Sex differences in the cardiovascular effects of GnRH analogues.

The integral role of the hypothalamic-pituitary-gonadal axis in reproductive processes makes it a prime therapeutic target. By inhibiting sex steroid synthesis, gonadotropin-releasing hormone (GnRH) analogues are used in the management of cancers, benign neoplasms, infertility and gender dysphoria. However, the wide application of these therapeutics raises concerns regarding the unintended effects upon the cardiovascular system. In males with prostate cancer, GnRH analogues when used as an androgen deprivation therapy appear to increase the risk of cardiovascular disease, which is the leading cause of death in this population. Therefore, due to the utilisation of GnRH analogues across the lifespan and gender spectrum, this relationship merits discussion. Existing data suggest an association between GnRH analogues and major adverse cardiovascular events in males. Conversely, females receiving GnRH analogues for breast cancer treatment appear to be at an increased risk of developing hypertension. In this narrative review, we describe the uses of GnRH analogues in adults, adolescents and children. We discuss whether sex plays a role in the cardiovascular effects of GnRH analogues and explore the significance of sex hormone receptors in the vasculature. We also consider confounding factors such as malignancy, advanced age and infertility.

A case report of myocardial infarction in a young transgender man with testosterone therapy: raising awareness on healthcare issues in the transgender community and a call for further research.

Background: People who are transgender may utilize masculinizing or feminizing gender-affirming hormonal therapy. Testosterone and oestrogen receptors are expressed throughout the cardiovascular system, yet the effects of these therapies on cardiovascular risk and outcomes are largely unknown. We report the case of a young transgender man with no discernible cardiovascular risk factors presenting with an acute coronary syndrome. Case summary: A 31-year-old transgender man utilizing intramuscular testosterone masculinizing gender-affirming hormonal therapy presented with central chest pain radiating to the left arm. He had no past medical history of hypertension, dyslipidaemia, diabetes, or smoking. Electrocardiography demonstrated infero-septal ST depression, and high-sensitivity troponin-I was elevated and increased to 19 686 ng/L. He was diagnosed with a non-ST-segment elevation myocardial infarction. Inpatient coronary angiography confirmed a critical focal lesion in the mid right coronary artery, which was managed with two drug-eluting stents. Medical management (i.e. aspirin, ticagrelor, atorvastatin, ramipril, and bisoprolol) and surveillance of residual plaque disease evident in the long tubular left main stem, proximal left anterior descending, and proximal circumflex vessels was undertaken. The masculinizing gender-affirming hormonal therapy was continued. Discussion: Despite a greater awareness of the potential risk of increased cardiovascular disease in transgender people, the fundamental lack of data regarding cardiovascular outcomes in transgender people may be contributing to healthcare inequalities in this population. We must implement better training, awareness, and research into transgender cardiovascular health to facilitate equitable and evidence-based outcomes.

Cardiovascular disease in transgender individuals.

The population of people identifying as transgender has grown rapidly in recent years, resulting in a substantive increase in individuals obtaining gender-affirming medical care to align their secondary sex characteristics with their gender identity. This has established benefits for patients including improvements in gender dysphoria and psychosocial functioning, while reducing adverse mental health outcomes. Despite these potential advantages, recent evidence has suggested that gender-affirming hormone therapy (GAHT) may increase the risk of cardiovascular disease. However, owing to a paucity of research, the mechanisms underpinning these increased risks are poorly understood. Moreover, previous research has been limited by heterogenous methodologies, being underpowered, and lacking appropriate control populations. Consequently, the need for evidence regarding cardiovascular health in LGBTQ + individuals has been recognised as a critical area for future research to facilitate better healthcare and guidance. Recent research investigating the effect of transmasculine (testosterone) GAHT on cardiovascular disease risk points to testosterone effecting the nitric oxide pathway, triggering inflammation, and promoting endothelial dysfunction. Equivalent studies focussing on transfeminine (oestrogen) GAHT are required, representing a crucial area of future research. Furthermore, when examining the effects of GAHT on the vasculature, it cannot be ignored that there are multiple factors that may increase the burden of cardiovascular disease in the transgender population. Such stressors include major psychological stress; increased adverse health behaviours, such as smoking; discrimination; and lowered socioeconomic status; all of which undoubtedly impact upon cardiovascular disease risk and offers the opportunity for intervention.

Post-COVID-19 illness and associations with sex and gender.

BACKGROUND: Post-COVID-19 syndromes have associated with female sex, but the pathophysiological basis is uncertain. AIM: There are sex differences in myocardial inflammation identified using cardiac magnetic resonance (CMR) in post-COVID-19 patients, and in patient reported health outcomes following COVID-19 infection. DESIGN: This prospective study investigated the time-course of multiorgan injury in survivors of COVID-19 during convalescence. METHODS: Clinical information, blood biomarkers, and patient reported outcome measures were prospectively acquired at enrolment (visit 1) and 28-60 days post-discharge (visit 2). Chest computed tomography (CT) and CMR were performed at visit 2. Follow-up was carried out for serious adverse events, including death and rehospitalization. RESULTS: Sixty-nine (43%) of 159 patients recruited were female. During the index admission, females had a lower peak C-reactive protein (74 mg/l (21,163) versus 123 mg/l (70, 192) p = 0.008) and peak ferritin (229 µg/l (103, 551) versus 514 µg/l (228, 1122) p < 0.001). Using the Modified Lake-Louise criteria, females were more likely to have definite evidence of myocardial inflammation (54% (37/68) versus 33% (30/90) p = 0.003). At enrolment and 28-60 days post-discharge, enhanced illness perception, higher levels of anxiety and depression and lower predicted maximal oxygen utilization occurred more commonly in women. The mean (SD, range) duration of follow-up after hospital discharge was 450 (88) days (range 290, 627 days). Compared to men, women had lower rates of cardiovascular hospitalization (0% versus 8% (7/90); p = 0.018). CONCLUSIONS: Women demonstrated worse patient reported outcome measures at index admission and 28-60 days follow-up though cardiovascular hospitalization was lower.

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.

Nailfold video-capillaroscopy in the study of cardiovascular disease: a systematic review.

OBJECTIVES: Nailfold video-capillaroscopy (NVC) is an inexpensive method of assessing microcirculation. We reviewed the literature to assess whether changes to the nailfold capillaries exist in patients with cardiovascular disease (CVD). METHODS: We searched PubMed, Scopus and Cochrane Library databases for original research articles relating to the use of noninvasive microvascular assessment in patients with CVD. Methodological quality was assessed with the 'Quality Assessment Tool for Observational Cohort and Cross-sectional Studies.' The results obtained from NVC were analysed qualitatively and compared with other forms of microvascular assessment. RESULTS: In total 2759 articles were screened, of which 22 studies involving 562 patients (~40% women) with CVD were included. Mean age ranged between 3.7-68.4 years (cases) and 4.0-58.0 years (controls). Reduced capillary density and increased capillary dimensions were seen in patients with pulmonary arterial hypertension (PAH). Among patients with systemic sclerosis, advanced scleroderma patterns can be used to identify patients with or at risk of developing PAH. Functional nailfold changes precede structural changes in patients with hypertension. However, the studies were heterogeneous in the diagnosis of disease and the measurement of nailfold parameters. Most studies did not exclude conditions with altered nailfold features, and only one study performed a power calculation. Furthermore, abnormal nailfold findings are present in patients without systemic disease. CONCLUSIONS: Structural and functional changes to the nailfold are a feature of established CVD and precede the development of PAH. However, heterogeneity in measurement and abnormal findings in healthy participants limit their use in the wider population.

Rural-urban difference in the prevalence of hypertension in West Africa: a systematic review and meta-analysis.

Urbanisation is considered a major contributor to the rising prevalence of hypertension in West Africa, yet the evidence regarding rural-urban differences in the prevalence of hypertension in the region has been mixed. A systematic literature search of four electronic databases: PubMed, Embase, African Journals Online, and WHO's African Index Medicus; and reference lists of eligible studies was carried out. Original quantitative studies describing the rural-urban difference in the prevalence of hypertension in one or more countries in West Africa, and published in English language from the year 2000 to 2021 were included. A random effects meta-analysis model was used to estimate the odds ratio of hypertension in rural compared to urban locations. A limited sex-based random effects meta-analysis was conducted with 16 studies that provided sex-disaggregated data. Of the 377 studies screened, 22 met the inclusion criteria (n = 62,907). The prevalence of hypertension was high in both rural, and urban areas, ranging from 9.7% to 60% in the rural areas with a pooled prevalence of 27.4%; and 15.5% to 59.2% in the urban areas with a pooled prevalence of 33.9%. The odd of hypertension were lower in rural compared to urban dwellers [OR 0.74, 95% CI: 0.66-0.83; p < 0.001]. The pooled prevalence of hypertension was 32.6% in males, and 30.0% in females, with no significant difference in the odds of hypertension between the sexes [OR 0.91, 95% CI: 0.8-1.05, p = 0.196]. Comprehensive hypertension control policies are needed for both rural, and urban areas in West Africa, and for both sexes.

Sex Differences in the Prevalence, Outcomes and Management of Hypertension.

PURPOSE OF REVIEW: To review recent data on sex differences in the prevalence, outcomes and management of hypertension. RECENT FINDINGS: Although hypertension is overall more common in males, females experience a much sharper incline in blood pressure from the third decade of life and consequently the prevalence of hypertension accelerates comparatively with age. Mechanisms responsible for these blood pressure trajectories may include the sustained vascular influence of hypertensive disorders of pregnancy, interactions between the renin-angiotensin-aldosterone system and sex hormones or even psychosocial gendered factors such as socioeconomic deprivation. Moreover, the impact of hypertension is not uniform and females are at higher risk of developing a multitude of adverse cardiovascular outcomes at lower blood pressure thresholds. Blood pressure is a sexually dimorphic trait and although significant differences exist in the prevalence, pathophysiology and outcomes of hypertension in males and females, limited data exist to support sex-specific blood pressure targets.

ST-elevation myocardial infarction due to coronary thrombus in a young patient with diabetic ketoacidosis and a new diagnosis of type 2 diabetes.

The association between cardiovascular disease and diabetes is increasingly understood and shared therapeutic targets are emerging. We describe the presentation and successful management of ST-elevation myocardial infarction (STEMI) secondary to coronary thrombus in a young patient with a new diagnosis of type 2 diabetes and diabetic ketoacidosis.

Sex steroids receptors, hypertension, and vascular ageing.

Sex hormone receptors are expressed throughout the vasculature and play an important role in the modulation of blood pressure in health and disease. The functions of these receptors may be important in the understanding of sexual dimorphism observed in the pathophysiology of both hypertension and vascular ageing. The interconnectivity of these factors can be exemplified in postmenopausal females, who with age and estrogen deprivation, surpass males with regard to hypertension prevalence, despite experiencing significantly less disease burden in their estrogen replete youth. Estrogen and androgen receptors mediate their actions via direct genomic effects or rapid non-genomic signaling, involving a host of mediators. The expression and subtype composition of these receptors changes through the lifespan in response to age, disease and hormonal exposure. These factors may promote sex steroid receptor-mediated alterations to the Renin-Angiotensin-Aldosterone System (RAAS), and increases in oxidative stress and inflammation, thereby contributing to the development of hypertension and vascular injury with age.

The Importance of Gender to Understand Sex Differences in Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. There is robust evidence of heterogeneity in underlying mechanism, manifestation, prognosis, and response to treatment of CVD between male and female patients. Gender, which refers to the socially constructed roles, behaviours, expressions, and identities of individuals, is an important determinant of CV health, and its consideration might help in attaining a broader understanding of the observed sex differences in CVD. Established risk factors such as hypertension, dyslipidemia, diabetes mellitus, obesity, and smoking are well known to contribute to CVD. However, despite the differences in CVD risk between male and female, most studies looking into the magnitude of effect of each risk factor have traditionally focused on male subjects. While biological sex influences disease pathophysiology, the psycho-socio-cultural construct of gender can further interact with this effect. Behavioural, psychosocial, personal, cultural, and societal factors can create, repress, or strengthen underlying biological CV health differences. Although mechanisms of action are largely unclear, it is suggested that gender-related factors can further exacerbate the detrimental effect of established risk factors of CVD. In this narrative review, we explore the current literature investigating the role of gender in CV risk and its impact on established risk factors as a fundamental step toward precision medicine.

Transgender adults, gender-affirming hormone therapy and blood pressure: a systematic review.

OBJECTIVES: Gender-affirming hormone therapy (GHT) is utilized by people who are transgender to align their secondary sex characteristics with their gender identity. Data relating to cardiovascular outcomes in this population are limited. We aimed to review the impact of GHT on the blood pressure (BP) of transgender individuals. METHODS: We searched PubMed/MEDLINE, SCOPUS and Cochrane Library databases for articles published relating to the BP of transgender adults commencing GHT. Methodological quality was assessed via the 'Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group'. RESULTS: Six hundred articles were screened, of which 14 studies were included in this systematic review encompassing 1309 individuals (∼50% transgender men and women) treated with GHT between 1989 and 2019. These articles were all pre-post observational studies without control groups. Mean ages ranged between 23.0-36.7 years (transgender men) and 25.2-34.8 years (transgender women). Interventions were diverse and included oral, transdermal and injectable hormonal preparations with 4 months to 5 years follow-up. Most studies in transgender men did not demonstrate a change in BP, whereas transgender women on GHT demonstrated both increases and decreases in SBP. These studies were heterogenous with significant methodological limitations and only two were determined to have a good quality rating. CONCLUSION: There is currently insufficient data to advise the impact of GHT on BP in transgender individuals. Better quality research is essential to elucidate whether exogenous sex hormones modulate BP in transgender people and whether this putative alteration infers poorer cardiovascular outcomes.

Sex and gender aspects in vascular pathophysiology.

Cardiovascular disease (CVD) is a leading cause of global mortality in men and women. The prevalence, pathophysiology, clinical manifestations and outcomes of CVD observed in these two populations is being increasingly recognized as distinct. In this editorial, we provide an overview of mechanisms related to differences in vascular pathophysiology between men and women and explore the contributions of both sex and gender.

Gender-Affirming Hormone Therapy, Vascular Health and Cardiovascular Disease in Transgender Adults.

Gender-affirming or cross-sex hormone therapy is integral to the management of transgender individuals yet our appreciation of the effects of such hormones on cardiovascular health is limited. Insights into vascular pathophysiology and outcomes in transgender people receiving sex steroids could be fundamental in providing better care for this population through the management of cardiovascular risk and more broadly advance our understanding of the role of sex and gender in vascular health and disease. In addition, there is a need to understand how gender-affirming hormone therapy impacts cardiovascular disease risk and events as transgender individuals age. This review explores the available evidence on the associations between gender-affirming hormones and cardiovascular events such as coronary artery disease, stroke, hypertension, thrombosis, lipid abnormalities, and diabetes mellitus. Current research about vascular outcomes in adults receiving hormonal therapy is limited by the absence of large cohort studies, lack of appropriate control populations, and inadequate data acquisition from gender identity services. Existing epidemiological data suggest that the use of estrogens in transgender females confers an increased risk of myocardial infarction and ischemic stroke. Conversely, transgender males receiving testosterone lack any consistent or convincing evidence of increased risk of cardiovascular or cerebrovascular disease. Further studies are required to confirm whether such risk exists and the mechanisms by which they occur.

Mortality risk remains higher in individuals with type 1 diabetes: A population-based cohort study (the Ayrshire diabetes follow-up cohort [ADOC]).

AIMS: Type 1 diabetes is associated with an increased risk of cardiovascular disease and all-cause mortality. Numerous studies have demonstrated that outcomes for diabetes are improved by intensive glycaemic control, blood pressure control, and treatment of dyslipidaemia in addition to cessation of smoking. The aim of this study was to compare mortalities in individuals with type 1 diabetes with that in non-diabetic individuals, and to investigate the effects of age, gender, glycaemic control, socio-economic status, hypertension, ischaemic heart disease (IHD), smoking status, body mass index (BMI) and dyslipidaemia. METHODS: A population-based analysis in Ayrshire and Arran, Scotland included 253 304 non-diabetic individuals and 1324 individuals with type 1 diabetes who were tracked from 2009 to 2014. RESULTS: Patients with type 1 diabetes had higher mortality rates than non-diabetic individuals (HR, 3.20; P < .01), with relative mortality in female individuals with type 1 diabetes being higher than that in males (OR, 2.38 vs 1.52; P < .01). Increasing age (HR, 2.37), smoking (HR, 1.85), IHD (HR, 1.62) and hypertension (HR, 1.21) (all P < .01) increased mortality risk. A hypertensive female with type 1 diabetes and IHD who smoked had an HR of 11.6 compared with a non-smoking, normotensive non-diabetic female without IHD. For a hypertensive male with type 1 diabetes and IHD who smoked, HR was 6.96. BMI > 30 kg/m2 was associated with reduced mortality risk in both non-diabetic (HR, 0.61) and diabetic subjects (HR, 0.40). CONCLUSIONS: This study confirmed that the risk of mortality in individuals with type 1 diabetes remains elevated. Further studies are required to understand how gender affects the disparity in mortality and why obesity appears to be protective.

Pharmacokinetics of metformin in patients with gastrointestinal intolerance.

AIMS: To assess potential causes of metformin intolerance, including altered metformin uptake from the intestine, increased anaerobic glucose utilization and subsequent lactate production, altered serotonin uptake, and altered bile acid pool. METHODS: For this pharmacokinetic study, we recruited 10 severely intolerant and 10 tolerant individuals, matched for age, sex and body mass index. A single 500-mg dose of metformin was administered, with blood sampling at 12 time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin and bile acid concentrations, and compared across the phenotypes. RESULTS: The intolerant individuals were severely intolerant to 500 mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median (interquartile range [IQR]) peak concentration 2.1 (1.7-2.3) mg/L and 2.0 (1.8-2.2) mg/L, respectively (P = .76); time to peak concentration 2.5 hours; median (IQR) area under the curve (AUC)0-24 16.9 (13.9-18.6) and 13.9 (12.9-16.8) mg/L*h, respectively (P = .72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CI 2.0-2.8 and 1.8-3.0 mmol/L, respectively), and similar incremental AUC0-24 in each cohort: tolerant cohort 6.98 (95% CI 3.03-10.93) and intolerant cohort 4.47 (95% CI -3.12-12.06) mmol/L*h (P = .55). Neither serotonin nor bile acid concentrations were significantly different. CONCLUSIONS: Despite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be attributable to local factors within the lumen or enterocyte.

Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study.

AIMS: Metformin is renally excreted and has been associated with the development of lactic acidosis. Although current advice is to omit metformin during illnesses that may increase the risk of acute kidney injury (AKI), the evidence supporting this is lacking. We investigated the relationship between AKI, lactate concentrations and the risk of lactic acidosis in those exposed to metformin. MATERIALS AND METHODS: We undertook a population-based case-control study of lactic acidosis in 1746 participants with Type 2 diabetes and 846 individuals without diabetes with clinically measured lactates with and without AKI between 1994 and 2014. AKI was stratified by severity according to "Kidney Disease: Improving Global Outcomes" guidelines. Mixed-effects logistic and linear regression were used to analyse lactic acidosis risk and lactate concentrations, respectively. RESULTS: Eighty-two cases of lactic acidosis were identified. In Type 2 diabetes, those treated with metformin had a greater incidence of lactic acidosis [45.7 per 100 000 patient years; 95% confidence interval (CI) 35.9-58.3] compared to those not exposed to this drug (11.8 per 100 000 patient years; 95% CI 4.9-28.5). Lactate concentrations were 0.34 mmol/L higher in the metformin-exposed cohort (P < .001). The risk of lactic acidosis was higher in metformin users [odds ratio (OR) 2.3; P = .002] and increased with AKI severity (stage 1: OR 3.0, P = .002; stage 2: OR 9.4, P < .001; stage 3: OR 16.1, P < .001). CONCLUSIONS: A clear association was found between metformin, lactate accumulation and the development of lactic acidosis. This relationship is strongest in those with AKI. These results provide robust evidence to support current recommendations to omit metformin in any illness that may precipitate AKI.