Two observational studies in the Russian Federation described patient demographics/clinical decision for treatment with recombinant human follicle-stimulating hormone:recombinant human luteinizing hormone (r-hFSH:r-hLH) 2:1 combination for ovarian stimulation (OS) during assisted reproductive technology (ART) and outcomes, respectively. The first (prospective) study enrolled 500 patients. After post-hoc regrouping to assign patients to discrete groups, 378 (75.6%) met the local Russian label for an r-hFSH:r-hLH 2:1 combination, 105 (21%) were treated according to other physician preference, and 17 (3.4%) met only the ESHRE Bologna criteria for a poor ovarian response. The clinical pregnancy rate per cycle was 30.4%. A total of 158/175 (90.3%) women achieving clinical pregnancy in the prospective study participated in the second (retrospective) study. The live birth rate per cycle was 25.8%. No new safety concerns were reported. These results support the use of the r-hFSH:r-hLH 2:1 combination in patients with a poor/suboptimal response to OS for ART treatment in the Russian Federation.

Background and Clinical Significance: The oocyte zona pellucida (ZP) is an extracellular glycoprotein matrix with essential roles in oogenesis, fertilization, and early embryonic development. Abnormal ZP morphology is associated with female infertility and adverse outcomes after assisted reproductive technology (ART), but its molecular basis remains incompletely understood. Case Presentation: We present three patients with female infertility, abnormal oocyte ZP morphology, and adverse embryological outcomes, including fertilization failure and early developmental arrest. Whole-genome sequencing identified an extremely rare heterozygous missense variant in the ZP4 gene (rs1254095560) in one patient, resulting in the p.Leu342Pro substitution at a conserved amino acid position within the functionally important ZP-C subdomain of the protein. In silico modeling showed that the p.Leu342Pro substitution may alter the spatial folding of the ZP4 protein. Conclusions: These results and the known role of ZP4 in the organization of the zona pellucida allow this variant to be considered a candidate genetic factor potentially associated with disruption of the zona pellucida structure. The absence of comparable, apparently pathogenic coding variants in ZP genes in two other patients with a similar zona pellucida phenotype suggests genetic heterogeneity of this phenotype.