Congenital Adrenal Hyperplasia (CAH)

Definition and Pathophysiology

1. Cholesterol side-chain cleavage enzyme (CYP11A1 / StAR)
2. 3β-hydroxysteroid dehydrogenase (HSD3B2)
3. 17α-hydroxylase / 17,20-lyase (CYP17A1)
4. 21-hydroxylase (CYP21A2) - the most common
5. 11β-hydroxylase (CYP11B1) - second most common

Enzyme Deficiencies

1. 21-Hydroxylase Deficiency (95% of all CAH)

• 17-hydroxyprogesterone (17-OHP) - the key diagnostic marker
• 17-hydroxypregnenolone, progesterone
• These are shunted to DHEA → androstenedione → testosterone (the active androgen in CAH)
• Also via the "backdoor" pathway: progesterone/17-OHP → DHT

• Prenatal androgen exposure begins at ~10 weeks' gestation (during external genitalia formation)
• Results in clitoromegaly, labial fusion, urogenital sinus - i.e., ambiguous genitalia (see Prader classification I-V)
• Internal Mullerian structures (uterus, fallopian tubes, ovaries) are normal

• Appear normal at birth (external genitalia are unaffected by excess androgens)
• Salt wasters develop adrenal crisis within 10-21 days of life: vomiting, dehydration, hyperkalemia, shock - may mimic pyloric stenosis
• Simple virilizers: penile and scrotal enlargement, pubic hair, acne, voice deepening, accelerated bone age within first 2-3 years ("little Hercules" musculature)
• Long-term: short stature (premature epiphyseal closure), infertility in 20-40%
• Testicular adrenal rest tumors (TARTs) in up to 30% - diagnosed by scrotal ultrasound

2. 11β-Hydroxylase Deficiency (~5-8% of CAH)

• Aldosterone synthesis is unaffected - NO salt wasting
• DOC has mineralocorticoid activity → hypertension (characteristic)
• Virilization is similar to 21-OHD

3. Other Rarer Forms

Prader Classification of Virilization

• Prader I: Clitoromegaly only, separate vaginal and urethral openings
• Prader II: Clitoromegaly, single perineal opening (urogenital sinus)
• Prader III: Enlarged phallus with urogenital sinus at base
• Prader IV: Penile urethra opens near the base of a male-appearing phallus
• Prader V: Complete male-appearing external genitalia (phallus with penile urethra at tip, empty "scrotum")

Diagnosis

Neonatal Screening

• Elevated 17-OHP on blood spot (filter paper) - standard of care in most countries
• Premature and sick infants may have false-positive elevations

Biochemical Evaluation

• Morning plasma 17-OHP: markedly elevated in classic 21-OHD (often >10,000 ng/dL)
• For non-classic CAH: basal 17-OHP <200 ng/dL (6 nmol/L) essentially rules out non-classic 21-OHD; if borderline, do ACTH stimulation test (250 mcg cosyntropin) with 1-hour 17-OHP
• Urinary 17-ketosteroids and pregnanetriol: elevated in classic disease
• Plasma renin activity: elevated in salt-wasting form (reflects aldosterone deficiency)
• Electrolytes: hyponatremia, hyperkalemia in salt-wasters
• Serum androstenedione, DHEA, testosterone: elevated

Imaging and Other Workup

• Karyotype: mandatory in any infant with ambiguous genitalia
• Pelvic ultrasound: confirm presence of uterus/ovaries in virilized 46,XX infant
• Scrotal ultrasound: screen for TARTs in males
• Bone age (wrist X-ray): assess degree of advancement from androgen excess

Management

Acute Adrenal Crisis (Salt-Wasting)

• IV hydrocortisone (stress dosing: 50-100 mg/m²/day or 1-2 mg/kg bolus)
• IV normal saline and dextrose for hyponatremic dehydration
• Correct hyperkalemia

Long-Term Medical Therapy

• Hydrocortisone is preferred in children (least effect on growth suppression)
  • Typical dose: 10-15 mg/m²/day in 2-3 divided doses
• Prednisolone or dexamethasone in adults (longer acting, better suppression of ACTH/androgens)
• Goal: suppress excess adrenal androgens while avoiding over-suppression (Cushingoid features, growth suppression)
• Monitoring: 17-OHP, androstenedione, bone age, growth velocity

• Fludrocortisone (9α-fluorohydrocortisone): 0.05-0.2 mg/day
• Sodium supplementation in infants
• Monitor plasma renin activity, blood pressure

Surgical Management (in virilized 46,XX females)

• Feminizing genitoplasty: clitoral reduction and vaginoplasty if indicated
• Timing and extent are individualized; multidisciplinary approach with endocrinology, urology, psychology
• Surgical intervention is typically deferred, particularly for vaginoplasty, until later childhood or adolescence when possible

Prenatal Treatment (experimental/controversial)

• Dexamethasone given to the mother starting before 9 weeks of gestation (before sex can be determined)
• Crosses the placenta, suppresses fetal ACTH, reduces virilization in 46,XX fetuses
• Given to 7 out of 8 fetuses unnecessarily (since only 1 in 8 pregnancies produces an affected female)
• Now not routinely recommended outside of research protocols due to concerns about maternal and fetal adverse effects

Psychological and Behavioral Aspects

• Gender role: preference for masculine-typical toys/activities ("tomboyish" behavior), less interest in child rearing
• Sexual orientation: higher rates of bisexual/homosexual orientation in women with salt-wasting form (proposed to reflect prenatal androgen imprinting of the brain)
• Gender identity: 4% of 46,XX CAH women report gender dysphoria; higher rates (15%) when raised as males
• Psychosocial support is an integral part of long-term management

Key Points Summary

• Goldman-Cecil Medicine, pp. 2515-2522
• Campbell-Walsh-Wein Urology, pp. 1291-1295

Addison Disease (Primary Adrenal Insufficiency)

Definition

Classification

Normal HPA Axis (for reference)

Etiology

1. Autoimmune (most common in industrialized world, ~80%)

• Isolated autoimmune adrenalitis - most common
• Polyglandular Autoimmune Syndrome Type 1 (PAS-1 / APS-1 / APECED):
  • Onset <20 years
  • Triad: hypoparathyroidism + mucocutaneous candidiasis + adrenal insufficiency
  • Due to AIRE gene mutation
• Polyglandular Autoimmune Syndrome Type 2 (PAS-2):
  • Onset >40 years
  • Associated with insulin-dependent diabetes mellitus, autoimmune thyroid disease (Hashimoto/Graves), alopecia areata, vitiligo
• Marker: anti-21-hydroxylase antibodies (present in nearly all autoimmune cases)
• Imaging: small adrenal glands

2. Infectious (~15% in US series)

• Tuberculosis - historically most common worldwide; adrenal tissue replaced by caseating granulomas; may show calcification on imaging
• Systemic fungal infections: histoplasmosis, paracoccidioidomycosis, cryptococcosis, blastomycosis, coccidioidomycosis
• AIDS-associated: CMV infiltration, Kaposi sarcoma, lymphoma, or drug effects (ketoconazole, rifampin)
• Early/recent infection (<2 years): bilateral adrenal enlargement; long-standing: calcification and atrophy

3. Hemorrhagic

• The adrenal gland is susceptible to hemorrhage because 3 arteries supply it but only 1 vein drains it - a "vascular dam" that predisposes to hemorrhage during hemodynamic stress
• Risk factors: thromboembolic disease, coagulopathy, anticoagulation (e.g., heparin), postoperative state, sepsis
• Waterhouse-Friderichsen syndrome: bilateral adrenal hemorrhage in the setting of fulminant meningococcemia
• Diagnosis: biochemical adrenal insufficiency + CT/MRI/ultrasound evidence of hemorrhage
• Prognosis: high mortality if missed

4. Infiltrative

• Bilateral metastases (lung, breast, kidney, gut carcinoma; lymphoma) - adrenal insufficiency uncommon unless extensive
• Amyloidosis
• Sarcoidosis

5. Other Causes

• Adrenoleukodystrophy (ALD): X-linked, 1 in 25,000; deficiency of peroxisomal membrane protein (ABCD1 gene) → accumulation of very long chain fatty acids (VLCFA) → inhibit ACTH signal transduction in adrenal cortex; also causes CNS demyelination (progressive spastic paraparesis, cognitive decline). In boys with Addison disease, must always be excluded. Elevated plasma C26:0 fatty acids is the diagnostic test.
• Drugs: Ketoconazole, mitotane, aminoglutethimide, trilostane, metyrapone (steroidogenesis inhibitors); etomidate (single dose can suppress cortisol)
• Congenital adrenal hypoplasia
• ACTH resistance (familial glucocorticoid deficiency)

Secondary Adrenal Insufficiency (not Addison, for comparison)

• Most common cause: exogenous glucocorticoid use (HPA axis suppression; typically at doses >15-20 mg hydrocortisone equivalent for >3 weeks)
• Structural pituitary/hypothalamic lesions: tumors, trauma, radiotherapy, lymphocytic hypophysitis, infiltration
• Key difference from Addison disease: no hyperpigmentation; no mineralocorticoid deficiency (aldosterone preserved)

Pathophysiology and Clinical Features

Hyperpigmentation - a Hallmark of Primary Adrenal Insufficiency

• Diffuse, but most pronounced in:
  • Sun-exposed areas
  • Pressure/friction sites: elbows, knees, knuckles
  • Skin creases (especially palmar creases)
  • Recent scars (a particularly useful sign)
  • Mucous membranes (buccal mucosa, gingiva, vaginal mucosa) - a key diagnostic pointer
  • Nipples and areolae
  • Nail beds
• Hyperpigmentation is NOT present in secondary adrenal insufficiency (ACTH is low or normal in those cases) - this distinction is diagnostically critical

Acute Adrenal Crisis (Addisonian Crisis)

• May be the first presentation, or may be precipitated by intercurrent illness/surgery in a known patient
• Features: orthostatic hypotension → cardiovascular collapse, abdominal pain, agitation, confusion, fever
• Labs: severe hyponatremia, hyperkalemia, hypoglycemia, eosinophilia, prerenal azotemia
• Life-threatening emergency - must treat immediately without waiting for confirmatory tests

Chronic Presentation

• Gradual onset: malaise, fatigue, weight loss, anorexia, arthralgias, back pain, GI symptoms
• Salt craving (sometimes extreme - e.g., craving pickle brine)
• Hyperpigmentation
• Vitiligo may be associated (in autoimmune cases)
• Associated features of polyglandular syndrome (hypothyroidism, diabetes, hypoparathyroidism)

Biochemical Features

Diagnosis

Screening Test

• Morning serum cortisol:

  • 18 μg/dL (500 nmol/L): virtually excludes adrenal insufficiency

  • <3 μg/dL (83 nmol/L): strongly suggests adrenal insufficiency
  • 3-18 μg/dL: indeterminate → needs stimulation testing

Gold Standard: ACTH (Cosyntropin) Stimulation Test

• Give 250 μg cosyntropin (synthetic ACTH 1-24) IV at any time of day
• Measure serum cortisol at 30 and 60 minutes
• Normal response: cortisol >18 μg/dL (by immunoassay); or >14 μg/dL by mass spectrometry/monoclonal assay
• Failure to reach this threshold = adrenal insufficiency
• A 1-μg dose may be used in the morning and is equally diagnostic, but dose preparation is more error-prone

Metyrapone Test

• Useful for mild or recent secondary adrenal insufficiency (where ACTH response may be preserved)
• Weight-based dose at midnight; cortisol and 11-deoxycortisol measured the next morning
• 11-deoxycortisol <7 μg/dL = adrenal insufficiency

Distinguishing Primary from Secondary

• Plasma ACTH: markedly elevated (>2× upper normal) in primary; low/normal in secondary
• Aldosterone + plasma renin activity: low aldosterone with high renin = primary (mineralocorticoid zone affected); normal in secondary
• Imaging:
  • Primary autoimmune: small adrenal glands
  • Primary infectious/infiltrative/hemorrhagic: large or calcified adrenals
  • Secondary: normal or small adrenals; pituitary/hypothalamic lesion on MRI

Identifying the Cause

• Anti-21-hydroxylase antibodies: present in nearly all autoimmune primary adrenal insufficiency
• If antibody-negative in a male: plasma VLCFA (C26:0) to exclude adrenoleukodystrophy
• CT adrenal imaging: to exclude infection, metastases, hemorrhage
• Screen for other autoimmune endocrinopathies (thyroid, parathyroid, glucose)

Treatment

Acute Adrenal Crisis - Emergency Management

1. Do not delay treatment - draw blood for cortisol measurement, then treat immediately
2. IV Hydrocortisone 100 mg bolus (has both glucocorticoid and mineralocorticoid activity at this dose)
3. IV normal saline (1-2 L rapidly) for volume expansion
4. IV dextrose (D5NS) for hypoglycemia
5. Continue hydrocortisone 50-100 mg IV every 6-8 hours or as continuous infusion
6. Identify and treat the precipitating cause (infection, etc.)
7. Transition to oral replacement once stable

Chronic Glucocorticoid Replacement

• Hydrocortisone (preferred): 10-12 mg/m²/day in 2-3 divided doses
  • Largest dose in the morning (mimics the normal diurnal cortisol peak)
  • One-third of daily dose given around 4 PM if split-dosing
  • Taking the morning dose 30 min before rising helps those with severe morning fatigue
• Prednisolone 4-7 mg daily: longer half-life, useful for afternoon/evening fatigue
• Dexamethasone: infrequently used (dose difficult to standardize)
• Monitoring: clinical assessment, electrolytes, bone density; avoid over-replacement (Cushingoid side effects)

Mineralocorticoid Replacement (primary adrenal insufficiency)

• Fludrocortisone (9α-fluorohydrocortisone) 50-300 μg/day orally
• Dose titrated to: normal blood pressure, normal serum sodium and potassium, normal plasma renin activity
• Patients should be encouraged to eat salt liberally and not restrict dietary sodium
• Note: Mineralocorticoid replacement is NOT needed in secondary adrenal insufficiency

DHEA Replacement

• Some patients with primary adrenal insufficiency have low DHEA
• Routine replacement is not supported by current evidence

Sick Day Rules and Stress Dosing - Critical Patient Education

• All patients must know to double or triple their glucocorticoid dose during:
  • Febrile illness (>38°C)
  • Vomiting/diarrhea (may need IM/IV hydrocortisone if unable to take oral medication)
  • Significant physical stress, trauma, surgery
• Patients should carry a steroid alert card and/or a medical alert bracelet
• IM hydrocortisone for self-injection should be prescribed for emergencies

Primary vs Secondary Adrenal Insufficiency - Key Differences

Recent Evidence

• Ilia et al., 2024 (PMID 39277840) found increased prevalence of adverse pregnancy and fetal outcomes in women with primary adrenal insufficiency - counseling on sick-day rules and stress dosing during pregnancy is particularly important.
• Dalakas et al., 2025 (PMID 40966723) confirmed increased all-cause mortality in primary adrenal insufficiency - likely driven by adrenal crises, cardiovascular events, and infections - reinforcing the need for optimized replacement therapy and crisis prevention.