Version July 2025
ALGORITHM —
INITIAL EVALUATION —
Congenital adrenal hyperplasias (CAHs) are autosomal recessive disorders; 21-hydroxylase deficiency due to mutations in the CYP21A2 gene accounts for approximately 95 percent of cases. The characteristic biochemical abnormality is a high serum concentration of 17-hydroxyprogesterone. 17-hydroxyprogesterone is also elevated in other forms of CAH (11-beta-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, and P450-oxidoreductase deficiency) (see "Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children and adolescents"):
●Classic CAH – Classic CAH is a severe form of the disorder in which there is 0 to 2 percent 21-hydroxylase enzyme activity and life-threatening cortisol deficiency. Most severely affected individuals are identified through neonatal screening. Other individuals are diagnosed in the neonatal period or in early infancy with adrenal insufficiency and salt wasting (and ambiguous genitalia in females).
●Nonclassic CAH – Nonclassic congenital adrenal hyperplasia (NCCAH) is a less severe form of the disorder in which there is 5 to 20 percent 21-hydroxylase enzyme activity and adequate cortisol production. Most patients with the nonclassic form will not be identified by neonatal screening. NCCAH may present in childhood with premature pubarche and body odor, accelerated growth velocity, and advanced bone age. Later in life, females present with signs of androgen excess (hirsutism, oligomenorrhea, acne) or infertility, and most males are asymptomatic.
In females, NCCAH may present similarly as polycystic ovary syndrome (PCOS). NCCAH is less common than PCOS but should be ruled out because there are risks that offspring could be affected with the more severe classic 21-hydroxylase deficiency, and the management can be different for NCCAH and PCOS.
An early morning (7:30 to 8:00 AM) serum 17-hydroxyprogesterone is a good screening test for NCCAH. In females with regular menstrual cycles, the sample should be obtained during the follicular phase. For females with amenorrhea or infrequent menses, or for males, the sample can be drawn in the morning on a random day. The early morning timing is critical because the 17-hydroxyprogesterone level falls rapidly during the course of the day. If the sample was not collected in the morning, obtain a repeat sample in the morning, preferably using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
The biochemical criteria used for diagnosis in males are the same as those used for females.
≤200 ng/dL (≤6 nmol/L) — A basal, morning serum 17-hydroxyprogesterone value (drawn in the early follicular phase in cycling females) ≤200 ng/dL makes NCCAH unlikely. Evaluate for alternative etiologies.
>200 to ≤1000 ng/dL (>6 to ≤30 nmol/L) — A basal, morning serum 17-hydroxyprogesterone value (drawn in the early follicular phase in cycling female patients) >200 to ≤1000 ng/dL strongly suggests the diagnosis of NCCAH. Perform adrenocorticotropic hormone (ACTH) stimulation test, measuring 17-hydroxyprogesterone and cortisol at baseline and 60 minutes after administration of ACTH (250 mcg). (Cortisol is measured to confirm that the test was performed properly and to identify the rare patient with partial, but usually clinically insignificant, cortisol deficiency.)
Stimulated serum 17-hydroxyprogesterone values are interpreted as follows:
●≤1000 ng/dL (≤30 nmol/L) – A level ≤1000 ng/dL excludes the diagnosis of NCCAH due to 21-hydroxylase deficiency. Rare false-negative results might occur following recent glucocorticoid therapy or incorrectly timed specimen collection. If there is a strong clinical suspicion for an inherited disorder of adrenal steroidogenesis, nonclassic 11-beta-hydroxylase deficiency should be considered and assessed with an ACTH-stimulated 11-deoxycortisol. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency'.)
●>1000 ng/dL (>30 nmol/L) – An elevation of this magnitude confirms the diagnosis of NCCAH. Approximately two-thirds of patients with nonclassic 21-hydroxylase deficiency carry a severe mutation, increasing the risk that offspring could be affected with the more severe classic 21-hydroxylase deficiency. Patients pursuing fertility should consider genotyping of the CYP21A2 gene:
•For mass spectrometry-based assays, which most reference laboratories use, a threshold of >1000 ng/dL (>30 nmol/L) for 17-hydroxyprogesterone is reliable for some defect in cortisol biosynthesis, most commonly nonclassic 21-hydroxylase deficiency. The only false positives are rare heterozygous carriers for classic 21-hydroxylase deficiency or other forms of NCCAH.
•For immunoassays, additional evaluation should be performed when peak 17-hydroxyprogesterone values are >1000 to 2000 ng/dL (>30 to 61 nmol/L) and when the clinical suspicion and/or family history are discordant. The next step in the evaluation is measuring an ACTH-stimulated serum 21-deoxycortisol and/or genotyping of the CYP21A2 gene. (See "Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children and adolescents".)
>1000 ng/dL (>30 nmol/L) — Using mass spectrometry-based assays, a basal, morning serum 17-hydroxyprogesterone value (drawn in the early follicular phase in cycling female patients) >1000 ng/dL is consistent with a diagnosis of NCCAH, usually due to 21-hydroxylase deficiency. For immunoassays, additional evaluation should be performed when 17-hydroxyprogesterone values are >1000 to 2000 ng/dL (>30 to 61 nmol/L) and when the clinical suspicion and/or family history are discordant. The next step in the evaluation is measuring an ACTH-stimulated serum 21-deoxycortisol and/or genotyping of the CYP21A2 gene.
REFERENCE RANGE —
The normal range for serum 17-hydroxyprogesterone varies during the menstrual cycle in females (typically <80 ng/dL [<2.4 nmol/L] during follicular phase) and is different in males. Interpretation of a specific abnormal test result should be based upon the reference range reported with that result.
CITATIONS —
The supporting references for this content are accessible in the linked topics.
