Medical management of congenital adrenal hyperplasia: can conventional therapy be replaced by novel treatments?

Congenital adrenal hyperplasia (CAH) is a disorder of decreased cortisol production coupled with an increase in androgens from a compensatory adrenocorticotropic hormone (ACTH) drive. Glucocorticoid and mineralocorticoid replacement is the standard treatment for CAH. The optimal goal is to ensure well-being, prevent adrenal crises and suppress excess androgens but this is unrealistic using conventional treatment. The price paid is childhood growth suppression and adult morbidity associated with obesity and cardiovascular disease. How can this conundrum be solved?

Hydrocortisone (HC) is the preferred glucocorticoid for children with CAH. A short half-life requires dosing three times daily, which is a challenge in infants. Longer-acting steroids have their place but generally only for adults. Despite cortisone being introduced 70 years ago to treat CAH, replicating the cortisol diurnal rhythm remains a challenge.

Immediate-release HC granules, Alkindi (Diurnal Ltd, UK), were developed for infants and children (1). They provide small dosing, flexibility and easy administration. Pharmacokinetic studies showed bioequivalence of Alkindi to the HC tablet.Two modified-release HC preparations are in clinical trials to try to match endogenous cortisol rhythm: Plenadren (immediate and delayed release; Shire Pharmaceuticals Ltd, UK) and Chronocort (delayed and prolonged release; Diurnal Ltd, UK). A morning dose of Plenadren in 16 healthy adults produced a similar cortisol exposure to three times daily HC, except later in the day (2). A supplementary dose of HC would still be needed.Chronocort was designed to mimic increasing cortisol levels overnight, peaking on awakening and falling to a nadir later in the day. Chronocort is taken twice daily in “toothbrush” mode at bedtime and on awakening. A phase 2 study in 16 adults with CAH showed profiles similar to endogenous cortisol; this resulted in reduced conventional HC doses and decreased androgens (3). A larger phase 3 study in 122 patients failed to confirm superiority over conventional treatment but the manufacturers of this agent have nevertheless been given permission to apply for EMA marketing authorization.

As an alternative to suppressing ACTH-induced androgens with modified HC, why not use a top-down approach to block ACTH? (Figure). The hypothalamic–pituitary–adrenal (HPA) axis is orchestrated by corticotrophin-releasing hormone or factor (CRH or CRF). Consequently, blocking this factor or the receptor to which it binds on the cell membrane of pituitary corticotroph cells would inhibit ACTH synthesis and reduce adrenal steroid production. A CRF1 receptor antagonist was studied in eight women with CAH in a phase 1b clinical trial (4), where a bedtime dose significantly reduced morning ACTH levels in a dose-dependent manner. In turn, this decreased concentrations of precursor steroids such as 17OH-progesterone and induced a reduction of androgens. Further studies of a novel approach to medical adrenalectomy are required but the results are promising.Perhaps a complete shutdown of adrenocortical function can be achieved safely and replacement doses of HC and a mineralocorticoid added. This form of block and replace regimen would be akin to the non-surgical treatment of hyperthyroidism.Other examples of non-conventional treatments for CAH include inhibiting the enzyme for adrenal androgen biosynthesis with abiraterone (5), blocking the action of androgens and oestrogens with steroid receptor antagonists (6), continuous infusion of HC by pump therapy similar to that used to treat insulin-dependent diabetes (7) and bilateral adrenalectomy (8). Such therapies have merit at an individual level, but are not suited for routine management of CAH.

Use of HC granules sprinkled on soft food is a practical step forward for infants and young children with CAH. Attempts to deliver HC to replicate endogenous cortisol secretion are progressing with some success. The more radical option of a neuroendocrine approach to the HPA axis by blocking CRH action also has exciting potential for the future medical management of CAH.

Support from the National Institute for Health Research Cambridge Biomedical Centre. R T-C is supported by the Cambridge Children’s Kidney Research Fund.

Professor Ieuan Hughes, Dr Rieko Tadokoro-Cuccaro
Department of Paediatrics, University of Cambridge, Cambridge, UK

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Martin Savage
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