What are the recommended diagnostic labs and treatment options for a patient with Non-Congenital Adrenal Hyperplasia (NCAH)?

Non-Classic Congenital Adrenal Hyperplasia (NCAH): Diagnosis and Treatment

NCAH due to 21-hydroxylase deficiency is diagnosed when ACTH-stimulated 17-hydroxyprogesterone (17-OHP) levels exceed 10 ng/ml (30 nmol/l), and most patients do not require glucocorticoid treatment unless they are symptomatic or seeking fertility. 1, 2, 3

Diagnostic Approach

Initial Screening

• Measure basal follicular phase 17-OHP as the first-line screening test in all women presenting with hirsutism, oligomenorrhea, infertility, premature pubarche, or acne 2, 3
• A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) warrants further evaluation with ACTH stimulation testing 3
• Basal 17-OHP ≥10 ng/ml (30 nmol/l) is diagnostic without need for stimulation testing 2, 3

Confirmatory Testing: ACTH Stimulation Test

The ACTH stimulation test is the gold standard for diagnosing NCAH 1, 4

• Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 5
• Measure 17-OHP at baseline and 60 minutes post-administration 1
• 17-OHP >10 ng/ml (30 nmol/l) after stimulation confirms NCAH diagnosis 1, 2, 3
• Levels between 2-10 ng/ml suggest heterozygote carrier status 3

Genetic Confirmation

• CYP21A2 gene mutation analysis should be offered to all patients with confirmed NCAH for genetic counseling purposes 4, 6, 3
• This is particularly important for patients planning pregnancy, as they may carry severe alleles that could result in classic CAH in offspring 6, 3
• Many NCAH patients are compound heterozygotes carrying one severe and one mild mutation 6

Distinguishing NCAH from PCOS

NCAH and PCOS present with overlapping features—both cause hirsutism, oligomenorrhea, polycystic ovaries, and insulin resistance 2. The key distinguishing features are:

• 17-OHP levels are the primary differentiator: NCAH shows significantly elevated 17-OHP (>10 ng/ml), while PCOS does not 2
• Progesterone and androstenedione are elevated in both conditions 2
• NCAH patients have higher rates of normal ovulation and lower likelihood of LH/FSH ratio >2 compared to PCOS, though overlap exists 2
• Screen all women with hyperandrogenic symptoms for NCAH before diagnosing PCOS 2, 3

Treatment Strategy

Asymptomatic Patients

Asymptomatic patients with NCAH do not require glucocorticoid treatment 1, 4

Symptomatic Patients: Treatment by Primary Concern

For Hirsutism and Cutaneous Symptoms

• Oral contraceptive pills and/or anti-androgens are first-line therapy for hirsutism, acne, and menstrual irregularity 3
• Avoid glucocorticoids as first-line for cosmetic concerns due to risk of iatrogenic complications 4, 6

For Infertility

• Ovulation induction is the treatment of choice for women seeking fertility 1, 3
• Low-dose glucocorticoids may benefit women with anovulation or recurrent miscarriage 3
• Some women may require assisted reproductive technology 3

For Glucocorticoid Treatment (When Indicated)

• Use the lowest possible glucocorticoid dose to minimize iatrogenic complications 4, 6
• Typical regimens include hydrocortisone 10-15 mg daily or prednisone 2.5-5 mg daily 4
• Monitor for long-term complications: obesity, insulin resistance, hypertension, osteoporosis, and fractures 4, 6

Pregnancy Management

• Women with NCAH have higher miscarriage risk and may benefit from glucocorticoid treatment during pregnancy 3
• Genetic counseling is essential before conception 3

Pediatric Considerations

• Glucocorticoid therapy may benefit children with accelerated growth or advanced bone age 3
• Treatment aims to normalize growth velocity and bone maturation 3

Critical Clinical Pitfalls

• NCAH is NOT characterized by cortisol insufficiency—these patients do not need stress-dose glucocorticoids before surgery unless they have been chronically treated with glucocorticoids 1
• Do not treat all NCAH patients with glucocorticoids reflexively; treatment must match the specific clinical concern 1, 3
• Long-term glucocorticoid therapy causes more harm than benefit in many NCAH patients—reserve for specific indications 4, 6
• Many NCAH cases remain undiagnosed due to mild symptoms or misdiagnosis as PCOS 4, 2

Monitoring and Follow-Up

• Regularly assess for metabolic complications including insulin resistance, cardiovascular disease, and metabolic syndrome 6
• Monitor bone mineral density in patients on chronic glucocorticoid therapy 6
• Some complications may result from prolonged hyperandrogenism rather than glucocorticoid treatment alone 4