Variant-specific contributions of CYP21A2 and CYP11B1 to the clinical and hormonal heterogeneity of polyendocrine metabolic ovarian syndrome phenotypes

Background: Polyendocrine Metabolic Ovarian Syndrome (PMOS) formerly known as Polycystic Ovary Syndrome (PCOS), characterized by hyperandrogenism, affects approximately 7.1–15.1% of women of reproductive age. While disease-causing CYP21A2 and CYP11B1 variants are well-studied, the contribution of synonymous variants to clinical and hormonal variations remains unclear. This study investigated whether synonymous and non-synonymous variants associated with phenotypic heterogeneity. Methods and results: A total of 275 premenopausal women (110 PMOS women and 165 healthy controls) underwent comprehensive clinical-biochemical evaluation. All exons and exon–intron boundaries of CYP21A2 and CYP11B1 were analyzed using direct sequencing. Genotype–phenotype associations were evaluated using non-parametric statistical tests and genetic model–based logistic regression analyses. Genotype and allele frequencies were similar between PMOS patients and controls; however, several variants showed distinct genotype–phenotype associations. Following false-discovery rate correction within predefined biological blocks, p.Val282Leu and non-classic congenital adrenal hyperplasia (NCAH)-related CYP21A2 variants remained significantly associated with elevated adrenocorticotropic-hormone(ACTH), while combined p.Leu9_Leu10insLeu/p.Arg103Lys/p.Ser269Thr/ p.Ser494Asn variants was linked to reduced ACTH. Carriers of NCAH-associated CYP21A2 allele exhibited significantly reduced sex hormone-binding globulin (SHBG) and higher modified Ferriman-Gallwey(FGS) levels. CYP21A2 synonymous p.Leu40=/p.Pro46 = variant associated with lower BMI. Additionally, combined CYP11B1 p.Leu75=/p.Asp82 = genotype remained significantly associated with reduced SHBG, while p.Arg43Gln/p.Ala386Val was associated with reduced FGS. Conclusion: The findings underscore the variant-specific and cumulative impact of CYP21A2 and CYP11B1 alterations on the adrenal axis and systemic androgen bioavailability. These results suggest that synonymous variants may actively modulate hormonal and clinical traits, contributing to the inter-individual variability of PMOS-related phenotypes independently of overt PMOS risk. © The Author(s), under exclusive licence to Springer Nature B.V. 2026.