Expression of circulating GRP78 and gp96, endoplasmic reticulum stress-related proteins, in menstrual and bladder pain sensitivity

Dysmenorrhea is often linked to uterine inflammation, but the additional factors and pathways that contribute to its pathophysiology remain poorly understood. Given growing evidence linking endoplasmic reticulum (ER) stress to inflammation and pain sensitization, we examined circulating ER stress-associated heat shock proteins (HSPs) GRP78 and gp96 in individuals with dysmenorrhea (n = 82), a dysmenorrhea subtype with bladder pain sensitivity (DYSB, n = 26) previously shown to increase risk for chronic pain, and controls (n = 19). After correcting for Menstrual phase, naproxen exposure, and oral contraceptive use, GRP78 was higher in DYSB than in DYS (ratio 1.33; p = .028), while gp96 was lower in both DYS (ratio 0.62; p = .019) and DYSB (ratio 0.59; p = .031) compared to controls. gp96 was also lower during the menstrual phase with naproxen compared to the non-menstrual phase (ratio 0.73; p = .014), whereas GRP78 was not significantly affected by menstrual phase, naproxen, or oral contraceptive use, and neither protein was associated with anxiety, depression, or sleep disturbance scores. These cross-sectional findings suggest that dysmenorrhea, particularly the bladder-sensitive subtype (DYSB), is associated with divergent circulating levels of two ER stress-related proteins. The inverse pattern of higher GRP78 and lower gp96 levels points to selective, rather than global, ER chaperone dysregulation as a candidate mechanism. However, future mechanistic and longitudinal investigations will be required to establish whether GRP78 and gp96 carry predictive or pathophysiological relevance.