The influence of menstrual cycle and oral contraceptive pill phases on the vascular response to hypoxia and sympathetic activation in healthy young women
INTRODUCTION: Hypoxia elicits peripheral vasodilation to preserve blood flow to metabolically active tissue and is accompanied by an increase in muscle sympathetic nervous system activity (MSNA). Prior data predominantly in male subjects, demonstrated the vasoconstrictive effects of MSNA are preserved in the setting of hypoxia. Because women are better able to attenuate or ignore the vasoconstrictive effects of MSNA at rest, we hypothesized women would exhibit greater hypoxic vasodilation (Aim 1). We further hypothesized women would attenuate the vasoconstrictive effects of sympathetic activation during both normoxia (Aim 2) and in the setting of hypoxia (Aim 3). The female sex hormone, estrogen, has been purported to be responsible for mediating the attenuated vasoconstriction to MSNA. As synthetic estrogen found in oral contraceptives is more biologically potent, we further hypothesized women taking oral contraceptives (OCPs) will better attenuate vasoconstriction relative to naturally cycling (NC) women during normoxia and hypoxia and this will be greatest during the high hormone phase of the pill or menstrual cycle. METHODS: Ten NC women, (25[plus or minus]1 yrs, 23[plus or minus]1 kg/m2) and ten women on OCPs, (24[plus or minus]1 yrs, 21[plus or minus]1 kg/m2) participated (N=20). Women were studied twice, once during the low hormone of the menstrual or pill cycle (menstrual cycle day, NC: 3.1[plus or minus]0.4; pill cycle day: OCP: 5.2[plus or minus]0.4) and once during the high hormone phase of the menstrual or pill cycle (menstrual cycle day, NC: 14.9[plus or minus]0.9; pill cycle day OCP: 16.6[plus or minus]0.6). Heart rate (ECG), blood pressure (finger photoplethysmography), forearm blood flow (venous occlusion plethysmography) and systemic blood flow (Modelflow) were continuously measured across three trials: 1) steady state hypoxia (80 percent SpO2); 2) sympathetic activation via two-minute cold pressor test (CPT); and 3) concomitant steady-state hypoxia and sympathetic activation via two-minute CPT. Forearm and systemic blood flow were normalized for blood pressure and expressed as forearm vascular conductance (FVC) and total vascular conductance (TVC), respectively. Data are reported from the last one minute of each trial. RESULTS: Hypoxia elicited a relative increase in FVC ( percent change from baseline) that was greater during the high hormone phase of the menstrual or pill cycle compared to the low hormone phase in both NC and women taking OCPs (p[less than]0.01). Sympathetic activation via CPT caused paradoxical local vasodilation in women taking OCPs, whereas NC women exhibited local vasoconstriction (p[less than]0.01). Concomitant hypoxia and sympathetic activation via CPT resulted in less systemic vasoconstriction compared to normoxia that was not different between groups or hormone phases (p=0.71). CONCLUSION: The hypoxic vasodilatory response is augmented during the high hormone phase of the menstrual or pill cycle. Exogenous estrogen found in OCPs may cause paradoxical vasodilation to sympathetic activation, whereas sympathetic activation in NC women with endogenous hormones elicits vasoconstriction. We observed a hypoxia-mediated attenuation of the systemic vasoconstrictor response to sympathetic activation in both NC women and women taking OCPs across all hormone phases. These data demonstrate the vascular response to autonomic and environmental stressors are influenced by female sex hormones and menstrual/pill cycle phase.