Examining the influence of the menstrual cycle, hormonal contraceptives, biological sex, and gender on cardiovascular and metabolic outcomes in healthy adults.

Abstract

Sex-differences in cardiometabolic physiology are evident; however, the inclusion of female participants in research studies for the purposes of exploration of sex-specific physiological responses is limited by the perceived complexity due to hormonal cycles. This dissertation examined the prevalence of sex-specific inclusion in human vascular exercise physiology research, investigate the influence of endogenous and exogenous sex hormones on cardiovascular, respiratory, and skeletal muscle metabolism, and consider sex- and gender-differences in peripheral vascular outcomes. The first study confirmed a sex-specific bias towards male inclusion in vascular exercise physiology research, with perceived hormonal complexity noted as one rationale for sex-specific exclusion. To address this perception, we reviewed the literature and identified a small effect of the menstrual cycle, and a more robust influence of oral contraceptive pills, on macrovascular endothelial function, with no influence on smooth muscle function or arterial stiffness. Our next set of studies objectively evaluated the influence of the natural menstrual and two generations of oral contraceptive pills on a comprehensive suite of cardiovascular, respiratory, and metabolic outcomes, and found largely no influence on these outcomes or the underlying vascular cellular regulation, apart from a small effect elevated endogenous and exogenous sex hormones on brachial artery endothelial function. Another area identified in our initial sex-inclusion review was the absence of gender-based research in vascular exercise physiology. Our final study found that biological sex aligned with gender identity, but not gender expression and influenced cardiovascular markers by including elevating systolic blood pressure, central arterial stiffness and endothelial function in males and men compared to females and women. Altogether, this dissertation provides substantial evidence for the lack of hormonal cycle influence of endogenous and exogenous sex hormones on three organ systems, which will open further incorporating females into research study design.