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.

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.

The Association Between Testosterone and Vascular Function in Reproductive-Aged Females With Chronic Kidney Disease.

Cardiovascular disease is the leading cause of death in women, and women with chronic kidney disease (CKD) experience especially elevated risk. This study examined the association between testosterone and vascular function in 61 reproductive-aged females with CKD. Testosterone levels and measures of vascular function were assessed, including pulse wave velocity, aortic augmentation, flow-mediated dilation (FMD), and velocity time integral. Multivariable linear regression analyses assessed the relationship between testosterone and each measure of vascular function. No associations were observed between testosterone and vascular function outcomes, although a significant positive association between testosterone-to-estradiol ratio and FMD was demonstrated. Although testosterone levels were not independently predictive of vascular function, the level of testosterone relative to estradiol was associated with FMD and may therefore influence endothelial function in the high-risk population of reproductive-aged female patients with CKD.

Alors que les maladies cardiovasculaires sont la cause principale de décès chez les femmes, les femmes atteintes d'une maladie rénale chronique (MRC) sont exposées à un risque particulièrement élevé. La présente étude vise à examiner l'association entre la testostérone et la fonction vasculaire de 61 femmes en âge de procréer atteintes d'une MCV. Nous avons évalué les concentrations de testostérone et les mesures de la fonction vasculaire, soit la vélocité de l'onde de pouls, l'augmentation de l'aorte, la dilatation médiée par le flux (DMF) et l'intégrale temps-vitesse. Les analyses multivariées de régression linéaire ont permis d'évaluer la relation entre la testostérone et chacune des mesures de la fonction vasculaire. Aucune association n'a été observée entre la testostérone et les résultats de la fonction vasculaire, bien qu'une association positive significative entre le ratio testostérone/œstradiol et la DMF ait été démontrée. Bien que les concentrations de testostérone n'étaient pas indépendamment prédictives de la fonction vasculaire, les concentrations de la testostérone relativement à l'œstradiol ont été associées à la DMF et peuvent par conséquent influencer la fonction endothéliale au sein de la population exposée à un risque élevé composée de patientes en âge de procréer atteintes d'une MRC.

Awareness of Hypertension in Reproductive-Aged Women Living With Chronic Kidney Disease.

Background: Hypertension is the most important modifiable cardiovascular risk factor among women. Chronic kidney disease (CKD), which affects 1 in 10 reproductive-aged women, increases the risk of hypertension; however, awareness of hypertension in this population is unknown. This study aimed to determine hypertension awareness among reproductive-aged women living with chronic kidney disease. Methods: Women aged 18 to 50 years with CKD were recruited from nephrology clinics in Calgary, Alberta, Canada. Participants completed a semistructured interview and focused chart review, serum and urine laboratory assessment, and a physical examination that included anthropomorphic measurements and 2 automated office blood pressure readings. Hypertension was defined according to the use of ≥ 1 antihypertensive medications and/or an automated office blood pressure reading of ≥ 135/85 mm Hg. Data were stratified by hypertension status, as well as by awareness, and descriptively presented as mean ± standard deviation, numerical values, and percentages. Results: Sixty-three participants with CKD were included. Thirty-eight (60%) participants had hypertension according to study definitions. Of those with hypertension, 30 participants (79%) were aware of their hypertension status. Conclusions: Hypertension awareness is relatively high in reproductive-aged women living with CKD. However, hypertension awareness is the critical component for hypertension management, and further work is necessary to optimize reduction of cardiovascular risk in this important population.

Contexte: L'hypertension est le principal facteur de risque cardiovasculaire modifiable chez les femmes. La néphropathie chronique, qui touche une femme en âge de procréer sur 10, augmente le risque d'hypertension, mais le niveau de sensibilisation de cette population à ce sujet est inconnu. La présente étude visait à déterminer le niveau de sensibilisation à l'hypertension chez les femmes en âge de procréer atteintes de néphropathie chronique. Méthodologie: Des femmes âgées de 18 à 50 ans atteintes de néphropathie chronique ont été recrutées dans les cliniques de néphrologie de Calgary, en Alberta (Canada). Les participantes ont été soumises à des entrevues semi-structurées, un examen ciblé du dossier médical, des analyses de laboratoire du sérum et de l'urine et un examen physique incluant des mesures anthropométriques et deux lectures automatisées de la pression artérielle réalisées en cabinet. L'hypertension a été définie de la façon suivante : (1) l'utilisation de ≥ 1 agent antihypertenseur, et/ou (2) une lecture automatisée de la pression artérielle en cabinet ≥ 135/85 mmHg. Les données ont été stratifiées selon le statut d'hypertension et le niveau de sensibilisation, et elles sont présentées de façon descriptive par la moyenne ± l'écart-type, les valeurs numériques et les pourcentages. Résultats: Soixante-trois participantes atteintes de néphropathie chronique ont été incluses dans l'étude. Trente-huit (60 %) participantes étaient atteintes d'hypertension selon la définition utilisée dans l'étude. Parmi les participantes hypertendues, 30 (79 %) étaient conscientes de leur statut d'hypertension. Conclusions: Le niveau de sensibilisation à l'hypertension est relativement élevé parmi les femmes en âge de procréer atteintes de néphropathie chronique. Toutefois, la sensibilisation à l'hypertension est un élément clé pour sa prise en charge, et d'autres travaux sont nécessaires pour optimiser la réduction du risque cardiovasculaire dans cette population importante.

Change of HeART: Cardiovascular Implications of Assisted Reproductive Technology.

Cardiovascular (CV) disease is the leading cause of death in women, and it may manifest differently than in men, in part related to sex-specific CV risk factors. In females, assisted reproductive technologies (ARTs) are commonly used to treat infertility, and they utilize controlled ovarian stimulation involving the administration of exogenous sex hormones. ARTs, and especially controlled ovarian stimulation, have been associated with an increased pregnancy and short-term CV risk, although the long-term CV implications of these treatments in individuals treated with ARTs and their offspring remain unclear. This review endeavors to provide a comprehensive examination of what is known about the relationship between ART and CV outcomes for females treated with ARTs, as well as their offspring, and recommendations for future research. Novel insights into female-specific CV risk factors are critical to reduce the disproportionate burden of CV disease in Canadian women. ART has revolutionized reproductive medicine, offering hope to millions of individuals with infertility worldwide, and a further understanding of the CV implications of this important sex-specific CV risk factor is warranted urgently.

Les maladies cardiovasculaires représentent la principale cause de décès chez les femmes, chez qui elles peuvent se manifester différemment, en partie en raison des facteurs de risque cardiovasculaire spécifiques au sexe. Chez les femmes, des technologies de procréation assistée (TPA) sont couramment utilisées pour traiter l'infertilité et font appel à la stimulation ovarienne contrôlée qui comporte l'administration d'hormones sexuelles exogènes. Les TPA, et particulièrement la stimulation ovarienne contrôlée, ont été associées à une hausse du risque cardiovasculaire pendant la grossesse et à court terme, alors que les implications cardiovasculaires à long terme de ces traitements chez les patientes traitées et leurs enfants demeurent nébuleuses. Cette analyse vise à brosser un portrait complet des connaissances acquises sur le lien entre les TPA et les issues cardiovasculaires chez les femmes qui y ont recours, ainsi que chez leurs enfants, et de formuler des recommandations pour de futures recherches. Il est essentiel d'avoir de nouveaux éclairages sur les facteurs de risque cardiovasculaire spécifiques aux femmes pour réduire le fardeau disproportionné des maladies cardiovasculaires chez les Canadiennes. Les TPA ont révolutionné la médecine de la reproduction, offrant de l'espoir à des millions de personnes touchées par l'infertilité dans le monde; il est toutefois urgent de mieux connaître les implications cardiovasculaires de ces importants facteurs de risque cardiovasculaire spécifiques au sexe.

Sex- and Gender-Based Reporting in Antihypertensive Medication Literature Informing Hypertension Guidelines.

BACKGROUND: Hypertension is the leading modifiable cardiovascular risk factor with recognized sex- and gender-based differences. We assessed the incorporation of sex and gender reporting in the antihypertensive medication literature informing hypertension guidelines. METHODS AND RESULTS: Literature cited in the International Society of Hypertension (2020), European Society of Cardiology/European Society of Hypertension (2018), American College of Cardiology/American Heart Association (2017), Latin American Society of Hypertension (2017), Pan-African Society of Cardiology (2020), and Hypertension Canada (2020) guidelines was systematically reviewed. Observational studies, randomized controlled trials, and systematic reviews involving antihypertensive medications were included. Studies with participants of a single sex, guidelines, and commentaries were excluded. Data on study participation-to-prevalence ratio by sex, analysis of baseline demographics and study outcomes by sex, and stratification of adverse events by sex were extracted. Of 1659 unique citations, 331 studies met inclusion criteria. Of those, 81% reported the sex of participants, and 22% reported a male-to-female participation-to-prevalence ratio of 0.8 to 1.2. Three percent of studies stratified baseline characteristics by sex, and 20% considered sex during analysis through statistical adjustment or stratification. Although 32% of studies reported adverse events, only 0.6% stratified adverse events by sex. Most (58%) studies reporting sex/gender used sex and gender terms interchangeably. CONCLUSIONS: Incorporation of sex- and gender-based considerations in study population, analysis, or reporting of results and adverse events is not common in the antihypertensive medication literature informing international hypertension guidelines. Greater attention to sex- and gender-based factors in research is required to optimally inform management of hypertension.

Female Reproductive Health and Contraception Use in CKD: An International Mixed-Methods Study.

Rationale & Objective: Female reproductive health is recognized as a predictor of morbidity, mortality, and quality of life, although data in the setting of chronic kidney disease (CKD) are limited. Study Design: A mixed-methods study was employed. Phase 1 was an anonymous, internet-based survey. Phase 2 was semistructured interviews offered to all respondents upon survey completion. Setting & Participants: The survey was disseminated internationally from October 4, 2021, to January 7, 2022, to individuals aged 18-50 years with both a uterus and CKD diagnosis. Outcomes: Menstrual health and contraceptive use by CKD stage (dialysis, nondialysis CKD, and transplant). Analytical Approach: Survey data were analyzed using descriptive statistics. Interview data were analyzed using the framework method of analysis. Results: Of 152 respondents, 98 (mean age 33 ± 0.7 years; n = 20 dialysis, n = 59 nondialysis CKD, n = 19 transplant) satisfied the inclusion criteria, representing 3 continents. The most common causes of CKD among survey respondents were hereditary causes in dialysis (n = 6, 30%) and glomerulonephritis in nondialysis CKD (n = 22, 37%) and transplant (n = 6, 32%). The majority reported heavy menstrual bleeding (n = 12, 86% dialysis; n = 46, 94% nondialysis CKD; n = 14, 100% transplant). Less than half of participants were consistently able to afford period products. Condoms were the most common contraceptive reported. Most participants reported no contraceptive use (n = 10, 50% dialysis; n = 37, 63% nondialysis CKD; n = 7, 37% transplant), primarily because of "fear". Interviews (n = 6) revealed a perception of a relationship between kidney function and menstrual health, concerns about contraceptive use, and a desire for greater multidisciplinary care to improve kidney and reproductive health. Limitations: Self-reported outcomes, need for internet access and a device. Conclusions: Abnormal menstruation and period poverty (ie, inability to afford period products and the socioeconomic consequences of menstruation) were common, and contraceptive use was low among female individuals with CKD, highlighting an important gap in the sex-specific care of this population. Plain-Language Summary: Chronic kidney disease (CKD) in female individuals is accompanied by menstrual disorders and low contraceptive use. However, most data are limited to the dialysis and transplant populations. Therefore, this mixed-methods study aimed to describe self-assessed menstruation and contraceptive use across all stages of CKD. People aged 18-50 years with a uterus and CKD diagnosis were invited to participate in an online survey shared internationally as well as an optional telephone interview. Abnormal menstruation and period poverty (ie, inability to afford period products and the socioeconomic consequences of menstruation) were common, and contraceptive use was low among female individuals with CKD, highlighting an important gap in the sex-specific care of this population.

Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society.

Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women.

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.

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.

Female sex-specific considerations to improve rigor and reproducibility in cardiovascular research.

Cardiovascular disease is the leading cause of death in women. Despite recognition of sex-specific differences in cardiovascular health, females are underrepresented across all aspects of cardiovascular research, playing a key role in reducing rigor and reproducibility in cardiovascular research and contributing to these poorer health outcomes. Therefore, we propose a framework to capture factors associated with the female sex at the preclinical, recruitment, data collection, and data analysis stages. In preclinical cardiovascular research, female experimental models are commonly excluded despite similar variability in findings compared with males. To reduce this sex bias, the inclusion of female models and the incorporation of sex as a biological variable are critical to improve reproducibility and inform clinical research and care. Although funding agencies have mandated the inclusion of women in clinical trials, greater efforts are needed to achieve optimal participation-to-prevalence ratio to increase the generalizability of results to real-world settings. Female participants face more stringent exclusion criteria in research compared with males owing to sex-specific factors. However, their routine exclusion from cardiovascular research is not only unethical but limits generalizability and applicability to clinical practice. Identifying sex assigned at birth, collecting information on female sex-specific and -predominant factors associated with cardiovascular health and risk, and stratifying data by sex, including adverse events, are essential to ensure reproducibility and relevance of findings to target populations. Increasing female representation and the incorporation of female sex-specific cardiovascular risk factors in cardiovascular research will not only lead to enhanced rigor and reproducibility but improved cardiovascular health for all.

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.

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.

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.

Reproductive Health in Chronic Kidney Disease: The Implications of Sex and Gender.

Chronic kidney disease (CKD) is frequently accompanied by reproductive health challenges in females and males alike. Progression of CKD is associated with escalating impairment of the hypothalamic-pituitary-gonadal axis, which facilitates evolving ovarian, testicular, and sexual dysfunction. Common clinical reproductive health complications in CKD include abnormal menstruation, impaired sexual health, and reduced fertility. Though sex-specific factors, such as sex hormones and gonadal function, have a strong influence on reproductive health outcomes in CKD, a person's gender and gendered experience also have important implications. Institutionalized gender, gendered perceptions of health, and health care-seeking behaviors, as well as adherence to medical care, all have critical effects on reproductive health in CKD. This review endeavors to explore the implications of both sex and gender on overall reproductive health in individuals living with CKD.

The effect of non-oral hormonal contraceptives on hypertension and blood pressure: A systematic review and meta-analysis.

Oral contraceptives (OC) are associated with increased risk of hypertension and elevated blood pressure (BP). Whether non-oral hormonal contraceptives have similar associations is unknown. We sought to investigate the effect of non-oral hormonal contraceptive (NOHC) use on the risk of hypertension and changes in BP, compared to non-hormonal contraceptive and OC use. We searched bibliographic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) until August 2020. Studies reporting risk of hypertension or changes in systolic and diastolic BP with NOHC use compared with either non-hormonal contraceptive or OC use. Abstract screening, full-text review, data extraction, and quality assessment were completed in duplicate. For studies reporting dichotomous outcomes, we reported results as relative risk with 95% confidence intervals (CI). A random-effects model was used to estimate pooled weighted mean difference and 95% CI of change in BP. Twenty-five studies were included. A lower incidence of hypertension was observed with injectable contraceptive use compared to non-hormonal contraceptive and OC use, although it was unclear if this was statistically significant. Compared to non-hormonal contraceptive use, injectable contraceptive use was associated with increased BP (SBP: 3.24 mmHg, 95%CI 2.49 to 3.98 mmHg; DBP: 3.15 mmHg, 95%CI 0.09 to 6.20 mmHg), the hormonal intra-uterine device use was associated with reduced BP (SBP: -4.50 mmHg, 95%CI -8.44 to -0.57 mmHg; DBP: -7.48 mmHg, 95% -14.90 to -0.05 mmHg), and the vaginal ring was associated with reduced diastolic BP (-3.90 mmHg, 95%CI -6.67 to -1.13 mmHg). Compared to OC use, the injectable contraceptive use was associated with increased diastolic BP (2.38 mmHg, 95%CI 0.39 to 4.38 mmHg). NOHC use is associated with changes in BP which differ by type and route of administration. Given the strong association between incremental increases in BP and cardiovascular risk, prospective studies are required.

Association between chronic conditions and urinary incontinence in females: a cross-sectional study using national survey data.

BACKGROUND: Urinary incontinence affects up to half of women, yet few speak to their health care provider about or receive treatment for the condition. To aid with identifying subpopulations at risk for urinary incontinence, we examined the associations between 10 chronic health conditions and urinary incontinence among Canadian adult females. METHODS: We conducted a cross-sectional analysis of survey data from the Canadian Community Health Survey (2013-2014) involving female respondents aged 25 years or older living in a private dwelling. Presence of chronic conditions and urinary incontinence were measured by self-report. We used logistic regression modelling with sampling weights, controlling for age, income, ethnicity, body mass index and smoking. Multiple imputation and probabilistic bias analysis were used to address missing covariate data and unmeasured confounding from parity. RESULTS: Our analysis included 60 186 respondents representing more than 12 million Canadian females, of whom 45.8% (95% confidence interval [CI] 45.0%-46.6%) reported at least 1 chronic condition. Chronic conditions were associated with more than twice the odds of urinary incontinence (adjusted odds ratio [OR] 2.42, 95% CI 2.02-2.89). Associations were largest for bowel disorders (adjusted OR 2.92, 95% CI 2.44-3.49); modest for chronic obstructive pulmonary disease (adjusted OR 2.00, 95% CI 1.63-2.45), asthma (adjusted OR 1.82, 95% CI 1.52-2.19), arthritis (adjusted OR 1.98, 95% CI 1.74-2.24) and heart disease (adjusted OR 1.73, 95% CI 1.48-2.02); and smallest for diabetes (adjusted OR 1.20, 95% CI 1.02-1.41) and high blood pressure (adjusted OR 1.27, 95% CI 1.12-1.44). Results slightly attenuated but did not substantively change after imputation and bias analysis. INTERPRETATION: We found that chronic conditions are associated with significantly higher odds of comorbid urinary incontinence among Canadian adult females, which is consistent with previous research. Our findings support routine inquiry regarding urinary incontinence symptoms among women accessing health care for chronic conditions.

Female sex-specific and -predominant cardiovascular risk factors and heart failure practice guidelines.

Heart failure (HF) etiology, presentation and prognosis differ by sex, with female sex-specific and -predominant risk factors playing important roles. We systematically reviewed the studies cited by the 2017 American College of Cardiology/ American Heart Association/ Heart Failure Society of America Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. Female cardiovascular risk factors were broadly categorized as female sex-specific (reproductive, pregnancy, menopausal) and female sex-predominant (depression, anthracycline exposure, autoimmune disease) risk factors. Of the 205 cited articles, only 3 studies (1.6%) reported any female sex-specific cardiovascular risk factor in the data analysis or results sections. Oral contraceptive use (n = 1), menopausal status (n = 2) and hormone replacement therapy (n = 2) were the only female sex-specific cardiovascular risk factors reported. No other female sex-specific or -predominant cardiovascular risk factor was reported by any of the eligible studies. Our work highlights that in addition to the need for proportional representation of women in heart failure clinical studies, inclusion of female sex-specific and -predominant risk factors in data collection and analysis is of paramount importance to guide heart failure care in the female population.