Association of Cumulative Lifetime Exposure to Female Hormones With Cerebral Small Vessel Disease in Postmenopausal Women in the UK Biobank

Background and objectives: Rates of cerebrovascular disease increase after menopause, which is often attributed to the absence of hormones. It remains unknown whether the cumulative exposure to hormones across a female person's premenopausal life extends the window of cerebrovascular protection to the postmenopausal period. To investigate this, we examined the relationship between lifetime hormone exposure (LHE) and cerebral small vessel disease in more than 9,000 postmenopausal women in the UK-Biobank.Methods: The cohort consisted of women (aged 40-69 years) who attended one of 22 research centers across the United Kingdom between 2006 and 2010. Women were excluded if they were premenopausal when scanned, had missing reproductive history data, self-reported neurologic disorders, brain cancer, cerebral vascular incidents, head or neurologic injury, and nervous system infection. Endogenous LHE (LHEEndo) was estimated by summing the number of years pregnant (LHEParity) with the duration of the reproductive period (LHECycle = age menopause - age menarche). Exogenous LHE (LHEExo) was estimated by summing the number of years on oral contraceptives and hormone replacement therapy. Cerebral small vessel disease was determined by estimating white matter hyperintensity volume (WMHV) from T2-fluid-attenuated inversion recovery brain MRI (acquired between 2014 and 2021), normalized to intracranial volume and log-transformed. Multiple linear regressions were used to assess the relationship between LHEEndo on WMHV adjusted for age, cardiovascular risk factors, sociodemographics, and LHEExo.Results: A total of 9,163 postmenopausal women (age 64.21 +/- 6.81 years) were retained for analysis. Average LHEEndo was 39.77 +/- 3.59 years. Women with higher LHEEndo showed smaller WMHV (adj-R (2) = 0.307, LHEEndo beta = -0.007 [-0.012 to -0.002], p < 0.01). LHEParity and LHECycle were independent contributors to WMHV (adj-R (2) = 0.308, p << 0.001; LHEParity beta = -0.022 [-0.042 to -0.002], p < 0.05; LHECycle beta = -0.006 [-0.011 to -0.001], p < 0.05). LHEExo was not significantly related to WMHV (LHEExo beta = 0.001 [-0.001 to 0.002], p > 0.05).Discussion: Women with more prolonged exposure to endogenous hormones show relatively smaller burden of cerebral small vessel disease independent of the history of oral contraceptive use or hormone replacement therapy. Our results highlight the critical role endogenous hormones play in female brain health and provide real-world evidence of the protective effects premenopausal endogenous hormone exposure plays on postmenopausal cerebrovascular health.