The Relation Between Sex, Menopause, and White Matter Hyperintensities: The Rhineland Study

Background and objective: Mounting evidence implies that there are sex differences in white matter hyperintensity (WMH) burden in the elderly. Questions remain regarding possible differences in WMH burden between men and women of younger age, sex-specific age trajectories and effects of (un)controlled hypertension, and the effect of menopause on WMH. Therefore, our aim is to investigate these sex differences and age-dependencies in WMH load across the adult life span, and to examine the effect of menopause.

Methods: This cross-sectional analysis was based on participants of the population-based Rhineland Study (30 – 95 years) who underwent brain MRI. We automatically quantified WMH using T1-weighted, T2-weighted and FLAIR images. Menopausal status was self-reported. We examined associations of sex and menopause with WMH load (logit-transformed and z-standardised) using linear regression models, while adjusting for age, age-squared, and vascular risk factors. We checked for an age*sex and (un)controlled hypertension*sex interaction and stratified for menopausal status comparing men with premenopausal women (persons aged ≤ 59 years), men with postmenopausal women (persons aged ≥ 45 years), and pre- with postmenopausal women (age range 45 – 59 years).

Results: Of 3410 participants with a mean age of 54.3 years (SD = 13.7), 1973 (57.9%) were women, of which 1167 (59.1%) were postmenopausal. We found that the increase in WMH load accelerates with age and in a sex-dependent way. Premenopausal women and men of similar age did not differ in WMH burden. WMH burden was higher and accelerated faster in postmenopausal women compared to men of similar age. Additionally, we observed changes related to menopause, in that postmenopausal women had more WMH than premenopausal women of similar age.. Women with uncontrolled hypertension had a higher WMH burden compared to men, which was unrelated to menopausal status.

Discussion: After menopause, women displayed a higher burden of WMH than contemporary premenopausal women and men, and an accelerated increase in WMH. Sex-specific effects of uncontrolled hypertension on WMH were not related to menopause. Further studies are warranted to investigate menopause-related physiological changes, that may inform on causal mechanisms involved in cerebral small vessel disease progression.