Cardiovascular risk assessment in patients with classical 21-hydroxylase deficiency: the impact of hyperandrogenism and glucocorticoid therapy on high-density lipoprotein (HDL) functionality

• Grant number: 23/16309-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date until: December 01, 2024
• End date until: November 30, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Tania Aparecida Sartori Sanchez Bachega
• Grantee: Ana Carolina Maués de Oliveira
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/26780-9 - Molecular and epigenetic research on Differences in Sexual Development (DSD): impact of scientific diffusion on the relationship between science and society, AP.TEM

Abstract

Introduction: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an inherited metabolic error that results in impaired cortisol and/or aldosterone synthesis and increased adrenal production of androgens. It presents a phenotypic spectrum that varies from prenatal virilization of the external genitalia, associated or not with salt wasting crisis in the neonatal period, which can progress to death. Its treatment aims to address glyco and mineralocorticoid deficiencies in order to prevent adrenal insufficiency crisis, reduce the secretion of androgenic steroids and promote adequate growth, puberty and fertility. However, titrating the ideal glucocorticoid dose at different stages of development is a challenge in clinical practice and patients are often exposed to hyper- or hypocortisolism, both of which can have metabolic consequences such as obesity, insulin resistance, type 2 diabetes mellitus. and systemic arterial hypertension. Data on cardiovascular risk in this population remain uncertain, possibly due to the heterogeneity of treatment and its hormonal targets in different monitoring centers, and it is also not well established whether this risk would be related to glucocorticoid treatment or to hyperandrogenism itself. The serum concentration of HDL cholesterol, a known determining factor in CVR, appears variable in different studies, and to date there is no research on its functionality in this rare disease. Objectives: To evaluate the impact of hyperandrogenism and glucocorticoid therapy on the cardiovascular risk of patients with classic forms of CAH, through the assessment of HDL functionality and its correlation with early markers of cardiovascular risk: visceral fat and wave velocity pulse. Case series and methods: 40 patients with classic CAH, aged over 18 years, will be evaluated, followed in a single center, undergoing treatment with cortisone acetate or hydrocortisone in childhood and low doses of dexamethasone or prednisone after obtaining final height. , with 20 patients in the group with good hormonal control and 20 patients in the group with poor control (high androgens); data will be compared to those of 20 healthy controls, matched for sex, age and BMI. The RCV will be evaluated by analyzing the functionality of the HDL particle, after its isolation by ultrafiltration; HDL will be used to measure the removal of 14C-cholesterol from macrophages; to inhibit LDL oxidation and to modulate the secretion of inflammatory cytokines in macrophages stimulated with lipopolysaccharides. In addition, correlation will be carried out with the quantification of visceral fat by abdominal computed tomography, with the assessment of insulin resistance using the revised QUICKI method and with the measurement of pulse wave velocity, which identifies subclinical atherosclerotic disease, measured by the speed of propagation of a pulse between the common carotid and femoral arteries. Justification: the study essentially aims to elucidate whether there is an increased cardiovascular risk in patients with CAH. We will use methodology that has not previously been studied in this population. We will determine whether this increased risk is associated with treatment or hyperandrogenism. With a homogeneous sample in relation to the therapeutic scheme used from childhood to adulthood, this study differs from others. The results will help with still controversial issues regarding therapeutic targets, and will probably contribute to improving the quality of life of these patients.