The Role of Estrogen and Testosterone in Determining Brain Blood Flow and Metabolic Regulation in Humans

Sex hormones have been demonstrated to influence cardiovascular function in humans and cerebrovascular function in preclinical models. Declines in gonadal function have been attributed to the development of chronic disease risk in humans, including stroke, cognitive decline and dementia but the pathophysiology of these disorders remains unclear, in part, because there remains a gap-in-knowledge of the regulatory actions of sex hormones on cerebrovascular function in males and females. Therefore, the major goal of this application is to determine the independent regulatory actions of testosterone and estradiol on cerebrovascular function in males and females, respectively. Determination of this fundamental physiology is needed to inform future studies evaluating the sex-specific pathology physiology of chronic diseases and/or the development of efficacious sex-specific interventions for improving chronic disease risk.

To the investigator's knowledge, there is minimal evidence in humans isolating the influence of these hormones on basic mechanisms of brain blood flow regulation in vivo. Cross-sectional studies demonstrate younger females show significantly higher resting cerebral blood flow (CBF) compared to young males however, this sex difference in CBF is lost after midlife. This loss of female 'protection' on CBF is often attributed to hormonal differences following menopause. Further evidence in animal models support a key role of estrogen in both resting CBF and reactivity. Crucially, these findings have not been replicated in humans, due to natural fluctuations in sex hormones. Research investigating natural hormonal fluctuations throughout the menstrual cycle and menopause provides conflicting findings, falling short on isolating the specific hormonal influences on cerebrovascular physiology likely due large interindividual variations in hormone levels and cycle lengths.

Similarly, the presence of normal physiological levels of testosterone has been shown to influence chronic disease risk including cardiovascular disease risk and peripheral vascular function. However, whether testosterone concentrations influence CBF in males remains incompletely understood with one study showing testosterone may enhance CBF in older hypogonadal men. Furthermore, testosterone can be converted to estradiol via a specific enzyme, aromatase; thus, it is unclear whether the findings of prior study were related to changes in testosterone or estradiol concentrations in hypogonadal males. A definitive role of these hormones in brain blood flow regulation remains to be elucidated.

Current published studies suffer from several key limitations. First, many studies are unable to isolate the impact of hormones and their causality on cerebrovascular function in humans. The inability to replicate findings from direct hormone manipulation in animals with observational data during natural hormone cycling in humans suggests measuring females during their menstrual cycles is not adequate for understanding the direct role of these hormones. There is a very large degree of variation both between and within individuals throughout their menstrual cycles, proving difficult to relate changes in function with hormone levels. In males, very limited research exists investigating how testosterone influences cerebrovascular function. Further, this research will have direct implications for peri- and postmenopausal women, who are regularly prescribed exogenous estradiol for symptom management. Understanding the role of hormones in healthy physiology will allow direct translation to a myriad of hormonal disorders, including endometriosis, polycystic ovary syndrome, uterine fibroids, and hypogonadism. Individuals with endometriosis are commonly prescribed oral GnRH antagonist, which can be combined with estradiol for prolonged use (> 6 months). Similarly, males with hypogonadism often supplement testosterone for prolonged periods with minimal negative effects.

This study will allow for isolation of estradiol in females and testosterone in males to investigate their role on cerebrovascular regulation. In contrast with previous observational studies throughout the menstrual cycle and menopause in females and aging in males, this study will provide a controlled environment to determine causal relationships between hormones and physiology without the presence of confounding variables. This study will address the gap in literature between interventional models in animals and observational studies in healthy humans. This study will provide fundamental understandings of healthy physiology that will shape future studies to investigate the role of estradiol and testosterone in clinical populations.