Cervicovaginal lavage fluid iron and manganese levels in women with and without vaginitis

TL;DR

Women with vaginitis had higher iron levels in cervicovaginal fluid compared to healthy controls, but manganese levels were similar.

Contribution

This study is the first to show that vaginitis is associated with elevated cervicovaginal iron levels, which may be reduced by zinc-based treatments.

Findings

Cervicovaginal iron concentrations were significantly higher in women with culture-positive vaginitis compared to controls.

Manganese concentrations did not differ between women with and without vaginitis.

Zinc-containing hydrogel treatment was associated with reduced iron elevation in vaginitis patients.

Abstract

Transition metals such as iron and manganese are critical for cellular metabolism, redox balance, and immune function, and they also influence host–pathogen interactions. Vaginitis is characterized by mucosal inflammation that may alter local trace-element homeostasis. We hypothesize that inflammatory conditions such as vaginitis may be associated with altered cervicovaginal iron and manganese levels. We performed a prospective, single-center cohort study at the University of Debrecen (Hungary) between April 2023 and April 2024, enrolling 80 women ≥ 18 years with vulvovaginal complaints. Participants were assessed at baseline and at weeks 4, 8, and 12 with clinical evaluation and cervicovaginal lavage (CVL) sampling, collected using metal-free instruments. Participants were randomized 1:1 to receive either fluconazole alone or a single baseline oral fluconazole plus an intravaginal zinc-containing hydrogel. CVL samples were digested and analyzed for iron and manganese using ICP-OES. Group comparisons were performed using linear mixed-effects models with a random intercept for participant. CVL Fe concentrations were higher in women with culture-positive vaginitis compared with controls (mean ± SD: 56.36 ± 24.84 vs. 44.64 ± 20.11), with a significant between-group difference in mixed-effects models (Δ = 8.82, 95% CI 0.74 to 16.89; p = 0.032). Mn concentrations did not differ between vaginitis and controls (1.42 ± 0.73 vs. 1.09 ± 0.77; p = 0.542). In subgroup analyses, Fe remained significantly higher in vaginitis compared with controls among women who did not use the hydrogel (60.69 ± 26.53 vs. 47.27 ± 21.87; p = 0.041), whereas the difference was attenuated and no longer significant among hydrogel users (53.64 ± 23.62 vs. 41.75 ± 17.71; p = 0.148). Within the vaginitis cohort, Fe and Mn concentrations were similar across culture-defined phenotypes (bacterial-positive vs. fungal-positive) and between fungal culture-negative and fungal-positive samples. Culture-positive vaginitis was associated with higher total cervicovaginal iron concentrations, while manganese remained largely unchanged. Adjunct topical zinc therapy appeared to temper the vaginitis-associated elevation in iron, consistent with improved mucosal integrity and reduced inflammation-driven iron availability. Total Fe and Mn concentrations in CVL did not distinguish vaginitis phenotypes, supporting their use primarily as reference values and motivating future work focused on bioavailable metal fractions and metal-binding host proteins. The study protocol was approved by the Hungarian National Institutional Review Medical Research Council (approval No. 3282-7/2023/EUIG).