Assessment of cardiovascular risk in individuals with Congenital Adrenal Hyperplasia through early identification methodologies of atherosclerosis.

• Grant number: 24/00182-6
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2025
• End date: March 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Tania Aparecida Sartori Sanchez Bachega
• Grantee: Tania Aparecida Sartori Sanchez Bachega
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Berenice Bilharinho de Mendonça ; Bruno Caramelli ; Heraldo Possolo de Souza ; Larissa Garcia Gomes ; Luiz Aparecido Bortolotto ; Maria Lucia Cardillo Corrêa Giannella ; Marisa Passarelli ; Thais Martins de Lima Salgado

Abstract

Introduction: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a genetic disorder that impairs the synthesis of cortisol and/or aldosterone, leading to increased adrenal production of androgens. Symptoms range from prenatal virilization of external genitalia, potentially including neonatal salt-loss crises with fatal outcomes. Treatment aims to replace hormonal deficiencies, to prevent adrenal crises, and to control androgen secretion to allow proper growth, puberty, and fertility. The challenging titration of glucocorticoid doses throughout development may lead to exposure to hyper- or hypocortisolism, both associated with metabolic consequences such as obesity, insulin resistance, type 2 diabetes mellitus, and hypertension. The cardiovascular risk (CVR) in this population remains uncertain due to treatment and hormonal target heterogeneity among different centers. It is also unclear whether CVR is related to glucocorticoid treatment or hyperandrogenism. The serum concentration of high-density lipoprotein cholesterol (HDL-c), a known determinant of CVR, varies among studies, with no data about its functionality in this rare disease. Objectives: To assess the impact of hyperandrogenism and glucocorticoid therapy on the CVR of patients with classical and non-classical (NC) forms of CAH by evaluating HDL particle functionality and its correlation with early CVR markers. Patients and Methods: Forty patients with classical CAH, aged over 18 years, treated with cortisone acetate or hydrocortisone in childhood and low doses of dexamethasone or prednisone after reaching final height, will be evaluated. Twenty patients with good hormonal control and 20 with poor control (elevated androgens) will be compared to 20 healthy controls matched for sex, age, and BMI. Additionally, 40 female patients with NC CAH, aged 33 ± 9 years, including 20 patients on glucocorticoid treatment since diagnosis, will be compared to 20 patients using oral contraceptives and 20 age- and BMI-matched healthy controls. Cardiovascular risk will be assessed by analyzing HDL particle functionality, measured by 14C-cholesterol removal from macrophages, inhibition of LDL oxidation, and modulation of inflammatory cytokine secretion in macrophages. Correlations will be made with visceral fat quantification by abdominal computed tomography, insulin resistance assessed by the revised Quantitative Insulin Sensitivity Check Index (QUICKIr), and subclinical atherosclerotic disease identified by pulse wave velocity. Justification: This study aims to elucidate whether there is an increased cardiovascular risk in CAH patients, utilizing sophisticated methodology not previously studied in this population. It will also determine if this risk could be associated with glucocorticoid therapy or with hyperandrogenism. This study stands out from others by involving homogeneous cohorts in terms of therapy employed from childhood to adulthood. The results will address controversial issues regarding therapeutic targets and are likely to contribute to improving the quality of life for these patients. (AU)