Association between serum estradiol and cardiovascular health among transgender adults using gender-affirming estrogen therapy.

Gender-affirming estrogen therapy (GAET) is commonly used for feminization in transgender and nonbinary (TNB) individuals, yet the optimal rate of change (ROC) in estradiol levels for cardiovascular health is unclear. We examined the association between serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were systematically searched (inception-April 2023) for original articles reporting serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Data extraction was completed in duplicate following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Stratified random effect meta-analyses using serum estradiol ROC (serum estradiolbaseline - serum estradiolfollow-up/study duration) was used to assess longitudinal studies (low, 0 < ROC ≤ 1 pg/mL/mo; moderate, 1 < ROC ≤ 3 pg/mL/mo; high, ROC ≥ 3 pg/mL/mo). Thirty-five studies (13 cross-sectional, 19 cohort, and 3 trials) were included. Two studies collectively reported 50 cardiovascular-related deaths, and four collectively reported 23 adverse cardiovascular events. Nineteen studies reporting cardiovascular risk factors were meta-analyzed by ROC stratum (low = 5; moderate = 6; high = 8), demonstrating an association between moderate [0.40, 95% confidence interval (CI): 0.22, 0.59 kg/m2, I2 = 28.2%] and high (0.46, 95% CI: 0.15, 0.78 kg/m2; I2 = 0.0%) serum estradiol ROC and increased body mass index. High (-6.67, 95% CI: -10.65, -2.68 mg/dL; I2 = 0.0%) serum estradiol ROC was associated with decreased low-density lipoproteins. Low (-7.05, 95% CI: -10.40, -3.70 mmHg; I2 = 0.0%) and moderate (-3.69, 95% CI: -4.93, -2.45 mmHg; I2 = 0.0%) serum estradiol ROCs were associated with decreases in systolic blood pressure. In TNB adults using GAET, serum estradiol ROC may influence cardiovascular risk factors, which may have implications for clinical cardiovascular outcomes.NEW & NOTEWORTHY In this systematic review and meta-analysis of 35 studies involving 7,745 participants, high rates of serum estradiol change were associated with small increases in body mass index. Moderate to high rates of change were associated with decreases in low-density lipoprotein. Low rates of change were associated with small decreases in systolic blood pressure. Rate of serum estradiol change in adults using gender-affirming estrogen therapy may influence cardiovascular risk factors, though further research is warranted.

Improving the inclusion of transgender and nonbinary individuals in the planning, completion, and mobilization of cardiovascular research.

Cardiovascular disease is the leading cause of morbidity and mortality globally. Transgender and nonbinary (TNB) individuals face unclear but potentially significant cardiovascular health inequities, yet no TNB-specific evidence-based interventions for cardiovascular risk reduction currently exist. To address this gap, we propose a road map to improve the inclusion of TNB individuals in the planning, completion, and mobilization of cardiovascular research. In doing so, the adoption of inclusive practices would optimize cardiovascular health surveillance and care for TNB communities.

Gender-affirming estrogen therapy route of administration and cardiovascular risk: a systematic review and narrative synthesis.

Transgender women (individuals assigned male sex at birth who identify as women) and nonbinary and gender-diverse individuals receiving gender-affirming estrogen therapy (GAET) are at increased cardiovascular risk. Nonoral (i.e., patch, injectable) compared with oral estrogen exposure in cisgender women (individuals assigned female sex at birth who identify as women) may be associated with lower cardiovascular risk, though whether this applies to transgender women and/or gender-diverse individuals is unknown. We sought to determine the association between the route of estrogen exposure (nonoral compared with oral) and cardiovascular risk in transgender women and gender diverse individuals. Bibliographic databases (MEDLINE, Embase, PsycINFO) and supporting relevant literature were searched from inception to January 2022. Randomized controlled trials and observational studies reporting cardiovascular outcomes, such as all-cause and cardiovascular mortality, adverse cardiovascular events, and cardiovascular risk factors in individuals using nonoral compared with oral gender-affirming estrogen therapy were included. The search strategy identified 3,113 studies, 5 of which met inclusion criteria (3 prospective cohort studies, 1 retrospective cohort study, and 1 cross-sectional study; n = 259 participants, range of duration of exposure of 2 to 60 mo). One out of five studies reported on all-cause and cardiovascular mortality or adverse cardiovascular events. All five studies reported lipid levels [low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC)], whereas only two studies reported systolic blood pressure (SBP) and diastolic blood pressure (DBP). Limited studies have examined the effect of the route of GAET on all-cause cardiovascular mortality, morbidity, and risk factors. In addition, there is significant heterogeneity in studies examining the cardiovascular effects of GAET.NEW & NOTEWORTHY This study is the first to summarize the potential effect of nonoral versus oral gender-affirming estrogen therapy use on cardiovascular risk factors in transgender women or nonbinary or gender-diverse individuals. Heterogeneity of studies in reporting gender-affirming estrogen therapy formulation, dose, and duration of exposure limits quantification of the effect of gender-affirming estrogen therapy on all-cause and cardiovascular mortality, adverse cardiovascular events, and cardiovascular risk factors. This systematic review highlights the needs for large prospective cohort studies with appropriate stratification of gender-affirming estrogen therapy by dose, formulation, administration route, and sufficient follow-up and analyses to limit selection bias to optimize the cardiovascular care of transgender, nonbinary, and gender-diverse individuals.

Differential effects of high-altitude exposure on markers of oxidative stress, antioxidant capacity, and iron profiles.

High-altitude (HA) exposure may stimulate significant physiological and molecular changes, resulting in HA-related illnesses. HA may impact oxidative stress, antioxidant capacity, and iron homeostasis, yet it is unclear how both repeated exposure and HA acclimatization may modulate such effects. Therefore, we assessed the effects of weeklong repeated daily HA exposure (2,900-5,050 m) in altitude-naïve individuals (n = 21 individuals, 13 females, mean ± SD, 25.3 ± 3.7 yr) to mirror the working schedule of HA workers (n = 19 individuals, all males, 41.1 ± 9.4 yr) at the Atacama Large Millimeter Array (ALMA) Observatory (San Pedro de Atacama, Chile). Markers of oxidative stress, antioxidant capacity, and iron homeostasis were measured in blood plasma. Levels of protein oxidation (P < 0.001) and catalase activity (P = 0.023) increased and serum iron (P < 0.001), serum ferritin (P < 0.001), and transferrin saturation (P < 0.001) levels decreased with HA exposure in both groups. HA workers had lower levels of oxidative stress, and higher levels of antioxidant capacity, iron supply, and hemoglobin concentration as compared with altitude-naïve individuals. On a second week of daily HA exposure, changes in levels of protein oxidation, glutathione peroxidase, and nitric oxide metabolites were lower as compared with the first week in altitude-naïve individuals. These results indicate that repeated exposure to HA may significantly alter oxidative stress and iron homeostasis, and the degree of such changes may be dependent on if HA is visited naïvely or routinely. Further studies are required to fully elucidate differences in HA-induced changes in oxidative stress and iron homeostasis profiles among visitors of HA.

Transgender and Nonbinary Individuals' Perceptions Regarding Gender-Affirming Hormone Therapy and Cardiovascular Health: A Qualitative Study.

BACKGROUND: Transgender and nonbinary individuals face substantial cardiovascular health uncertainties. The use of gender-affirming hormone therapy can be used to achieve one's gender-affirming goals. As self-rated health is an important predictor of health outcomes, an understanding of how this association is perceived by transgender and nonbinary individuals using gender-affirming hormone therapy is required. The objective of this research was to explore transgender and nonbinary individuals' perceptions of cardiovascular health in the context of using gender-affirming hormone therapy. METHODS: In this qualitative study, English-speaking transgender and nonbinary adults using gender-affirming hormone therapy for 3 months or more were recruited from across Canada using purposive and snowball sampling methods. Semistructured interviews were conducted through videoconference to explore transgender and nonbinary individuals' perceptions of the association between gender-affirming hormone therapy and cardiovascular health between May and August 2023. Data were transcribed verbatim, and transcripts were analyzed independently by 3 reviewers using thematic analysis. RESULTS: Twenty-one participants were interviewed (8 transgender women, 9 transgender men, and 3 nonbinary individuals; median [range] age, 27 [20-69] years; 80% White participants). Three main themes were identified: cardiovascular health was not a primary concern in the decision-making process with regard to gender-affirming hormone therapy, the improved well-being associated with gender-affirming hormone therapy was felt to contribute to improved cardiovascular health, and health care provider knowledge and attitude facilitate the transition process. CONCLUSIONS: Gender-affirming hormone therapy in transgender and nonbinary individuals is perceived to improve cardiovascular health. Given the positive associations between care aligned with patient priorities, self-rated health, and health outcomes, these findings should be considered as part of shared decision-making and person-centered care.

Characterization of the literature informing health care of transgender and gender-diverse persons: A bibliometric analysis.

BACKGROUND AND OBJECTIVE: Transgender and gender-diverse (TGD) persons experience health inequities compared to their cisgender peers, which is in part related to limited evidence informing their care. Thus, we aimed to describe the literature informing care provision of TGD individuals. DATA SOURCE, ELIGIBILITY CRITERIA, AND SYNTHESIS METHODS: Literature cited by the World Professional Association of Transgender Health Standards of Care Version 8 was reviewed. Original research articles, excluding systematic reviews (n = 74), were assessed (n = 1809). Studies where the population of interest were only caregivers, providers, siblings, partners, or children of TGD individuals were excluded (n = 7). Results were synthesized in a descriptive manner. RESULTS: Of 1809 citations, 696 studies met the inclusion criteria. TGD-only populations were represented in 65% of studies. White (38%) participants and young adults (18 to 29 years old, 64%) were the most well-represented study populations. Almost half of studies (45%) were cross-sectional, and approximately a third were longitudinal in nature (37%). Overall, the median number of TGD participants (median [IQR]: 104 [32, 356]) included in each study was approximately one third of included cisgender participants (271 [47, 15405]). In studies where both TGD and cisgender individuals were included (n = 74), the proportion of TGD to cisgender participants was 1:2 [1:20, 1:1]. Less than a third of studies stratified results by sex (32%) or gender (28%), and even fewer included sex (4%) or gender (3%) as a covariate in the analysis. The proportion of studies with populations including both TGD and cisgender participants increased between 1969 and 2023, while the proportion of studies with study populations of unspecified gender identity decreased over the same time period. CONCLUSIONS: While TGD participant-only studies make up most of the literature informing care of this population, longitudinal studies including a diversity of TGD individuals across life stages are required to improve the quality of evidence.

The Effect of Biological Sex on Arterial Stiffness and Renin-Angiotensin-Aldosterone System Activity in Response to Cyclooxygenase-2 (COX-2) Inhibition.

Background: Cardiovascular disease is the leading cause of death globally. Cyclooxygenase (COX)-derived prostaglandins play an important role in cardiovascular health regulation. Animal studies suggest a greater vascular dependence on prostaglandins in female subjects, but whether this extends to humans is unknown. We aimed to assess the effect of COX-2 inhibition on blood pressure and arterial stiffness, validated markers of cardiovascular risk, in human adults. Methods: Healthy premenopausal females and males were studied in high-salt balance before and after 14 days of daily oral celecoxib, 200 mg ingestion, on 2 identical study days. Blood pressure (BP) and pulse-wave velocity (PWV) were measured at baseline and in response to an Angiotensin II (AngII) challenge, a validated marker of renin-angiotensin-aldosterone system activity. Results: Thirteen females (age [mean ± standard deviation], 38 ± 13 years) and 11 males (age, 34 ± 9 years) were studied. Pre-COX-2 inhibition, resting measures of systolic (S)BP (P = 0.2) and diastolic (D)BP (P = 0.1) were similar between sexes. Post-COX-2 inhibition, resting SBP (P < 0.001) and DBP (P = 0.02) were significantly lower in females than in males. COX-2 inhibition was not associated with changes in arterial parameters by sex (change in DBP: P = 0.54; change in PWV: P = 0.55; females vs males). COX-2 inhibition was associated with increased SBP (P = 0.039 vs pre-COX-2 inhibition), but no change in DBP (P = 0.16) or PWV (P = 0.52) response to AngII challenge in females. Measures did not differ in response to AngII pre- vs post-COX-2 inhibition in males (SBP: P = 0.88; DBP: P = 0.93; PWV: P = 0.97). Conclusions: The effects of COX-2 inhibition on arterial function may differ by sex, but further studies are needed. Given the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk, increased attention regarding sex-specific pathophysiology is warranted.

Contexte: Les maladies cardiovasculaires sont la principale cause de décès dans le monde. Les prostaglandines dérivées de la cyclo-oxygénase (COX) jouent un rôle important dans la régulation de la santé cardiovasculaire. Des études menées chez l'animal suggèrent une plus grande dépendance vasculaire aux prostaglandines chez les femelles, mais on ne sait pas si ces observations s'appliquent à l'humain. Notre objectif était d'évaluer les effets de l'inhibition de la COX-2 sur la pression artérielle et la rigidité artérielle, des marqueurs validés du risque cardiovasculaire, chez l'humain adulte. Méthodologie: Des mâles et des femelles non ménopausées en bonne santé ayant un équilibre salin élevé ont été examinés lors de deux jours identiques de l'étude avant et après 14 jours de traitement par le célécoxib à raison de 200 mg par jour par voie orale. La pression artérielle (PA) et la vitesse de l'onde de pouls (VOP) ont été mesurées au départ et en réponse à une épreuve de provocation à l'angiotensine II, un marqueur validé de l'activité du système rénine-angiotensine-aldostérone. Résultats: Treize femelles (âge moyen ± écart-type, 38 ± 13 ans) et 11 mâles (âgé, 34 ± 9 ans) ont été étudiés. Avant l'inhibition de la COX-2, la PA systolique (PAS) (p = 0,2) et la PA diastolique (PAD) (p = 0,1) au repos étaient comparables chez les deux sexes. Après l'inhibition de la COX-2, la PAS (p < 0,001) et la PAD (p = 0,02) au repos étaient significativement plus basses chez les femelles que chez les mâles. L'inhibition de la COX-2 n'a pas été associée à des modifications des paramètres artériels en fonction du sexe (modification de la PAD : p = 0,54; modification de la VOP : p = 0,55; femelles vs mâles). L'inhibition de la COX-2 a été associée à une augmentation de la PAS (p = 0,039 vs avant l'inhibition de la COX-2), mais à aucun changement de la PAD (p = 0,16) ou de la VOP (p = 0,52), après une épreuve de provocation à l'angiotensine II chez les femelles. Les résultats en réponse à une épreuve de provocation à l'angiotensine II ne différaient pas avant et après l'inhibition de la COX-2 chez les mâles (PAS : p = 0,88; PAD : p = 0,93; VOP : p = 0,97). Conclusions: Les effets de l'inhibition de la COX-2 sur la fonction artérielle pourraient varier en fonction du sexe, mais d'autres études sont requises. Compte tenu du lien entre les anti-inflammatoires non stéroïdiens (AINS) et le risque cardiovasculaire, une attention accrue doit être accordée à la physiopathologie en fonction du sexe.

Menstrual Abnormalities and Reproductive Lifespan in Females with CKD: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Menstrual abnormalities and shortened reproductive lifespan are associated with shorter life expectancy and higher cardiovascular and osteoporosis risk in the general population, although the magnitude of these reproductive factor irregularities in females with CKD is unclear. This systematic review and meta-analysis aimed to summarize the current knowledge regarding menstrual abnormalities and reproductive lifespan among females with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A comprehensive bibliographic search (MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature [CINAHL]) was completed from database inception to February 2022 to identify all original articles reporting on females of reproductive age with nondialysis-dependent/nonkidney transplant CKD, dialysis-dependent CKD, or kidney transplantation and menstruation patterns, age of menarche, and/or menopause. Data extraction and study quality assessment were completed in duplicate. Random effects meta-analyses were used to derive pooled proportions estimates. RESULTS: Forty-six studies were identified, and 35 were meta-analyzed, stratified by KRT modality and reported outcome. Menstrual abnormalities were present in 19%-47% of patients on hemodialysis and 75% of patients on peritoneal dialysis. Kidney transplantation was associated with a 7%-30% decrease in menstrual abnormalities. Reproductive lifespan was 32 years (95% confidence interval, 30 to 34 years). Although significant heterogeneity was present, study quality ranged from fair to good, and no evidence of publication bias was noted. CONCLUSIONS: Menstrual abnormalities and shorter reproductive lifespan are common in females with CKD, although kidney transplantation may improve menstrual health.

Serum oestradiol levels and risk of adverse cardiovascular events associated with gender-affirming oestrogen therapy: a protocol for a systematic review and meta-analysis.

INTRODUCTION: The use of gender-affirming oestrogen therapy (GAOT) is an integral part of the gender-affirming transition process for transgender women (assigned male at birth who identify as women) and gender-diverse individuals. However, its use may present significant cardiovascular implications, which may be influenced by systemic oestradiol levels. Therefore, we aim to establish the association between serum oestradiol levels and incidence of adverse cardiovascular events in individuals using GAOT. METHODS AND ANALYSIS: We will conduct a systematic review addressing the association between serum oestradiol levels and risk of adverse cardiovascular events in individuals using GAOT. Our primary outcome is the incidence of adverse cardiovascular events, our secondary outcome is the incidence of cardiovascular-related mortality and our tertiary outcome is cardiovascular-related risk factors. Electronic databases (Cochrane Central Register of Controlled Trials, Embase, MEDLINE and Web of Science) will be searched from inception until September 2022. Two investigators will independently complete screening to determine appropriateness of inclusion. Extracted data will include information on serum sex hormone levels (oestradiol and testosterone), participants, GAOT (route of administration, formulations, dosages and duration of exposure), incidence of cardiovascular outcomes, study quality and risk of bias. Inter-reviewer reliability will be calculated at both phases. Data will be presented both descriptively and meta-analysed using a random effects model, if appropriate. Heterogeneity will be explored and meta-regressed if noted. ETHICS AND DISSEMINATION: Ethics approval is not needed. We will disseminate findings through international conferences, distributions to transgender and gender-diverse support organisations, decision-makers and key stakeholders. The final systematic review will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42021247717.

Effectiveness of an individualized home-based physical activity program in surgery-free non-endarterectomized asymptomatic stroke patients: a study protocol for the PACAPh interventional randomized trial.

BACKGROUND: Carotid atherosclerotic plaques remain silent until their rupture, which may lead to detrimental ischemic events such as strokes. This is due, in part, to intraplaque hemorrhages (IPH) and the resulting inflammatory processes, which may promote carotid plaque vulnerability. Currently, the benefits of carotid endarterectomy remain unclear for asymptomatic patients. Interestingly, the completion of physical activity (PA) may have beneficial effects; however, the paucity of current data warrants robust longitudinal interventions. We therefore aim to study the effects of a 6-month longitudinal personalized home-based PA program on IPH, biological, and inflammatory markers in asymptomatic stroke patients. METHODS: Eighty patients (≥ 18 years old) will be recruited for the Physical Activity and Carotid Atherosclerotic Plaque Hemorrhage (PACAPh) clinical trial from the Hospices Civils de Lyon. Patients will be eligible if they present with carotid stenosis ≥ 50% and are asymptomatic from any ischemic events for at least 6 months. Recruited patients will be randomized into either a PA or a control group, and assessed at baseline and after 6 months. At both time points, all patients will be assessed using magnetic resonance imaging to assess IPH, blood sampling to measure inflammatory markers and monocytic phenotyping, PA and sedentary behavior questionnaires, 6-min walking test, and maximal isometric quadricep contraction test. The randomized PA intervention will consist of reaching a daily walking step goal individually tailored to each patient. Steps will be collected using a wirelessly connected wristband. The number of steps completed by individuals in the PA group will be re-evaluated bimonthly to encourage walking habits. DISCUSSION: The PACAPh study is the first of its kind representing a feasible, easily accessible therapeutic strategy for asymptomatic stroke patients. We hypothesize that the personalized home-based PA program will reduce IPH and modulate inflammatory and biological parameters in patients presenting with carotid plaques. If the results of the PACAPh study prove to be beneficial on such health parameters, the implementation of such kind of intervention in the daily treatment of these patients would be an advantageous and cost-effective practice to adopt globally. TRIAL REGISTRATION: This study has been approved by the National Ethics Committee (IDRCB:2019-A01543-54/SI:19.06.21.40640). ClinicalTrials.gov NCT04053166.

Pro-Oxidant/Antioxidant Balance during a Prolonged Exposure to Moderate Altitude in Athletes Exhibiting Exercise-Induced Hypoxemia at Sea-Level.

This study examined to what extent athletes exhibiting exercise-induced hypoxemia (EIH) possess an altered redox status at rest, in response to exercise at sea level (SL) and during moderate altitude exposure. EIH was defined as a fall in arterial O2 saturation of at least 4% during exercise. Nine endurance athletes with EIH and ten without (NEIH) performed a maximal incremental test under three conditions: SL, one (H1) and five (H2) days after arrival to 2400 m. Gas exchange and peripheral capillary oxygen saturation (SpO2) were continuously monitored. Blood was sampled before exercise and after exercise cessation. Advanced oxidation protein products (AOPP), catalase, ferric-reducing antioxidant power, glutathione peroxidase, superoxide dismutase (SOD) and nitric oxide metabolites (NOx) were measured in plasma by spectrophotometry. EIH athletes had higher AOPP and NOx concentrations at pre- and post-exercise stages compared to NEIH at SL, H2 but not at H1. Only the EIH group experienced increased SOD activity between pre- and post-exercise exercise at SL and H2 but not at H1. EIH athletes had exacerbated oxidative stress compared to the NEIH athletes at SL and H2. These differences were blunted at H1. Oxidative stress did not alter the EIH groups' aerobic performance and could lead to higher minute ventilation at H2. These results suggest that higher oxidative stress response EIH athletes could be involved in improved aerobic muscle functionality and a greater ventilatory acclimatization during prolonged hypoxia.

Impact of aerobic exercise, sex, and metabolic syndrome on markers of oxidative stress: results from the Brain in Motion study.

Oxidative stress may be involved in disease pathology and dependent on both modifiable and nonmodifiable factors. This study aimed to assess exercise-induced changes in markers of oxidative stress among older, sedentary adults and to determine the effects of metabolic syndrome (MetS) status, aerobic capacity, age, sex, and weight on these biomarkers. Two hundred and six participants (means ± SE; 66.8 ± 6.4 yr, 104 women) of the Brain in Motion study underwent a 6-mo aerobic exercise intervention. At three time points, venous blood samples were collected and analyzed for markers of oxidative stress [advanced oxidation protein products (AOPP), malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and antioxidant status: catalase, uric acid (UA), superoxide dismutase (SOD), and ferric-reducing ability of plasma (FRAP)]. AOPP levels significantly decreased after 6 mo of aerobic exercise (P = 0.003). This decrease was not modified by MetS status (P = 0.183). Subjects with MetS possessed significantly higher levels of AOPP (P < 0.001), MDA (P = 0.004), and FRAP (P = 0.049) across the intervention (months 0-6). Men possessed significantly higher levels of FRAP (P < 0.001), catalase (P = 0.023), and UA (P = 0.037) across the intervention (months 0-6). Sex-MetS status interaction analyses revealed that the effect of MetS is highly sex dependent. These findings are multifaceted because the effect of MetS status seems distinctly different between sexes, pointing to the importance of acknowledging modifiable and nonmodifiable factor differences in individuals who possess conditions where oxidative stress may be part of the etiology.NEW & NOTEWORTHY Oxidative stress is implicated in a myriad of conditions, namely cardiovascular disease risk factors. This article details the effect of aerobic exercise, sex, and metabolic syndrome on markers of oxidative stress. We conclude that 6 mo of aerobic exercise significantly decreased oxidative stress, and further, that there is an effect of metabolic syndrome status on oxidative stress and antioxidant status levels, which are highly dependent on the sex of the individual.