Version July 2025
21OHD: 21-hydroxylase deficiency; ACTH: corticotropin; CAH: congenital adrenal hyperplasia; IM: intramuscularly; IV: intravenously.
* Initial testing for nonclassic 21OHD entails measurement of an unstimulated 17-hydroxyprogesterone level obtained before 8:30 AM. Indeterminate results include a value >200 and ≤1000 ng/dL (6 and 30 nmol/L) measured by any assay method or a value >1000 and ≤2000 ng/dL (30 and 61 nmol/L) measured by immunoassay.
Cosyntropin (ACTH) stimulation testing can be performed at any time of day and, in cycling females, during any phase of the menstrual cycle. A serum cortisol level is obtained to assess for partial cortisol deficiency, which is evident in approximately 30% of patients with nonclassic 21OHD.
¶ In rare cases, a stimulated 17-hydroxyprogesterone level >1000 and ≤2000 ng/dL (30 and 61 nmol/L) may be evident with defects in cortisol biosynthesis other than nonclassic 21OHD. Such values may be seen in individuals who are heterozygote carriers for classic 21OHD or those with CAH due to 11-hydroxylase deficiency. If the individual has no clinical evidence of hyperandrogenism (suggesting carrier status) or family history of another cause of CAH, then genotyping of the CYP21A2 gene is warranted for diagnostic confirmation.
Δ The serum cortisol level measured during ACTH stimulation testing is used to diagnose cortisol deficiency. In nonclassic 21OHD, enzymatic activity is usually sufficient for adequate cortisol production. However, mild cortisol deficiency may be evident in approximately 30% of patients with nonclassic 21OHD. These individuals do not require daily glucocorticoid replacement but should receive stress-dose glucocorticoid therapy during severe physiologic stress. In classic 21OHD, overt cortisol deficiency is present, and daily glucocorticoid replacement therapy is required. The specific cutoffs for subnormal cortisol production vary based on the age of the patient and the type of cortisol assay used. Refer to other UpToDate content on the diagnosis and management of adrenal insufficiency in children and adults.
◊ A low threshold for administering stress-dose glucocorticoids is warranted if a patient develops signs of adrenal crisis during acute physiologic stress, particularly for patients who marginally meet the cutoff for preserved cortisol production.
