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. Deletions or mutations of the cytochrome P450 21-hydroxylase gene result in decreased synthesis of glucocorticoids and often mineralocorticoids. The impaired glucocorticoid feedback inhibition at the hypothalamic and anterior pituitary levels leads to increased secretion of CRH and ACTH, respectively, adrenal hyperplasia, and increased production of adrenal androgens and steroid precursors prior to the enzymatic defect.

The clinical spectrum of 21-hydroxylase deficiency is quite broad, ranging from most severe to mild forms, depending on the degree of 21-hydroxylase activity. Accordingly, three main clinical phenotypes have been described: i) classic salt-wasting (SW), ii) classic simple virilizing (SV) and iii) non classic (NC). In addition to the impaired adrenocortical function, patients with classic CAH have compromised adrenomedullary function, which leads to a reduction in epinephrine and metanephrine stores, and decreased production of catecholamines and their metabolites.

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. Therefore, iatrogenic Cushing’s syndrome and hyperandrogenism may develop in tandem, and represent the main problems encountered in the clinical management of patients with classic CAH.

The limitations of standard medical therapy include:

(i) inability to replicate physiologic cortisol production with exogenous administration of glucocorticoid;

(ii) hyperresponsiveness of the hypertrophied adrenal glands to ACTH and increased androgen production following a small ACTH challenge in the event of escape from pituitary suppression;

(iii) difficulty in suppressing ACTH secretion from the anterior pituitary due to the decreased sensitivity to glucocorticoid feedback inhibition, as well as the fact that glucocorticoid feedback is only one of the mechanisms governing ACTH secretion;

(iv) resistance to replacement therapy, given that the increased concentrations of androgens and steroid precursors compete with the exogenously administered glucocorticoids and mineralocorticoids for the same receptors, placing patients with classic CAH at greater risk of stress-induced salt-losing crises than their healthy or Addisionian counterparts.

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 6 hours later. This is more evident in females, given that they have significantly shorter half-life of cortisol than males. In addition, puberty imposes greater difficulty in attaining adrenocortical suppression despite optimal substitution therapy and adherence to medical treatment. Cortisol clearance is increased, especially in females, through alterations in 11β-HSD1 activity, leading to decreased reactivation to cortisol. Furthermore, the increase in growth hormone production increases glomerular filtration rate, while estradiol in both males and females increases cortisol binding globulin. The net effect of those alterations in cortisol pharmacokinetics is a decrease in circulating cortisol concentrations and loss of the HPA axis control, if the fixed dosing of hydrocortisone is not changed.

Novel medical therapies that have been explored for the treatment of classic CAH include hydrocortisone formulations with pharmacokinetic parameters that would mimic more closely physiologic cortisol secretion, the continuous subcutaneous hydrocortisone infusion, and the use of CRF1 receptor antagonists.

Several studies investigated the possibility of developing hydrocortisone formulations with pharmacokinetic parameters that would recreate or mimic more closely physiologic cortisol secretion. The development of these hydrocortisone modified-release formulations was based on a multi-layered multi-particulate technology, where the sustained release and enteric coats could be varied to provide differing release profiles. Essentially, hydrocortisone was coated onto an inert microcrystalline core, which was further covered with a sustained-release layer and an enteric coat layer. When given twice-daily, these formulations provided cortisol exposure similar to that seen in physiologic cortisol concentrations in a healthy reference population and in dexamethasone-suppressed healthy volunteers. Therefore, delayed- and extended release hydrocortisone formulations provide physiologic cortisol replacement in patients with CAH, which is expected to offer improved biochemical control and quality of life, and to decrease the risk for co-morbidities owing to under- and/or over-treatment with glucocorticoids in these patients.

In addition to using modified-release hydrocortisone formulation, efforts have been made to simulate physiologic cortisol secretion by using continuous subcutaneous hydrocortisone infusion (CSHCI). CSHCI results in decreased ACTH and higher cortisol concentrations in the morning, a more physiological 24-hour salivary cortisol and cortisone profile, and adequate suppression of 17-OHP concentrations and adrenal androgen secretion.

Finally, CRF receptor antagonists were explored as a potential treatment in classic CAH. A single dose of a CRF1 receptor antagonist produces clinically significant, dose-dependent reductions in the 08:00h ACTH and 17OHP concentrations in females with classic CAH. Therefore, the use of CRF1 receptor antagonists is a promising agent for the treatment of patients with classic CAH as a strategy to reduce ACTH production without increasing glucocorticoid treatment above the physiologic replacement dose. Advancing CRF1 receptor antagonists into larger, longer term multi-dose trials will allow better assessment of the efficacy in mitigating adrenal androgen overproduction and improving outcomes in patients with classic CAH.

In summary, patients with classic CAH present with impaired adrenocortical function, impaired adrenomedullary function and associated metabolic abnormalities owing to hypercortisolism and/or hyperandrogenism. Modified-release hydrocortisone formulations offer the prospect of physiologic glucocorticoid replacement, with adequate suppression of adrenal androgen production and without exposing patients to supraphysiologic cortisol concentrations. CRF1 receptor antagonists might also be a promising therapeutic approach for patients with classic CAH.