Divergent Associations of the VEGF (–2578C/A) Polymorphism with Imaging-Based Severity and Symptom Profile of Adenomyosis in Infertile Women: An Exploratory Analysis

TL;DR

This study found that a specific VEGF gene variant is linked to more severe adenomyosis on imaging but fewer painful symptoms in infertile women.

Contribution

The study reveals a genetic variant's divergent effects on imaging severity and symptoms in adenomyosis.

Findings

The VEGF–2578C/A AA+CA genotypes are associated with higher odds of adenomyosis and increased ultrasound severity.

AA+CA carriers with adenomyosis experience less dysmenorrhea despite more severe imaging findings.

Other VEGF polymorphisms (−936C/T and −634G/C) showed no significant associations with adenomyosis features.

Abstract

Background and Objectives: Adenomyosis is increasingly being recognized as a heterogeneous uterine disorder with variable clinical expressions. Current ultrasound-based classifications do not consistently align structural severity with symptom burden. Given its role in angiogenesis, inflammation, and endometrial remodeling, vascular endothelial growth factor (VEGF) signaling may influence both morphological features and clinical manifestations. This study evaluated the association between three VEGF polymorphisms (−2578C/A, −634G/C, −936C/T) and adenomyosis presence, ultrasound-based severity, and symptoms in infertile women undergoing in vitro fertilization (IVF). Materials and Methods: In this prospective cohort study, 85 infertile women were assessed for adenomyosis using MUSA criteria and Exacoustos grading. VEGF genotyping was performed by PCR-RFLP. Clinical data included menstrual bleeding status scores and dysmenorrhea intensity. Results: Under a dominant model, the variant genotypes (AA+CA) of the VEGF–2578C/A polymorphism −2578 A showed increased odds of adenomyosis versus CC (adjusted OR = 4.00, 95% CI: 1.48–10.84; p = 0.0037). The A allele frequency was higher in women with adenomyosis (57.14% vs. 33%), which was consistent with increased susceptibility (OR = 2.71, 95% CI: 1.44–5.09; p = 0.003). The AA + CA genotypes were more frequent with higher ultrasound-based severity (p = 0.0029; 50% vs. 72% vs. 100% across increasing severity strata); however, among women with adenomyosis, AA + CA carriers had lower odds of clinically relevant dysmenorrhea (adjusted OR = 0.18, 95% CI: 0.06–0.55; p = 0.0017), which remained significant after correction for multiple testing (adjusted p = 0.0051). No significant associations were identified for −936C/T or −634G/C across adenomyosis presence, ultrasound-based severity, number of sonographic features, dysmenorrhea, or heavy menstrual bleeding (all p > 0.05). Conclusions: These preliminary findings suggest divergent associations of VEGF −2578C/A with structural severity versus symptom expression, supporting a partial dissociation between ultrasound-defined severity and clinical phenotype in adenomyosis.