Management of Congenital Adrenal Hyperplasia (CAH) due to 21- hydroxylase deficiency involves a delicate balance between risks associated with hyperandrogenemia and those associated with chronic glucocorticoid overexposure and continues to be a challenging task with multiple unmet needs. Glucocorticoids, administered not only to replace cortisol deficiency, but also to suppress adrenocorticotropic hormone (ACTH)-driven hyperandrogenism, are associated with lifelong disruption of the physiological circadian rhythm. Fatigue, obesity, insulin resistance, diabetes, impaired bone health, and psychological morbidity are attributed to the iatrogenic non-physiological cortisol profiles in these individuals resulting from typically used hydrocortisone replacement regimens. The evidence for impaired quality of life and poor health outcomes in individuals with CAH is rising and is likely related to both disease- and treatment-associated morbidity. (1-3)

Recent interventions aiming to achieve a more physiological cortisol profile in individuals with CAH provide hope for the patients, caregivers, and providers. Modified-release glucocorticoid preparations, corticotropin-releasing factor (CRF) 1 receptor antagonists, and ACTH-receptor antagonists have demonstrated some proof to the principle of improved androgen control with less glucocorticoids in clinical trials. (4-12) The application to clinical practice and whether the benefits are substantial or not remains to be confirmed particularly in the long-term.

It is not easy to quantify the disease burden and the anticipated benefit from new interventions on disease control and patient quality of life. More studies and data are required to recognize the different aspects of CAH burden and connect the findings to the potential benefits of such new interventions to the CAH community.

The CAH management landscape requires better utilization of available tools in achieving a better long-term quality of life. The aim of the article collection is to invite researchers and experts in the field to share their experience and enhance the available knowledge on CAH disease burden and views on current and emerging therapies.

We welcome original research articles, reviews, and other article types focusing on but not limited to:

• Advancements in Glucocorticoid Therapy: Evaluations of modified-release glucocorticoid preparations, CRF1 receptor antagonists, and ACTH-receptor antagonists in achieving more physiological cortisol profiles.

• Long-Term Health Outcomes in CAH: Studies exploring the impact of current and emerging treatments on metabolic health, bone density, cardiovascular risk, and psychological well-being.

• Quality of Life and Patient Perspectives: Research on the lived experiences of individuals with CAH, including the psychosocial burden and the impact of lifelong glucocorticoid therapy.

• Personalized Treatment Approaches: Investigations into precision medicine strategies, including genetic and biomarker-driven approaches for optimizing CAH management.

• Bridging the Gap Between Research and Clinical Practice: Studies assessing how recent therapeutic advancements translate into real-world clinical applications and long-term benefits.

• Novel Tools for Disease Burden Assessment: Development and validation of new metrics for quantifying disease burden and treatment effectiveness in individuals with CAH.

1. New MI, Lekarev O, Mancenido D, Parsa A, Yuen T. Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency. Genetic Steroid Disorders 2014. p. 29-51.

2. Porter J, Blair J, Ross RJ. Is physiological glucocorticoid replacement important in children? Arch Dis Child. 2017; 102:199-205.

3. Khattab A, Marshall I. Management of congenital adrenal hyperplasia: beyond conventional glucocorticoid therapy. Curr Opin Pediatr. 2019; 31:550-554.

4. Newfield RS, Sarafoglou K, Fechner PY, Nokoff NJ, Auchus RJ, Vogiatzi MG, Jeha GS, Giri N, Roberts E, Sturgeon J, Chan JL, Farber RH. Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents with Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2023; 108:2871-2878.

5. Auchus RJ, Sarafoglou K, Fechner PY, Vogiatzi MG, Imel EA, Davis SM, Giri N, Sturgeon J, Roberts E, Chan JL, Farber RH.. Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2022 Feb 17.

6. Sarafoglou K, Kim MS, Lodish M, Felner EI, Martinerie L, Nokoff NJ, Clemente M, Fechner PY, Vogiatzi MG, Speiser PW, Auchus RJ, Rosales GBG, Roberts E, Jeha GS, Farber RH, Chan JL; CAHtalyst Pediatric Trial Investigators. Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia. N Engl J Med. 2024; 391:493-503.

7. Auchus RJ, Hamidi O, Pivonello R, Bancos I, Russo G, Witchel SF, Isidori AM, Rodien P, Srirangalingam U, Kiefer FW, Falhammar H, Merke DP, Reisch N, Sarafoglou K, Cutler GB Jr, Sturgeon J, Roberts E, Lin VH, Chan JL, Farber RH; CAHtalyst Adult Trial Investigators. Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia. N Engl J Med. 2024; 391:504-514.

8. Once Daily Oral Atumelnant (CRN04894) Induces Rapid and Profound Reductions of Androstenedione and 17-hydroxyprogesterone in Participants with Classical Congenital Adrenal Hyperplasia: Initial Results From a12-Week, Phase 2, Open-Label Study
Richard J. Auchus, MD, PhD, Peter J. Trainer, MD, Kathryn Jean Lucas, MD3, et al
Poster: Annual Meeting of the Endocrine Society (ENDO); 6/03/2024.

9. Atumelnant (CRN04894) Induces Rapid and Sustained Reductions in Serum and Urine Cortisol in Patients With ACTH-Dependent Cushing Syndrome During a Phase 1b/2a, Single Center, 10-Day, Inpatient, Open-Label Study. Henrik Elenius, Raven McGlotten, Casey Moore, et al. Poster: Annual Meeting of the Endocrine Society (ENDO); 6/03/2024.

10. Merke, D. P., et al). Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2021;106: e2063-e2077.

11. Nowotny, H., et al. Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis. Endocrine 2021; 71:586-594.

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New Insights in the Management of Congenital Adrenal Hyperplasia