (MD 0.061; 95% CI -0.04 to 0.126), with moderate heterogeneity. The number of embryos reaching day 3 was significantly higher with LPOS (MD 0.77; 95% CI 0.29 to 1.25). No significant differences were found for clinical pregnancy rate (RR 1.26; 95% CI 0.78 to 2.02), fertilization rate (RR 1.04; 95% CI 0.91 to 1.20), pregnancy loss rate (RR 0.97; 95% CI 0.27 to 3.43), or cancellation rate (RR 0.89; 95% CI 0.34 to 2.30). Stimulation duration was significantly longer in LPOS, while total gonadotropin dose and serum estradiol on trigger day did not differ significantly. The overall certainty of evidence ranged from low to very low; therefore, findings should be interpreted as preliminary and might change as additional studies become available.

Luteal-phase ovarian stimulation appears to be an effective alternative to conventional FPOS for poor responders, demonstrating similar reproductive outcomes with possible quantitative benefits in embryo yield. However, the evidence is limited, and research is ongoing; therefore, results are pending and further large-scale randomized controlled trials are required to confirm these findings.

This review was prospectively registered in PROSPERO (ID: CRD420251010075; registration date: 12/05/2025).