The Role of Menopause in White Matter Hyperintensity Volume, Load in Women

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Researchers assessed whether WMH load differed based on sex and age across the adult life span, and they examined the effect of menopause.

Following menopause, women exhibit a higher burden of white matter hyperintensities (WMHs) than contemporary premenopausal women and men, as well as an increase in WMH, according to study results published in the journal Neurology.

A cross-sectional analysis was conducted among the initial 5000 consecutive participants enrolled in the ongoing, prospective, single-center, population-based Rhineland Study who underwent brain magnetic resonance imaging (MRI). All individuals aged between 30 and 95 years from 2 geographically defined areas in Bonn, Germany, were invited to participate. The only exclusion criterion for study enrollment was insufficient proficiency in the German language or lack of mental capacity to provide singed informed consent.

With increased evidence suggesting that sex differences in WMH exist in the elderly, researchers sought to examine sex differences and age-dependencies in WMH load across the adult life span and to evaluate the impact of menopause. Questions persist with respect to possible differences in WMH burden between men and women of a younger age, sex-specific age trajectories, and impact of uncontrolled hypertension, and the effect of menopause on WMH.

In the analysis, “sex refers to biological sex, with women being biological female and men biological male at birth,” the researchers explained. Menopause was evaluated as status (ie, yes or no) at baseline examination, which was self-reported. Women were classified as postmenopausal in the following situations:

  • Underwent bilateral oophorectomy
  • No menstruation for more than 1 year not due to pregnancy, breastfeeding, or contraception
  • Older than 60 years of age

WMH was automatically quantified with the use of T1-weighted, T2-weighted, and FLAIR MRI scans. WMH was defined as “hyperintense signals in the white matter tracts on T2-weighted images.”

Hypertension was defined as follows:

  • Systolic blood pressure of 140 mm Hg or greater
  • Diastolic blood pressure of 90 mm Hg or greater
  • Use of antihypertensive medication

Diabetes was defined as follows:

  • Fasting plasma glucose level of 7 mmol/L or more
  • Hemoglobin A1c of 6.5% or more
  • Use of antidiabetic medication

History of coronary heart disease, smoking status, body mass index (BMI), use of lipid-lowering medication, and level of education were also obtained.

Among a total of 3410 study participants, 1973 were women and 1167 of them were postmenopausal. Among the postmenopausal women, 216 were on hormone therapy. The mean participant age was 54.3±13.7 years. Hypertension was reported in 1208 of the participants, with 660 of these individuals having uncontrolled hypertension.

In the overall study cohort, the mean WMH volume was 0.5 mL (range, 02 mL-1.2 mL); the median WMH load was 0.1% (range, 0.1%-0.3%).

Study findings revealed that with increasing age, WMH load increased exponentially, with sex effects changing over the age span (age*sex interaction, P <.001) and sex differences becoming more pronounced after menopause. The effects of age on WMH were stronger among women than among men (95% CI, 0.04-0.05).

Per subgroup analysis, WMH load did not differ in premenopausal women and men up to the age of 59 years, with WMH load increasing linearly with age (95% CI, 0.02-0.03). Postmenopausal women, in contrast, had a higher WMH load compared with men of a similar age. The increase in WMH burden accelerated with age, which differed in men vs women (age*sex interaction, P =.03).

Nonlinear age effects were stronger among women (95% CI, 0.05-0.06) compared with men. Additionally, postmenopausal women had a higher WMH burden compared with premenopausal women of the same age range (95% CI, 0.07-0.35). In both premenopausal women and postmenopausal women 45 to 59 years of age, WMH burden increased linearly with age (95% CI, 0.01-0.04).

Further, those participants with controlled and uncontrolled hypertension exhibited more WMH than did normotensive participants, which was dependent on sex (sex*uncontrolled hypertension interaction, P <.005), with this association stronger in women than in men. An interaction between sex*uncontrolled hypertension in premenopausal women and men until the age of 59 years was reported as well (P =.02).

Hormone therapy had no impact on WMH load in postmenopausal women. The researchers stated this suggests that “[hormone therapy] after menopause does not continue this protective effect on the brain.”

Several limitations in the study warrant mention. The baseline questionnaire used did not capture the sex and gender identity of the study participants in sufficient detail to account for the full and diverse patient spectrum. Although biological sex differences in WMH burden were evaluated, gender differences were not taken into account; thus, the study results cannot be generalized to a gender-diverse population.

“Our results demonstrate the necessity to account for different trajectories for men and women, and menopausal status. This further underscores the importance of sex-specific medicine, and the requirement for a more attentive therapy for older/postmenopausal women, especially with advanced vascular risk factors,” the researchers concluded.


Lohner V, Pehlivan G, Sanroma G, et al. The relation between sex, menopause, and white matter hyperintensities: the Rhineland Study. Neurology. Published online June 29, 2022. doi:10.1212/WNL.0000000000200782