Williams Jennifer S, Cheng Jem L, Stone Jenna C, Kamal Michael J, Cherubini Joshua M, Parise Gianni, MacDonald Maureen J
Vascular Dynamics Lab, Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada.
Molecular Exercise Physiology & Muscle Aging Lab, Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada.
Am J Physiol Heart Circ Physiol. 2024 Oct 1;327(4):H1019-H1036. doi: 10.1152/ajpheart.00672.2023. Epub 2024 Aug 23.
Historical exclusion of females in research has been, in part, due to the perceived influence of natural menstrual (NAT) and oral contraceptive pill (OCP) cycles on vascular outcomes. NAT and OCP cycle phases may influence brachial artery (BA) endothelial function, however, findings are mixed. Minimal research has examined arterial stiffness, smooth muscle, and lower limb endothelial function. The purpose of this study was to investigate the influence of NAT and OCP cycles on cardiovascular outcomes and cellular regulation. Forty-nine premenopausal females ( = 17 NAT, = 17 second generation OCP, = 15 third generation OCP) participated in two randomized order visits in the low (LH, early follicular/placebo) and high (HH, midluteal/active) hormone cycle phases. BA and superficial femoral artery (SFA) endothelial function [flow-mediated dilation (FMD) test], smooth muscle function (nitroglycerine-mediated dilation test), and carotid and peripheral (pulse wave velocity) arterial stiffness were assessed. Cultured female human endothelial cells were exposed to participant serum for 24 h to examine endothelial nitric oxide synthase (eNOS) and estrogen receptor-α (ERα) protein content. BA FMD was elevated in the HH vs. LH phase, regardless of group (HH, 7.7 ± 3.5%; LH, 7.0 ± 3.3%; = 0.02); however, allometric scaling for baseline diameter resulted in no phase effect (HH, 7.6 ± 2.6%; LH, 7.1 ± 2.6%; = 0.052, = 0.35). SFA FMD, BA, and SFA smooth muscle function, arterial stiffness, and eNOS and ERα protein content were unaffected. NAT and OCP phases examined have minimal influence on vascular outcomes and ERα-eNOS pathway, apart from a small effect on BA endothelial function partially explained by differences in baseline artery diameter. Comprehensive evaluation of the cardiovascular system in naturally cycling and second and third generation OCP users indicates no major influence of hormonal phases examined on endothelial function and smooth muscle function in the arteries of the upper and lower limbs, arterial stiffness, or underlying cellular mechanisms. Study findings challenge the historical exclusion of female participants due to potentially confounding hormonal cycles; researchers are encouraged to consider the hormonal environment in future study design.
过去研究中女性被排除在外，部分原因是认为自然月经（NAT）周期和口服避孕药（OCP）周期会对血管结局产生影响。NAT和OCP周期阶段可能会影响肱动脉（BA）内皮功能，然而，研究结果并不一致。极少有研究考察动脉僵硬度、平滑肌以及下肢内皮功能。本研究的目的是调查NAT和OCP周期对心血管结局及细胞调节的影响。49名绝经前女性（ = 17名处于自然月经周期， = 17名使用第二代OCP， = 15名使用第三代OCP）在低激素周期阶段（LH，卵泡早期/安慰剂）和高激素周期阶段（HH，黄体中期/活性药物）以随机顺序参与了两次访视。评估了BA和股浅动脉（SFA）的内皮功能[血流介导的扩张（FMD）试验]、平滑肌功能（硝酸甘油介导的扩张试验）以及颈动脉和外周动脉僵硬度（脉搏波速度）。将培养的女性人内皮细胞暴露于参与者血清24小时，以检测内皮型一氧化氮合酶（eNOS）和雌激素受体-α（ERα）蛋白含量。无论组别如何，HH期的BA FMD均高于LH期（HH，7.7±3.5%；LH，7.0±3.3%； = 0.02）；然而，对基线直径进行异速生长标度后未发现周期阶段效应（HH，7.6±2.6%；LH，7.1±2.6%； = 0.052， = 0.35）。SFA FMD、BA和SFA平滑肌功能、动脉僵硬度以及eNOS和ERα蛋白含量均未受影响。除了对BA内皮功能有微小影响（部分可由基线动脉直径差异解释）外，所考察的NAT和OCP周期阶段对血管结局及ERα - eNOS途径影响极小。对自然月经周期女性以及第二代和第三代OCP使用者的心血管系统进行综合评估表明，所考察的激素周期阶段对上下肢动脉的内皮功能、平滑肌功能、动脉僵硬度或潜在细胞机制无重大影响。研究结果对过去因潜在混淆的激素周期而将女性参与者排除在外的做法提出了挑战；鼓励研究人员在未来研究设计中考虑激素环境。
