Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study

Menopause and the perimenopausal transition involve profound hormonal and metabolic changes that may impair brain function. Beyond structural alterations, reduced cerebral bioenergetics could underlie the cognitive complaints often reported during this period. Because creatine serves as a key neuronal energy buffer and is influenced by estrogen, this study examined brain creatine concentrations in perimenopausal women and their associations with neurocognitive symptoms and serum estradiol.

Twelve healthy perimenopausal women (mean age 49.8 ± 5.4 years) experiencing irregular cycles and at least one perimenopausal symptom underwent multi-voxel 1H-magnetic resonance spectroscopy to quantify total brain creatine across bilateral frontal, precentral, and parietal gray- and white-matter regions and the thalamus. Serum estradiol was measured by ELISA, and symptom severity was rated on visual analog scales. Associations were assessed using Kendall's τ.

Mean whole-brain creatine concentration (6.31 ± 0.98 mM) was significantly lower than reference values in younger adults (Z = -1.65, P = 0.049). Lower creatine levels in the thalamus, right precentral, and right parietal white matter correlated with greater concentration difficulties (τ = -0.38 to -0.51, P ≤ 0.049), while right frontal white-matter creatine positively correlated with headache severity (τ = 0.41, P = 0.034). Serum estradiol averaged 119.5 ± 109.5 pg/mL and was inversely associated with right parietal gray-matter creatine (τ = -0.37, P = 0.049).

Perimenopausal women exhibited lower cerebral creatine than younger adults, with region-specific reductions linked to concentration difficulties and estradiol levels. These findings suggest that estrogen-related changes in brain bioenergetics may contribute to cognitive symptoms during the menopausal transition.