Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. The most frequent form of the disease is steroid 21-hydroxylase deficiency, which accounts for 90-95% of all cases of CAH.
Current treatment of classic CAH aims to provide adequate glucocorticoid and, when necessary, mineralocorticoid substitution to prevent adrenal crises and to suppress the excessive secretion of CRH and ACTH, thereby reducing circulating concentrations of adrenal androgens and steroid precursors. However, achieving and maintaining adrenal androgen suppression is far more challenging than preventing adrenal crises, and in a significant number of patients it has proven impossible to control hyperandrogenism without employing supraphysiologic doses of glucocorticoid. In our studies, we have demonstrated that the inability to replicate physiologic cortisol concentrations with administration of hydrocortisone, which is the preferred glucocorticoid during childhood and adolescence, is primarily due to the pharmacokinetic properties of this medication. More specifically, Hydrocortisone tablets have almost complete bioavailability, which leads to supraphysiologic cortisol concentrations within 1-2 hours after administration, but very short half-life, so cortisol concentrations decline monoexponentially and become undetectable 4-6 hours later. This is more evident in females, given that they have significantly shorter half-life of cortisol than males.
In further studies, we showed that patients with the classic form of the disease have significantly higher concentrations of leptin, insulin, and higher insulin resistance index and blood pressure compared with normal subjects. Furthermore, they have compromised adrenomedullary function, as evidenced by the significantly lower plasma epinephrine and metanephrine concentrations, and urinary epinephrine excretion compared to normal subjects. These alterations are likely to predispose patients with classic CAH to the development of metabolic syndrome and atherosclerotic cardiovascular disease in adult life.