Menstrual and oral contraceptive pill cycles minimally influence vascular function and associated cellular regulation in premenopausal females.

BACKGROUND: 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. METHODS: Forty-nine premenopausal females (n=17 NAT, n=17 2nd generation OCP, n=15 3rd generation OCP) participated in two randomized order visits in the low (LH: early follicular/placebo) and high (HH: mid-luteal/active) hormone cycle phases. BA and 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 24h to examine endothelial nitric oxide synthase (eNOS) and estrogen receptor alpha (ERα) protein content. RESULTS: BA FMD was elevated in the HH versus LH phase, regardless of group (HH:7.7±3.5%, LH:7.0±3.3%, p=0.02); however, allometric scaling for baseline diameter resulted in no phase effect (HH:7.6±2.6%, LH:7.1±2.6%, p=0.052, d=0.35). SFA FMD, BA and SFA smooth muscle function, arterial stiffness, and eNOS and ERα protein content were unaffected. CONCLUSIONS: 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.

The impacts of endogenous progesterone and exogenous progestin on vascular endothelial cell, and smooth muscle cell function: A narrative review.

Vascular endothelial and smooth muscle cell dysfunction proceed the development of numerous vascular diseases, such as atherosclerosis. Both estrogen and progesterone receptors are present on vascular endothelial and smooth muscle cells, and therefore it has been postulated that these compounds may affect vascular function. It has been well-established that estrogen is a vasoprotective compound, however, the effects of progesterone on vascular function are not well understood. This narrative review summarizes the current research investigating the impact of both endogenous progesterone, and exogenous synthetic progestin on vascular endothelial and smooth muscle cell function and identifies discrepancies on their effects in vitro and in vivo. We speculate that an inverted-U dose response curve may exist between nitric oxide bioavailability and progesterone concentration, and that the androgenic properties of a progestin may influence vascular function. Future research is needed to discern the effects of both endogenous progesterone and exogenous progestin on vascular endothelial and smooth muscle cell function with consideration for the impacts of progesterone/progestin dose, and progestin type.

The impact of natural menstrual cycle and oral contraceptive pill phase on substrate oxidation during rest and acute submaximal aerobic exercise.

Previous research has identified sex differences in substrate oxidation during submaximal aerobic exercise including a lower respiratory exchange ratio (RER) in females compared with males. These differences may be related to differences in sex hormones. Our purpose was to examine the impact of the natural menstrual cycle (NAT) and second- and third-generation oral contraceptive pill (OCP2 and OCP3) cycle phases on substrate oxidation during rest and submaximal aerobic exercise. Fifty female participants (18 NAT, 17 OCP2, and 15 OCP3) performed two experimental trials that coincided with the low (i.e., nonactive pill/early follicular) and the high hormone (i.e., active pill/midluteal) phase of their cycle. RER and carbohydrate and lipid oxidation rates were determined from gas exchange measurements performed during 10 min of supine rest, 5 min of seated rest, and two 8-min bouts of submaximal cycling exercise at ∼40% and ∼65% of peak oxygen uptake (V̇o2peak). For all groups, there were no differences in RER between the low and high hormone phases during supine rest (0.73 ± 0.05 vs. 0.74 ± 0.05), seated rest (0.72 ± 0.04 vs. 0.72 ± 0.04), exercise at 40% (0.77 ± 0.04 vs. 0.78 ± 0.04), and 65% V̇o2peak (0.85 ± 0.04 vs. 0.86 ± 0.03; P > 0.19 for all). Similarly, carbohydrate and lipid oxidation rates remained largely unchanged across phases during both rest and exercise, apart from higher carbohydrate oxidation in NAT vs. OCP2 at 40% V̇o2peak (P = 0.019) and 65% V̇o2peak (P = 0.001). NAT and OCPs do not appear to largely influence substrate oxidation at rest and during acute submaximal aerobic exercise.NEW & NOTEWORTHY This study was the first to examine the influence of NAT and two generations of OCPs on substrate oxidation during rest and acute submaximal aerobic exercise. We reported no differences across cycle phases or groups on RER, and minimal impact on carbohydrate or lipid oxidation apart from an increase in carbohydrate oxidation in NAT compared with OCP2 during exercise. Based on these findings, NAT/OCP phase controls may not be necessary in studies investigating substrate oxidation.

Examination of Sex-Specific Participant Inclusion in Exercise Physiology Endothelial Function Research: A Systematic Review.

Background: To combat historical underrepresentation of female participants in research, guidelines have been established to motivate equal participation by both sexes. However, the pervasiveness of female exclusion has not been examined in vascular exercise physiology research. The purpose of this study was to systematically quantify the sex-specific prevalence of human participants and identify the rationales for sex-specific inclusion/exclusion in research examining the impact of exercise on vascular endothelial function. Methods: A systematic search was conducted examining exercise/physical activity and vascular endothelial function, assessed via flow mediated dilation. Studies were categorized by sex: male-only, female-only, or mixed sex, including examination of the sample size of males and females. Analysis was performed examining sex-inclusion criteria in study design and reporting and rationale for inclusion/exclusion of participants on the basis of sex. Changes in proportion of female participants included in studies were examined over time in 5 year cohorts. Results: A total of 514 studies were identified, spanning 26 years (1996-2021). Of the total participants, 64% were male and 36% were female, and a male bias was identified (32% male-only vs. 12% female-only studies). Proportions of female participants in studies remained relatively constant in the last 20 years. Male-only studies were less likely to report sex in the title compared to female-only studies (27 vs. 78%, p < 0.001), report sex in the abstract (72 vs. 98%, p < 0.001) and justify exclusion on the basis of sex (15 vs. 55%, p < 0.001). Further, male-only studies were more likely to be conducted in healthy populations compared to female-only studies (p = 0.002). Qualitative analysis of justifications identified four themes: sex-specific rationale or gap in the literature, exclusion of females based on the hormonal cycle or sex-differences, maintaining congruence with the male norm, and challenges with recruitment, retention and resources. Conclusions: This systematic review provides the first analysis of sex-based inclusion/exclusion and rationale for sex-based decisions in human vascular exercise physiology research. These findings contribute to identifying the impact of research guidelines regarding inclusion of males and females and the perceived barriers to designing studies with equal sex participation, in an effort to increase female representation in vascular exercise physiology research. Systematic Review Registration: CRD42022300388.