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  • Review Article
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Management challenges and therapeutic advances in congenital adrenal hyperplasia

Nature Reviews Endocrinology volume 18, pages 337–352 (2022)Cite this article

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Abstract

Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although major advances in molecular biology have delineated steroidogenic mechanisms and the genetics of CAH, management and treatment of this condition continue to present challenges. Management is complicated by a combination of comorbidities that arise from disease-related hormonal derangements and treatment-related adverse effects. The clinical outcomes of CAH can include life-threatening adrenal crises, altered growth and early puberty, and adverse effects on metabolic, cardiovascular, bone and reproductive health. Standard-of-care glucocorticoid formulations fall short of replicating the circadian rhythm of cortisol and controlling efficient adrenocorticotrophic hormone-driven adrenal androgen production. Adrenal-derived 11-oxygenated androgens have emerged as potential new biomarkers for CAH, as traditional biomarkers are subject to variability and are not adrenal-specific, contributing to management challenges. Multiple alternative treatment approaches are being developed with the aim of tailoring therapy for improved patient outcomes. This Review focuses on challenges and advances in the management and treatment of CAH due to 21-hydroxylase deficiency, the most common type of CAH. Furthermore, we examine new therapeutic developments, including treatments designed to replace cortisol in a physiological manner and adjunct agents intended to control excess androgens and thereby enable reductions in glucocorticoid doses.

Key points

  • Challenges in the management of congenital adrenal hyperplasia (CAH) arise from multiple hormonal imbalances, the intrinsic tendency of the CAH-affected adrenal gland to overproduce androgens and limited treatment options, which often necessitate glucocorticoid excess.

  • The relationship between glucocorticoid and mineralocorticoid actions should be considered in the management of replacement therapies in CAH.

  • Patients are at risk of life-threatening adrenal crises with hypoglycaemia, most often triggered by infectious illnesses and exacerbated by adrenaline deficiency.

  • Traditional biomarkers vary with glucocorticoid dose or time of day and are not adrenal-specific, reflecting the need for new biomarkers; for example, the biologically active 11-oxygenated androgens, which are elevated in CAH.

  • Circadian glucocorticoid replacement and adjunct non-glucocorticoid therapies promise to enable glucocorticoid dose reduction; furthermore, the development of personalized gene and cellular therapies is under way.

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Fig. 1: Hormonal alterations in classic CAH.
Fig. 2: Adrenal hyperplasia with extensive adrenocortical reticularis.
Fig. 3: Cortisol and synthetic glucocorticoid profiles over 24 hours.
Fig. 4: Chemical structures of current oral glucocorticoid and mineralocorticoid preparations used in the management of classic congenital adrenal hyperplasia.
Fig. 5: Novel therapeutic approaches in classic CAH.

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  1. National Institutes of Health Clinical Center, Bethesda, MD, USA

    Ashwini Mallappa & Deborah P. Merke

  2. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA

    Deborah P. Merke

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D.P.M. received research funds from Diurnal Limited through the National Institutes of Health Cooperative Research and Development Agreement. During the writing of this manuscript, A.M. took up employment at AstraZeneca and is currently employed there.

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Nature Reviews Endocrinology thanks Antonio Balsamo, who co-reviewed the manuscript with Rita Ortolano, Anna Nordenström and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Mallappa, A., Merke, D.P. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol 18, 337–352 (2022). https://doi.org/10.1038/s41574-022-00655-w

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