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.

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.

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.