What is the treatment for non-classical congenital adrenal hyperplasia (NCCAH)?

Treatment of Non-Classical Congenital Adrenal Hyperplasia (NCCAH)

Treatment for non-classical congenital adrenal hyperplasia (NCCAH) should be reserved for symptomatic patients, with glucocorticoids, antiandrogens, and oral contraceptives being the main therapeutic approaches, tailored to the specific symptoms and fertility goals of the patient. 1

Clinical Presentation and Diagnosis

NCCAH is a milder variant of 21-hydroxylase deficiency characterized by:

• In females: Hirsutism (60-80%), acne (30%), androgenic alopecia (2-8%), menstrual irregularities (56%), and rarely clitoromegaly (6-20%) 1
• In males: Often asymptomatic, occasionally presenting with premature pubarche, tall stature, gynecomastia, or testicular adrenal rest tumors 1

Laboratory evaluation is recommended for patients who have acne and additional signs of androgen excess 2. Diagnosis typically requires:

• Elevated 17-hydroxyprogesterone levels 2
• Additional hormonal testing may include free and total testosterone, DHEA-S, androstenedione, luteinizing hormone, and follicle-stimulating hormone 2

Treatment Algorithm

1. Symptomatic Females

For Hyperandrogenism (Hirsutism, Acne, Alopecia):

• First-line options:

  • Oral contraceptives (estrogen-progestin combinations) 1
  • Antiandrogens:
    • Spironolactone (50-200 mg daily) 1
    • Cyproterone acetate 1
    • Flutamide (use with caution as it decreases cortisol clearance by 27%) 3

• For acne specifically:

  • Topical treatments: Benzoyl peroxide, topical retinoids, or combinations 2
  • For moderate to severe acne: Consider systemic antibiotics in combination with topical therapy 2

For Menstrual Irregularities:

• Combined oral contraceptives 1

2. Patients Requiring Adrenal Suppression

• Glucocorticoid therapy (when androgen suppression is primary goal):

  • Hydrocortisone: 10-30 mg daily in divided doses 4
  • Prednisone: 5-10 mg daily equivalent 4
  • Dexamethasone: Lower doses due to higher potency and longer half-life

• Dosing considerations:

  • Morning dosing provides better suppression of morning ACTH surge 5
  • Maximum effect of hydrocortisone occurs approximately 3 hours after morning dose 5
  • Evening dose suppression continues until approximately 5:00 AM 5

3. Fertility Management

• For women with infertility:

  • Glucocorticoids to suppress adrenal androgens and improve ovulation 1
  • Consider reproductive endocrinology referral

• For men with fertility concerns:

  • Evaluation for testicular adrenal rest tumors 1
  • Glucocorticoid therapy if tumors are present

Monitoring and Follow-up

• Regular assessment of clinical symptoms
• Monitoring for side effects of glucocorticoid therapy:
  • Lipodystrophy, hypertension, cardiovascular disease, osteoporosis, and metabolic disorders 4
• Periodic measurement of adrenal androgens to assess treatment efficacy

Special Considerations

• Risk of overtreatment: Glucocorticoid excess can lead to iatrogenic Cushing's syndrome 6
• Risk of undertreatment: Inadequate androgen suppression can lead to persistent symptoms 6
• Bone health: NCCAH may be associated with normal or increased bone mineral density due to androgen exposure 1
• Metabolic risks: Some evidence suggests NCCAH may be associated with mild insulin resistance and increased cardiovascular risk 1

Treatment Duration

Treatment duration depends on symptoms and life stage:

• May be required long-term for persistent symptoms
• Can be adjusted or discontinued when symptoms resolve (e.g., post-reproductive years)
• Novel therapies are under investigation for severe cases 7

NCCAH treatment requires balancing androgen suppression against the risks of glucocorticoid excess, with treatment decisions guided by symptom severity, fertility goals, and individual response to therapy.