Congenital Adrenal Hyperplasia

Professor Evangelia Charmandari

Professor of Pediatrics – Pediatric and Adolescent Endocrinology
National and Kapodistrian University of Athens Medical School
First Department of Pediatrics, ‘Aghia Sophia’ Children’s Hospital

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.


22. Kyritsi EM, Koltsida G, Farakla I, Papanikolaou A, Critselis E, Mantzou E, Zoumakis E, Kolaitis G, Chrousos GP, Charmandari EPsychological vulnerability to stress in carriers of congenital adrenal hyperplasia due to 21-hydroxylase deficiencyHormones (Athens). 2017; 16(1): 42-53.

21. Hindmarsh PC, Charmandari EVariation in absorption and half-life of hydrocortisone influence plasma cortisol concentrationsClinical Endocrinology (Oxford) 2015; 82(4): 557-61.

20. Peters CJ, Hill N, Dattani MT, Charmandari E, Matthews DR, Hindmarsh PC. Deconvolution analysis of 24h serum cortisol profiles informs the amount and distribution of hydrocortsione replacement therapyClinical Endocrinology (Oxford) 2012; 78(3): 347-51.

19. Charmandari E, Chrousos GP. Metabolic syndrome manifestations in classic congenital adrenal hyperplasia: Do they predispose to atherosclerotic cardiovascular disease and secondary polycystic ovary syndrome? Annals of the New York Academy of Sciences 2006; 1083: 37-53.

18. Charmandari E, Chrousos GP, Merke DP. Adrenocorticotropin hypersecretion and pituitary microadenoma following bilateral adrenalectomy in a patient with classic 21-hydroxylase deficiencyJournal of Pediatric Endocrinology & Metabolism 2005; 18(1): 97-101.

17. Charmandari E, Brook CGD, Hindmarsh PC. Classic congenital adrenal hyperplasia and puberty. European Journal of Endocrinology 2004; 151 Suppl 3: U77-82.

16. Weise M, Mehlinger SL, Drinkard B, Rawson E, Charmandari E, Chrousos GP, Merke DP. Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term high-intensity exerciseJournal of Clinical Endocrinology & Metabolism 2004; 89(8): 3670-3684.

15. Charmandari E, Merke DP, Negro PJ, Keil MF, Martinez PE, Haim A, Gold PW, Chrousos GP. Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stressJournal of Clinical Endocrinology & Metabolism 2004; 89(5): 2228-2236.

14. Weise M, Mehlinger SL, Drinkard B, Rawson E, Charmandari E, Hiroi M, Eisenhofer G, Yanovski J, Chrousos GP, Merke DP. Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high intensity exerciseJournal of Clinical Endocrinology & Metabolism 2004; 89(2): 591-597.

13. Charmandari E, Pincus SM, Matthews DR, Johnston A, Brook CGD, Hindmarsh PC. Sexual dimorphism in the synchrony of joint growth hormone and cortisol secretion in children with classic 21-hydroxylase deficiencyJournal of Pediatric Endocrinology & Metabolism 2003; 16(8): 1119-1130.

12. Roche E, Charmandari E, Dattani MT, Hindmarsh PC. Blood pressure in children and adolescents with congenital adrenal hyperplasia (21-hydroxylase deficiency) – A preliminary reportClinical Endocrinology (Oxford) 2003; 58(5): 589-596.

11. Charmandari E, Calis KA, Keil MF, Mohassel MR, Remaley A, Merke DP. Flutamide decreases cortisol clearance in patients with congenital adrenal hyperplasiaJournal of Clinical Endocrinology & Metabolism 2002; 87(7): 3197-3200.

10. Charmandari E, Eisenhofer G, Mehlinger SL, Carlson A, Wesley R, Keil MF, Chrousos GP, New MI, Merke DP. Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiencyJournal of Clinical Endocrinology & Metabolism 2002; 87(7): 3031-3037.

9. Charmandari E, Johnston A, Honour JW, Brook CGD, Hindmarsh PC. Treatment with flutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasiaJournal of Pediatric Endocrinology & Metabolism 2002; 15(4): 435-439.

8. Charmandari E, Pincus SM, Matthews DR, Johnston A, Brook CGD, Hindmarsh PC. Oral hydrocortisone administration in children with classic 21-hydroxylase deficiency leads to more synchronous joint GH and cortisol secretionJournal of Clinical Endocrinology & Metabolism 2002; 87(5): 2238-2244.

7.Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos GP, Merke DP. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: Potential clinical implicationsJournal of Clinical Endocrinology & Metabolism 2002; 87(5): 2114-2120.

6. Charmandari E, Brook CGD, Hindmarsh PC. Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty? Archives of Disease in Childhood 2002; 86(4): 266-269.

5. Charmandari E, Matthews DR, Johnston A, Brook CGD, Hindmarsh PC. Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: Is current replacement therapy satisfactory? Journal of Clinical Endocrinology & Metabolism 2001; 86(10): 4679-4685.

4. Charmandari E, Lichtarowicz-Krynska E, Hindmarsh PC, Aynsley-Green A, Brook CGD. Congenital adrenal hyperplasia: management during critical illnessArchives of Disease in Childhood 2001; 85(1): 26-28.

3. Charmandari E, Hindmarsh PC, Johnston A, Brook CGD. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Alterations in cortisol pharmacokinetics at pubertyJournal of Clinical Endocrinology & Metabolism 2001; 86(6): 2701-2708.

2. Charmandari E, Johnston A, Brook CGD, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasiaJournal of Endocrinology 2001; 169(1): 65-70.

1. Charmandari E. Is hydrocortisone clearance 50% slower in the evening than in the morning? Journal of Clinical Endocrinology & Metabolism 2001; 86(2): 948-949.