The disproportionate rise in cerebrovascular disease risk for females in the first 10 years post-menopause indicates a role for ovarian sex hormones (i.e., oestrogen and progesterone) in healthy cerebrovascular function and regulation. However, the exact influence of changing sex hormones across the lifespan on the cerebrovasculature is yet to be elucidated. The primary aim of this thesis was to determine the influence of sex hormones on cerebrovascular function.
A systematic review and meta-analysis established that hormone replacement therapy in post-menopausal females has the potential to improve cerebrovascular function, as reflected by a significant reduction in pulsatility index. Further, the effects of changing sex hormones in other hormone groups (e.g., menstrual cycle, menopause) remains unclear due to the substantial heterogeneity and limited evidence in the literature. Subsequently, three experimental studies examined measures of cerebrovascular function across the menstrual cycle, between males and females, and between pre- and post-menopausal females. Firstly, cerebrovascular responsiveness (indexed via measures of middle/posterior cerebral blood flow velocity (MCAv/PCAv) responses to altered arterial partial pressure of carbon dioxide (CO2)) across the menstrual cycle revealed a greater MCAv-CO2 responsiveness to hypocapnia during ovulation (O) when compared to the early follicular (EF) phase. Assessment of sex differences showed cerebrovascular-CO2 responsiveness to hypo- and hypo-to-hypercapnia was greater in females during EF in the PCA, and females during O in the MCA, when compared to males. Use of passive heat stress as an additional perturbation did not change cerebrovascular-CO2 responsiveness across the menstrual cycle, while a diminished PCA responsiveness to hypercapnia during heat stress was only evident in males. Finally, pre-menopausal females were shown to have an improved MCAv-CO2 responsiveness to hypercapnia compared to post-menopausal females, irrespective of menstrual phase. Preliminary data indicates possible differences between pre- and post-menopausal females in internal carotid artery (ICA) responsiveness to hypercapnia, and in cerebral autoregulation (indexed via MCAv responses to repeated squat-to-stand-induced changes in blood pressure).
Collectively, these findings indicate that 1) acute fluctuations in oestrogen across the menstrual cycle can alter the vasoconstrictive capacity of the MCA, while progesterone appears to counteract the effects of oestrogen. 2) Sex differences in cerebrovascular-CO2 responsiveness are dependent on menstrual phase and the insonated vessel, and differences are present even when females are early follicular phase of the menstrual cycle. Further, cerebrovascular responses to passive heating are sex specific. Finally, 3) post-menopausal females have a blunted MCAv responsiveness to hypercapnia compared to pre-menopausal females. Overall, the findings that pre-menopausal females exhibit improved intracranial cerebrovascular-CO2 responsiveness compared to both young males and post-menopausal females supports the premise that sex hormones play a protective role in cerebrovascular function
