Blood pressure responses to handgrip exercise but not apnea or mental stress are enhanced in women with a recent history of preeclampsia.

Preeclampsia is a risk factor for future cardiovascular diseases. However, the mechanisms underlying this association remain unclear, limiting effective prevention strategies. Blood pressure responses to acute stimuli may reveal cardiovascular dysfunction not apparent at rest, identifying individuals at elevated cardiovascular risk. Therefore, we compared blood pressure responsiveness to acute stimuli between previously preeclamptic (PPE) women (34±5yr, 13±6 months postpartum) and women following healthy pregnancies (CTRL; 29±3yr, 15±4 months postpartum). Blood pressure (finger photoplethysmography calibrated to manual sphygmomanometry-derived values; PPE: n=12, CTRL: n=12) was assessed during end-expiratory apnea, mental stress, and isometric handgrip exercise protocols. Integrated muscle sympathetic nerve activity (MSNA) was assessed in a subset of participants (peroneal nerve microneurography; PPE: n=6, CTRL: n=8). Across all protocols, systolic blood pressure (SBP) was higher in PPE than CTRL (main effects of group all P<0.05). Peak changes in SBP were stressor-specific: peak increases in SBP were not different between PPE and CTRL during apnea (+8±6 vs. +6±5mmHg, P=0.32) or mental stress (+9±5 vs. +4±7mmHg, P=0.06). However, peak exercise-induced increases in SBP were greater in PPE than CTRL (+11±5 vs. +7±7mmHg, P=0.04). MSNA was higher in PPE than CTRL across all protocols (main effects of group all P<0.05), and increases in peak MSNA were greater in PPE than CTRL during apnea (+44±6 vs. +27±14burst/100hb, P=0.04) and exercise (+25±8 vs. +13±11burst/100hb, P=0.01) but not different between groups during mental stress (+2±3 vs. 0±5burst/100hb, P=0.41). Exaggerated pressor and sympathetic responses to certain stimuli may contribute to the elevated long-term risk for cardiovascular disease in PPE.

Guidelines on the use of sex and gender in cardiovascular research.

In cardiovascular research, sex and gender have not typically been considered in research design and reporting until recently. This has resulted in clinical research findings from which not only all women, but also gender-diverse individuals have been excluded. The resulting dearth of data has led to a lack of sex- and gender-specific clinical guidelines and raises serious questions about evidence-based care. Basic research has also excluded considerations of sex. Including sex and/or gender as research variables not only has the potential to improve the health of society overall now, but it also provides a foundation of knowledge on which to build future advances. The goal of this guidelines article is to provide advice on best practices to include sex and gender considerations in study design, as well as data collection, analysis, and interpretation to optimally establish rigor and reproducibility needed to inform clinical decision-making and improve outcomes. In cardiovascular physiology, incorporating sex and gender is a necessary component when optimally designing and executing research plans. The guidelines serve as the first guidance on how to include sex and gender in cardiovascular research. We provide here a beginning path toward achieving this goal and improve the ability of the research community to interpret results through a sex and gender lens to enable comparison across studies and laboratories, resulting in better health for all.

The Biological Basis of Sex Differences in Athletic Performance: Consensus Statement for the American College of Sports Medicine.

ABSTRACT: Biological sex is a primary determinant of athletic performance because of fundamental sex differences in anatomy and physiology dictated by sex chromosomes and sex hormones. Adult men are typically stronger, more powerful, and faster than women of similar age and training status. Thus, for athletic events and sports relying on endurance, muscle strength, speed, and power, males typically outperform females by 10%-30% depending on the requirements of the event. These sex differences in performance emerge with the onset of puberty and coincide with the increase in endogenous sex steroid hormones, in particular testosterone in males, which increases 30-fold by adulthood, but remains low in females. The primary goal of this consensus statement is to provide the latest scientific knowledge and mechanisms for the sex differences in athletic performance. This review highlights the differences in anatomy and physiology between males and females that are primary determinants of the sex differences in athletic performance and in response to exercise training, and the role of sex steroid hormones (particularly testosterone and estradiol). We also identify historical and nonphysiological factors that influence the sex differences in performance. Finally, we identify gaps in the knowledge of sex differences in athletic performance and the underlying mechanisms, providing substantial opportunities for high-impact studies. A major step toward closing the knowledge gap is to include more and equitable numbers of women to that of men in mechanistic studies that determine any of the sex differences in response to an acute bout of exercise, exercise training, and athletic performance.

Testosterone-associated blood pressure dysregulation in women with androgen excess polycystic ovary syndrome.

We tested the hypothesis that hyperandrogenemia in androgen excess polycystic ovary syndrome (AE-PCOS) is a primary driver in blood pressure (BP) dysregulation via altered sympathetic nervous system activity (SNSA), reduced integrated baroreflex gain and increased renin-angiotensin system (RAS) activation. We measured resting SNSA (microneurography), integrated baroreflex gain, and RAS with lower body negative pressure in obese insulin-resistant (IR) women with AE-PCOS [n = 8, 23 ± 4 yr; body mass index (BMI) = 36.3 ± 6.4 kg/m2] and obese IR controls (n = 7, control, 29 ± 7 yr; BMI = 34.9 ± 6.8 kg/m2), at baseline (BSL), after 4 days of gonadotropin-releasing hormone antagonist (ANT, 250 µg/day) and 4 days of ANT + testosterone (ANT + T, 5 mg/day) administration. Resting BP was similar between groups for systolic blood pressure (SBP; 137 ± 14 vs. 135 ± 14 mmHg, AE-PCOS, control) and diastolic BP (89 ± 21 vs. 76 ± 10 mmHg, AE-PCOS, control). BSL integrated baroreflex gain was similar between groups [1.4 ± 0.9 vs. 1.0 ± 1.3 forearm vascular resistance (FVR) U/mmHg], but AE-PCOS had lower SNSA (10.3 ± 2.0 vs. 14.4 ± 4.4 burst/100 heartbeats, P = 0.04). In AE-PCOS, T suppression increased integrated baroreflex gain, which was restored to BSL with ANT + T (4.3 ± 6.5 vs. 1.5 ± 0.8 FVR U/mmHg, ANT, and ANT + T, P = 0.04), with no effect in control. ANT increased SNSA in AE-PCOS (11.2 ± 2.4, P = 0.04). Serum aldosterone was greater in AE-PCOS versus control (136.5 ± 60.2 vs. 75.7 ± 41.4 pg/mL, AE-PCOS, control, P = 0.04) at BSL but was unaffected by intervention. Serum angiotensin-converting enzyme was greater in AE-PCOS versus control (101.9 ± 93.4 vs. 38.2 ± 14.7 pg/mL, P = 0.04) and reduced by ANT in AE-PCOS (77.7 ± 76.5 vs. 43.4 ± 27.3 µg/L, ANT, and ANT + T, P = 0.04) with no impact on control. Obese, IR women with AE-PCOS showed decreased integrated baroreflex gain and increased RAS activation compared with control.NEW & NOTEWORTHY Here we present evidence for an important role of testosterone in baroreflex control of blood pressure and renal responses to baroreceptor unloading in women with a common, high-risk androgen excess polycystic ovary syndrome (AE-PCOS) phenotype. These data indicate a direct effect of testosterone on the vascular system of women with AE-PCOS independent of body mass index (BMI) and insulin-resistant (IR). Our study indicates that hyperandrogenemia is a central underlining mechanism of heightened cardiovascular risk in women with PCOS.

Effects of androgen excess and body mass index on endothelial function in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be established. Therefore, we 1) compared endothelial function between lean and overweight/obese (OW/OB) women with and without androgen excess (AE)-PCOS and 2) examined androgens as potential modulators of endothelial function in these women. The flow-mediated dilation (FMD) test was applied in 14 women with AE-PCOS (lean: n = 7; OW/OB: n = 7) and 14 controls (CTRL; lean: n = 7, OW/OB: n = 7) at baseline (BSL) and following 7 days of ethinyl estradiol supplementation (EE; 30 µg/day) to assess the effect of a vasodilatory therapeutic on endothelial function; at each time point we assessed peak increases in diameter during reactive hyperemia (%FMD), shear rate, and low flow-mediated constriction (%LFMC). BSL %FMD was attenuated in lean AE-PCOS versus both lean CTRL (5.2 ± 1.5 vs. 10.3 ± 2.6%, P < 0.01) and OW/OB AE-PCOS (5.2 ± 1.5 vs. 6.6 ± 0.9%, P = 0.048). A negative correlation between BSL %FMD and free testosterone was observed in lean AE-PCOS only (R2 = 0.68, P = 0.02). EE increased %FMD in both OW/OB groups (CTRL: 7.6 ± 0.6 vs. 10.4 ± 2.5%, AE-PCOS: 6.6 ± 0.9 vs. 9.6 ± 1.7%, P < 0.01), had no impact on %FMD in lean AE-PCOS (5.17 ± 1.5 vs. 5.17 ± 1.1%, P = 0.99), and reduced %FMD in lean CTRL (10.3 ± 2.6 vs. 7.6 ± 1.2%, P = 0.03). Collectively, these data indicate that lean women with AE-PCOS exhibit more severe endothelial dysfunction than their OW/OB counterparts. Furthermore, endothelial dysfunction appears to be mediated by circulating androgens in lean but not in OW/OB AE-PCOS, suggesting a difference in the endothelial pathophysiology of AE-PCOS between these phenotypes.NEW & NOTEWORTHY We present evidence for marked endothelial dysfunction in lean women with androgen excess polycystic ovary syndrome (AE-PCOS) that is 1) associated with free testosterone levels, 2) impaired relative to overweight/obese women with AE-PCOS, and 3) unchanged following short-term ethinyl estradiol supplementation. These data indicate an important direct effect of androgens on the vascular system in women with AE-PCOS. Our data also suggest that the relationship between androgens and vascular health differs between phenotypes of AE-PCOS.

Correlations between salivary- and blood-derived gonadal hormone assessments and implications for inclusion of female participants in research studies.

Even in the 21st century, female participants continue to be underrepresented in human physiology research. This underrepresentation is attributable in part to the perception that the inclusion of females is more time consuming, less convenient, and more expensive relative to males because of the need to account for the menstrual cycle in cardiovascular study designs. Accounting for menstrual cycle-induced fluctuations in gonadal hormones is important, given established roles in governing vascular function and evidence that failure to consider gonadal hormone fluctuations can result in misinterpretations of biomarkers of cardiovascular disease. Thus, for cardiovascular researchers, the inclusion of females in research studies implies a necessity to predict, quantify, and/or track indexes of menstrual cycle-induced changes in hormones. It is here that methodologies are lacking. Gold standard measurement requires venous blood samples, but this technique is invasive and can become both expensive and technically preclusive when serial measurements are required. To this end, saliva-derived measures of gonadal hormones provide a means of simple, noninvasive hormone tracking. To investigate the feasibility of this technique as a means of facilitating research designs that take the menstrual cycle into account, the purpose of this review was to examine literature comparing salivary and blood concentrations of the primary gonadal hormones that fluctuate across the menstrual cycle: estradiol and progesterone. The data indicate that there appear to be valid and promising applications of salivary gonadal hormone monitoring, which may aid in the inclusion of female participants in cardiovascular research studies.

Precision medicine requires understanding how both sex and gender influence health.

Progress in studying sex as a biological variable (SABV) is slow, and the influence of gendered effects of the social environment on biology is largely unknown. Yet incorporating these concepts into basic science research will enhance our understanding of human health and disease. We provide steps to move this process forward.

Are there sex differences in risk for exertional heat stroke? A translational approach.

NEW FINDINGS: What is the topic of this review? Whether there are sex differences in exertional heat stroke. What advances does it highlight? This review utilizes a translational model between animal and human research to explore possible physical and physiological differences with respect to risk and treatment of exertional heat stroke. ABSTRACT: Exertional heat stroke (EHS) is a potentially fatal condition brought about by a combination of physical activity and heat stress and resulting in central nervous system dysfunction and organ damage. EHS impacts several hundred individuals each year ranging from military personnel, athletes, to occupational workers. Understanding the pathophysiology and risk factors can aid in reducing EHS across the globe. While we know there are differences between sexes in mechanisms of thermoregulation, there is currently not a clear understanding of if or how those differences impact EHS risk. The purpose of this review is to assess the current status of the literature surrounding EHS from risk factors to treatment using both animal and human models. We use a translational approach, considering both animal and human research to elucidate the possible influence of female sex hormones on temperature regulation and performance in the heat and highlight the specific areas with limited research. While more work is necessary to comprehensively understand these differences, the current research presented provides a good framework for future investigations.

Pathophysiological effects of androgens on the female vascular system.

Sex hormones and their respective receptors affect vascular function differently in men and women, so it is reasonable to assume they play a role in the sex differences in cardiovascular disease states. This review focuses on how the effects of testosterone on arterial vessels impact the female vasculature. In women with androgen-excess polycystic ovary syndrome, and in transgender men, testosterone exposure is associated with high blood pressure, endothelial dysfunction, and dyslipidemia. These relationships suggest that androgens may exert pathophysiological effects on the female vasculature, and these effects on the female vasculature appear to be independent from other co-morbidities of cardiovascular disease. There is evidence that the engagement of androgens with androgen receptor induces detrimental outcomes in the female cardiovascular system, thereby representing a potential causative link with sex differences and cardiovascular regulation. Gender affirming hormone therapy is the primary medical intervention sought by transgender people to reduce the characteristics of their natal sex and induce those of their desired sex. Transgender men, and women with androgen-excess polycystic ovary syndrome both represent patient groups that experience chronic hyperandrogenism and thus lifelong exposure to significant medical risk. The study of testosterone effects on the female vasculature is relatively new, and a complex picture has begun to emerge. Long-term research in this area is needed for the development of more consistent models and controlled experimental designs that will provide insights into the impact of endogenous androgen concentrations, testosterone doses for hormone therapy, and specific hormone types on function of the female cardiovascular system.

Menstrual cycle and thermoregulation during exercise in the heat: A systematic review and meta-analysis.

Research conducted on exercise in the heat has been largely conducted in males, leaving women understudied. Of research including women, results are inconsistent on the impact of menstrual cycle phase on thermoregulation. OBJECTIVES: The purpose of this systematic review is to quantify published investigations in thermal physiology that include menstrual cycle comparisons and assess aggregate data of investigations that include menstrual cycle variation and aerobic exercise in the heat. METHODS: 367 research articles were identified via systematic review and inclusion criteria and yielded 9 papers included in this analysis for a total number of 83 research subjects. Effect size estimates (Hedge's g) were utilized for initial (pre-exercise) and post-exercise internal body temperature (rectal or esophageal, Tint), sweat rate, mean skin temperature, and exercise heart rate. RESULTS: Pooled effect size showed significantly greater initial Tint (1.231±0.186, p<0.01) and post-exercise Tint (0.455±0.153, p<0.01) in the luteal compared to follicular phases. No significant differences were present in mean skin temperature, sweat rate, or exercise heart rate across menstrual phases in analyses of aggregate data. CONCLUSIONS: The limited available data suggest that observed increases in initial Tint in the luteal phase are maintained throughout and post-exercise without an observed impact in sweat rate or mean skin temperature.

A recent history of preeclampsia is associated with elevated central pulse wave velocity and muscle sympathetic outflow.

Preeclampsia is associated with the development of cardiovascular diseases later in life. To investigate this phenomenon, we compared established markers of cardiovascular dysregulation between previously preeclamptic women (PPE; n = 12, 13 ± 6 mo postpartum, 34 ± 6 yr) and women who had previously had an uncomplicated pregnancy [control (CTRL); n = 12, 15 ± 4 mo postpartum; 29 ± 3 yr]. We hypothesized that PPE would present with elevated arterial stiffness (assessed as central and peripheral pulse wave velocity) and muscle sympathetic nerve activity (MSNA; microneurography) and blunted baroreflex sensitivity (BRS) relative to CTRL. Blood pressure (Finometer) was similar between PPE and CTRL (mean arterial pressure: 94 ± 11 vs. 89 ± 9, P = 0.16). Central (6.92 ± 0.21 vs. 6.24 ± 0.22 m/s, P = 0.04) but not peripheral arterial stiffness (7.52 ± 0.19 vs. 7.09 ± 0.19 m/s, P = 0.13) was elevated in PPE versus CTRL (values normalized to MAP). MSNA was also elevated in PPE versus CTRL (22 ± 7 vs. 13 ± 5 bursts/min, P = 0.01), although this was independent of arterial stiffness (central: r2 = 0.01, P = 0.74; peripheral: r2 = 0.01, P = 0.74). Cardiovagal BRS was blunted in PPE versus CTRL (15 ± 5 vs. 28 ± 1 ms/mmHg, P = 0.01), whereas sympathetic vascular BRS was similar (-3.2 ± 0.9 vs. -3.1 ± 1.4 bursts·100 hb-1·mmHg-1, P = 0.88). Cardiovagal and sympathetic BRS were inversely correlated in both CTRL (r2 = 0.43; P = 0.05) and PPE (r2 = 0.69; P = 0.04), supporting a compensatory mechanism resulting in normal blood pressures in both groups. Overall, these data indicate that PPE retain their ability to buffer elevated MSNA. We propose that the higher incidence of cardiovascular disease observed later in life in PPE results from this arterial stiffness, combined with the loss of protective vascular mechanisms and the "unmasking" of high MSNA.NEW & NOTEWORTHY We demonstrate that resting muscle sympathetic nerve activity is elevated in women with a recent history of preeclampsia relative to women who have recently had uncomplicated pregnancies and without a history of preeclampsia. Structural changes in the central arteries are associated with arterial stiffness following preeclampsia, independent of changes in the sympathetic nervous system. The structural changes are observed in these relatively young previously preeclamptic women, indicating elevated cardiovascular risk. Our data suggest that with aging (and the gradual loss of vascular protection for women, as established by others), this risk will become exaggerated compared with women who have had normal pregnancies.

Compromised endothelial function in transgender men taking testosterone.

CONTEXT: Transgender men (TGM) are persons assigned female gender at birth with a male gender identity and are routinely treated with testosterone. Androgen excess is associated with endothelial dysfunction among cisgender females (CGF) and is an early sign of atherosclerosis and hypertension. OBJECTIVE: To determine the effect of testosterone treatment on endothelial function in TGM. SETTING: The John B. Pierce Laboratory and Yale School of Medicine. SUBJECTS: Eleven TGM (age 27 ± 5 years; BMI 24.4 ± 3.7 kg/m2 ) receiving testosterone (T) and 20 CGF (28 ± 5 years; BMI 26.0 ± 5.1 kg/m2 ) during the early follicular phase of their menstrual cycle. DESIGN AND OUTCOME MEASURES: We evaluated brachial vasodilatory responses following stimuli designed to elicit shear stress using 5-minute occlusion to determine endothelial function (flow-mediated vasodilation, FMD). RESULTS: Total T was greater in the TGM compared to CGF (484.6 ± 122.5 vs 1.5 ± 0.7 ng/dL), as was free T (83.9 ± 32.4 vs 1.9 ± 0.8 pg/dL). FMD was markedly lower in the TGM (4.5 ± 2.7%) compared to the CGF (8.1 ± 2.9%, P = .002) indicating significantly diminished endothelial function in TGM. CONCLUSIONS: We have shown for the first time that in TGM the androgen-dominant hormonal milieu was associated with impaired endothelial function. Endothelial dysfunction precedes clinically detectable atherosclerotic plaque in the coronary arteries, so is an important marker for clinical cardiovascular risk. Therefore, attention to cardiovascular risk factors should be integral to the care of transgender men.