Background/Objectives: This study aims to investigate whether Signal Transducer and Activator of Transcription 4 (STAT4) influences the anti-tumor immune response and is possibly involved in the initiation or relapse of pituitary adenomas (PAs) by examining STAT4 polymorphisms and serum levels. This research seeks to uncover potential connections that could inform future therapeutic strategies and improve our understanding of PA pathogenesis. Materials and Methods: This study was conducted at the Laboratory of Ophthalmology, Lithuanian University of Health Sciences. DNA was extracted from peripheral venous blood samples, and the genotyping of four STAT4 SNPs (rs7574865, rs10181656, rs7601754, and rs10168266) was performed using real-time PCR with TaqMan® Genotyping assays. The serum STAT4 levels were measured via ELISA, and the optical density was read at 450 nm. Genotype frequencies, allele distributions, and serum STAT4 levels were statistically analyzed to assess associations with pituitary adenoma occurrence. Results: A binary logistic regression revealed that the STAT4 rs7574865 GT + GG genotypes vs. TT were associated with 1.7-fold increased odds of PA occurrence under the dominant genetic model (p = 0.012). The stratification by gender showed no significant associations in females; however, in males, the STAT4 rs10168266 CC + CT genotypes compared to TT were linked to 2.5-fold increased odds of PA under the dominant genetic model (p = 0.005). STAT4 rs10181656, rs7574865, rs7601754, and rs10168266 were analyzed to evaluate the associations with the pituitary adenoma size. We found that the STAT4 rs7574865 GG genotype was statistically significantly less frequent in the macro PA group compared to in the reference group (p = 0.012). For PA relapse, the rs7574865 G allele was less frequent in the PA group without relapse (p = 0.012), and the GT + GG genotypes were associated with a 1.8-fold increase in the PA group without relapse occurrence (p = 0.008). The serum STAT4 levels were higher in the PA patients compared to those of the reference group (p < 0.001). Elevated STAT4 serum levels were observed in PA patients with the STAT4 rs10181656 CC or CG genotypes (CC: p = 0.004; CG: p = 0.023), and with the rs7574865 GG or GT genotypes (GG: p = 0.003; GT: p = 0.021). The PA patients with the STAT4 rs7601754 AA genotype exhibited higher serum levels compared to those of the reference group (p < 0.001). Similarly, higher serum levels were found in the PA patients with the STAT4 rs10168266 CC or CT genotypes (CC: p = 0.004; CT: p = 0.027). A haplotype frequency analysis revealed no statistically significant results. Conclusions: The STAT4 genotypes were significantly associated with the PA occurrence, size, and relapse. Elevated serum STAT4 levels were observed in the PA patients, highlighting its potential role in PA pathogenesis.
