The role of glucocorticoid receptor sensitivity in congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of rare autosomal recessive
disorders characterized by enzymatic deficiencies in adrenal steroidogenesis,
primarily due to 21-hydroxylase deficiency, affecting approximately 1 in 15,000
individuals. This enzymatic defect results in impaired cortisol synthesis and
the accumulation of precursors steroids (PS) and adrenal androgens (AA).
Lifelong glucocorticoid replacement therapy is required to manage cortisol
insufficiency, and patients must adjust their cortisol dosage during stress to
prevent life-threatening adrenal crises. Over- or undertreatment can lead to
long-term complications: undertreatment may result in infertility,
cardiovascular disease, and metabolic disorders, while overtreatment can cause
obesity, hypertension, and other metabolic symptoms. The cortisol dosage
required to normalize AA levels is often supraphysiological and varies widely
between individuals, which we hypothesize is due to interindividual variability
in glucocorticoid receptor sensitivity (GRS) and the modulatory effects of
elevated PS on glucocorticoid receptor activity (GRA). Comparing this
variability with patients with Cushing*s syndrome, who experience excess
cortisol and likely altered GRS, and healthy volunteers could provide important
insights. A better understanding of these factors could lead to more
personalized and optimized therapeutic strategies, reducing the risks of both
over- and undertreatment in patients with CAH.

The aim of this study is to investigate the GRS in CAH patients and compare
these findings with patients with Cushing's syndrome and healthy controls.
Additionally, this study will examine the influence of PS and AA on GRA to
better understand the variability in treatment response in CAH.

an explorative cross-sectional study using an ex vivo PBMC mode

For patients and healthy volunteers, there is no direct benefit in
participating in this study. However, by participating, they can contribute to
the acquisition of scientific knowledge and the development of biomarkers to
predict response to treatment and prevent complications due to over- or
undertreatment. The risks associated with this study are negligible, as no
additional interventions beyond routine patient care will be performed. Blood
will be collected when a venipuncture is already scheduled. Therefore, this
study is considered to impose a low burden on patients.