Introduction
Recent scientific effort has started to delineate how ovarian hormones, which regularly fluctuate during the menstrual cycle, influence neural and cerebrovascular tissue. This may underlie the relationships between later hormonal decline and neurodegenerative disease risk1. To fully profile how hormones interact with cerebrovascular function, it is vital to consider, not just resting physiology, but also dynamic aspects of cerebrovasculature that support neural activity.
This study uses hypercapnic cerebrovascular reactivity (CVR) and visually-evoked haemodynamic response function (HRF) to investigate the influence of menstrual-related changes in oestradiol and progesterone on dynamic aspects of the cerebrovascular system.
Methods
21 menstruating females (age mean[SD]= 22.9[3.91] years) completed a 3T MRI (Siemens MAGNETOM Prisma) scanning session during the early follicular (EFP; day 1-4; N=17), late follicular (LFP; day 10-12; N=17), and mid-luteal (MLP; day 20-22; N=18) phase of their menstrual cycle (14 completed all three). All took place at the same time of day, after fasting for 4-6 hours. Circulating hormones were measured via blood samples. All procedures were compliant with ethical standards.
Simultaneous blood oxygen level dependant (BOLD)-CVR and cerebral blood flow (CBF)-CVR data were collected using a pseudocontinuous arterial spin labelling (pCASL) acquisition during periods of hypercapnia (5% CO2) with PETCO2 monitoring (maximum repetition time [TR]=3600ms, echo time [TE] 1=10ms, TE2=30ms, in-plane resolution=3.4×3.4, slice thickness=6.5mm, GRAPPA acceleration factor=3). The HRF was estimated using a whole brain EPI scan during 100% contrast checkerboard presentation (TR=2s, TE=30ms, resolution=2mm3, multi-band acceleration factor=4).
The HRF timeseries was fit with a gamma variate model. Three metrics were extracted– peak amplitude (PA), time-to-peak (TTP), and full-width-half-max (FWHM). PETCO2 traces were used in modelling CVR maps. BOLD-CVR (∆%BOLD/mmHgCO2) and CBF-CVR values (∆ml/100g/min/mmHgCO2) were extracted across the whole brain, while HRF metrics were extracted from visually-responsive regions. Mixed linear models investigated the contribution of hormones to vascular outcomes across phases. Progesterone was regressed against oestradiol to allow investigation of independent variation (hereby called resProgesterone).
Results
Oestradiol accounted for a significant amount of global CVR variance, both for CBF-CVR (χ2(1)= 50.92; p<0.001; average variation attributed to oestradiol across a cycle in this sample=1.01∆ml/100g/min/mmHgCO2) and for BOLD-CVR (χ2(1)=59.14; p<0.001; average variation attributed to oestradiol across a cycle in this sample=0.1∆%BOLD/mmHgCO2). ResProgesterone however, was only significantly associated with global CBF-CVR (χ2(1)=26.71; p<0.001; average variation attributed to resProgesterone=0.6∆ml/100g/min/mmHgCO2).
For HRF, increasing oestradiol was associated with slightly higher PA (χ2(1)=20.55; p<0.001; average variation attributed to oestradiol across a cycle in this sample=0.1%BOLD) and earlier TTP (χ2(1)=10.036; p=0.002; average variation attributed to oestradiol across a cycle=0.4 seconds). Increasing resProgesterone was associated with narrower FWHM (χ2(1)=28.71; p<0.001; average variation attributed to resProgesterone=0.5 seconds). No significant regional effects were found.
Conclusions
This study found evidence that dynamic cerebrovascular functions are associated with menstrual-related ovarian hormones. These effects were small but notable within the context of the regular menstrual cycle and raise questions about larger hormonal variations, such as within pregnancy or menopause. This may be a potential mechanism underlying menstrual symptomatology and has implications for fMRI studies that assume intact neurovascular coupling processes in women, regardless of menstrual staging, to make inferences about neural activity.