Objective:

The aim of this study was to examine the relationship between lifetime exposure to endogenous and exogenous gonadal hormones on white matter hyperintensities (WMH) in post-menopausal women. 

Background:

The onset of menopause accelerates the development of brain biomarkers of small vessel disease, such as WMH, supporting the cerebrovascular-protective effects of hormones.  However, whether this effect is influenced by lifetime exposure to hormones is unclear.   

Design/Methods:

Two measures of lifetime endogenous hormone exposure (ENHE) were explored:  1) cumulative number of years with a natural menstrual cycle and 2) cumulative number of live childbirths in women having never received hormone replacement therapy (HRT, n=6039).  For exogenous hormone exposure (EXHE): 1) the use of oral HRT and 2) topical HRT (n=246).  WMH volume was obtained from preprocessed T2-FLAIR images. 

Results:

In a linear model adjusted for intracranial volume, age, oral contraceptive use, socio-demographics, and cardiovascular risk factors, both ENHEcycle and EMNHEparity were negatively associated with WMH (R2 = 0.30, F = 241, DF = 6027, p<0.0001; βparity = -0.025, p = 0.006; βcycle = -0.003 p = 0.017).  For EXHE, women who received topical HRT had significantly lower WMH volume than oral HRT (t=1.99, p= 0.048) after correcting for intracranial volume, age, socio-demographics, cardiovascular risk factors, ENHEcycle and ENHEparity.

Conclusions:

Our results provide further evidence that lifetime exposure to endogenous hormones appears to have an independent protective effect on WMH burden, and extending this with exogenous topical HRT may confer additional protection.  The stronger effect of parity may be due to prolonged exposure to elevated estrogen resulting in long-lasting structural or functional changes in the small cerebral vessels.