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Reproductive & Endocrine Systems

Congenital adrenal hyperplasia

Core Principle of Congenital Adrenal Hyperplasia
🧷 Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive disorders caused by enzyme deficiencies in cortisol synthesis.
🧷 When cortisol production is impaired, loss of negative feedback causes ACTH to rise, driving adrenal hyperplasia and shunting steroid precursors into alternate pathways.
🧷 The specific enzyme deficiency determines which precursors accumulate and which hormones are deficient, creating distinct clinical phenotypes.
🧷 Board fundamental: CAH always involves cortisol deficiency with compensatory ACTH elevation — the varying presentations depend on which other hormones are affected.
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The Adrenal Steroidogenesis Pathway
📍 Cholesterol → pregnenolone → 17-hydroxypregnenolone → DHEA (via 17α-hydroxylase)
📍 Pregnenolone → progesterone → 17-hydroxyprogesterone → androstenedione (via 21-hydroxylase)
📍 Progesterone → 11-deoxycorticosterone → corticosterone → aldosterone (mineralocorticoid pathway)
📍 17-hydroxyprogesterone → 11-deoxycortisol → cortisol (glucocorticoid pathway)
📍 Each enzyme block causes accumulation of precursors above the block and deficiency of products below.
📍 Board pearl: Draw this pathway — enzyme location determines the pattern of hormone excess and deficiency.
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21-Hydroxylase Deficiency: The Classic CAH
🔹 Accounts for 90-95% of all CAH cases — the default diagnosis when CAH is mentioned without specification.
🔹 Blocks conversion of 17-hydroxyprogesterone → 11-deoxycortisol AND progesterone → 11-deoxycorticosterone.
🔹 Results in cortisol deficiency, aldosterone deficiency (in severe cases), and androgen excess from precursor shunting.
🔹 Elevated 17-hydroxyprogesterone is the diagnostic marker — this is the screening test for newborns.
🔹 Board pearl: 21-hydroxylase deficiency = ↓cortisol, ↓aldosterone, ↑androgens, ↑17-hydroxyprogesterone.
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Clinical Presentations of 21-Hydroxylase Deficiency
⭐ Salt-wasting form (75%): severe enzyme deficiency → mineralocorticoid deficiency → hyponatremia, hyperkalemia, dehydration, shock in first 2-3 weeks of life.
⭐ Simple virilizing form (25%): partial enzyme activity preserves some aldosterone production → virilization without salt wasting.
⭐ XX infants: ambiguous genitalia at birth due to in utero androgen exposure (clitoromegaly, labial fusion, urogenital sinus).
⭐ XY infants: normal male genitalia at birth, but develop precocious puberty if untreated.
⭐ Board clue: Ambiguous genitalia in XX infant + salt wasting = classic 21-hydroxylase deficiency.
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11β-Hydroxylase Deficiency: The Hypertensive CAH
✅ Second most common CAH (5-8%), blocking the final step of cortisol synthesis: 11-deoxycortisol → cortisol.
✅ Also blocks 11-deoxycorticosterone → corticosterone in the aldosterone pathway.
✅ 11-deoxycorticosterone accumulates and has mineralocorticoid activity → hypertension and hypokalemia.
✅ Androgen excess still occurs due to precursor shunting → virilization.
✅ Board distinction: Virilization + hypertension + hypokalemia = 11β-hydroxylase deficiency (opposite electrolytes from 21-hydroxylase).
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17α-Hydroxylase Deficiency: The Sexually Infantile CAH
🧠 Blocks both 17-hydroxylation (pregnenolone → 17-hydroxypregnenolone) AND 17,20-lyase activity (17-hydroxypregnenolone → DHEA).
🧠 Cannot produce androgens or cortisol, but mineralocorticoid pathway remains intact.
🧠 Precursors flood into mineralocorticoid synthesis → 11-deoxycorticosterone accumulation → hypertension and hypokalemia.
🧠 XX patients: normal female external genitalia but absent puberty (no sex hormones).
🧠 XY patients: female external genitalia (no testosterone), undescended testes, absent puberty.
🧠 Board pearl: Hypertension + absent puberty in either sex = 17α-hydroxylase deficiency.
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Rare Forms of CAH
⚡ 3β-Hydroxysteroid dehydrogenase deficiency: blocks conversion of all Δ5 to Δ4 steroids → severe cortisol and aldosterone deficiency with mild virilization from DHEA.
⚡ StAR protein deficiency (lipoid CAH): cannot transport cholesterol into mitochondria → complete absence of all steroid synthesis → severe salt wasting, XY sex reversal.
⚡ P450 oxidoreductase deficiency: affects multiple P450 enzymes → combined features of 17α-hydroxylase and 21-hydroxylase deficiencies.
⚡ Board approach: These are rare — focus on recognizing the three main forms.
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Diagnosis of CAH
📌 Newborn screening: 17-hydroxyprogesterone elevation detects 21-hydroxylase deficiency.
📌 Confirmatory testing: measure specific precursors that accumulate above each enzyme block.
📌 ACTH stimulation test may unmask partial deficiencies by maximally stimulating the pathway.
📌 Genetic testing identifies specific mutations for family counseling.
📌 Prenatal diagnosis possible via amniocentesis or chorionic villus sampling in at-risk families.
📌 Board pearl: Elevated 17-hydroxyprogesterone = 21-hydroxylase; elevated 11-deoxycortisol = 11β-hydroxylase.
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Treatment Principles of CAH
📣 Replace deficient hormones: hydrocortisone for cortisol deficiency, fludrocortisone for aldosterone deficiency.
📣 Suppress ACTH to prevent ongoing stimulation of androgen production — requires supraphysiologic glucocorticoid doses.
📣 Monitor growth velocity, bone age, and 17-hydroxyprogesterone levels to assess treatment adequacy.
📣 Stress-dose steroids required during illness or surgery to prevent adrenal crisis.
📣 Board concept: Treatment simultaneously replaces what's missing and suppresses what's excessive.
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Management of Ambiguous Genitalia
🔸 XX infants with virilization: assign female gender, as they have ovaries and uterus with fertility potential.
🔸 Genital reconstruction surgery controversial — timing debated between early childhood vs. adolescence/adulthood.
🔸 Psychological support essential for patients and families navigating gender identity and sexual function.
🔸 XY infants typically have normal male genitalia and are raised male.
🔸 Board approach: Gender assignment based on karyotype and internal anatomy, not external appearance.
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Late-Onset (Non-Classic) CAH
🧷 Partial 21-hydroxylase deficiency with residual enzyme activity → milder phenotype presenting later in life.
🧷 Presents in adolescence or adulthood with hyperandrogenism: hirsutism, acne, irregular menses, infertility.
🧷 No salt wasting or ambiguous genitalia — cortisol production usually adequate at baseline.
🧷 Diagnosis: elevated baseline or ACTH-stimulated 17-hydroxyprogesterone.
🧷 Board distinction: Young woman with PCOS-like symptoms + elevated 17-hydroxyprogesterone = late-onset CAH.
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CAH and Adrenal Crisis
📍 All forms with cortisol deficiency risk life-threatening adrenal crisis during stress.
📍 Triggers: infection, surgery, trauma, or any physiologic stress exceeding the body's cortisol production capacity.
📍 Presentation: hypotension, shock, hypoglycemia, hyponatremia, hyperkalemia, vomiting, altered mental status.
📍 Management: immediate IV hydrocortisone (not dexamethasone — need mineralocorticoid activity), IV fluids, dextrose.
📍 Board emergency: CAH patient with fever and hypotension = adrenal crisis until proven otherwise.
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Prenatal Treatment of CAH
🔹 Dexamethasone crosses the placenta and suppresses fetal adrenal androgen production.
🔹 Started before 9 weeks gestation in at-risk pregnancies to prevent virilization of affected female fetuses.
🔹 Must treat all pregnancies initially since fetal sex and affected status unknown early.
🔹 Discontinued if fetus is male or unaffected female after prenatal testing.
🔹 Controversial due to unnecessary exposure of unaffected fetuses and potential long-term effects.
🔹 Board concept: Prenatal dexamethasone prevents virilization but doesn't cure the underlying enzyme deficiency.
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Fertility and CAH
⭐ Females with classic CAH have reduced fertility due to multiple factors.
⭐ Elevated androgens suppress gonadotropins and interfere with follicular development.
⭐ Adrenal rest tumors can develop in ovaries, impairing function.
⭐ Genital reconstruction may affect sexual function and vaginal delivery.
⭐ Males may develop testicular adrenal rest tumors (TARTs) causing infertility.
⭐ Board pearl: Optimizing hormone replacement improves but doesn't normalize fertility.
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Molecular Genetics of CAH
✅ CYP21A2 gene mutations cause 21-hydroxylase deficiency — located in HLA complex on chromosome 6.
✅ Severity correlates with residual enzyme activity: null mutations → salt wasting; missense mutations → simple virilizing or non-classic.
✅ CYP11B1 mutations cause 11β-hydroxylase deficiency.
✅ CYP17A1 mutations cause 17α-hydroxylase deficiency.
✅ Genetic testing enables prenatal diagnosis and carrier screening in affected families.
✅ Board relevance: Autosomal recessive inheritance = 25% recurrence risk for carrier parents.
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CAH Differential Diagnosis
🧠 Virilized female infant: CAH (most common), maternal androgen exposure, aromatase deficiency, androgen-secreting tumor.
🧠 Salt-wasting crisis: CAH, congenital adrenal hypoplasia, aldosterone synthase deficiency.
🧠 Ambiguous genitalia: CAH, androgen insensitivity syndrome, 5α-reductase deficiency, gonadal dysgenesis.
🧠 Precocious puberty: CAH, androgen-secreting tumors, McCune-Albright syndrome, familial male precocious puberty.
🧠 Board approach: Measure 17-hydroxyprogesterone first — elevated in >90% of CAH cases.
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Complications and Monitoring
⚡ Short stature from premature epiphyseal fusion if undertreated (excess androgens) or overtreated (excess glucocorticoids).
⚡ Obesity and metabolic syndrome from chronic glucocorticoid therapy.
⚡ Osteoporosis risk with long-term supraphysiologic glucocorticoid doses.
⚡ Adrenal rest tumors in gonads — screen with ultrasound.
⚡ Psychological issues related to genital ambiguity, gender identity, and chronic disease.
⚡ Board monitoring: Growth velocity, bone age, and hormone levels guide therapy adjustments.
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Board High-Yield CAH Patterns
📌 Salt wasting + virilization = 21-hydroxylase deficiency
📌 Hypertension + virilization = 11β-hydroxylase deficiency
📌 Hypertension + sexual infantilism = 17α-hydroxylase deficiency
📌 Elevated 17-hydroxyprogesterone = 21-hydroxylase deficiency
📌 Elevated 11-deoxycortisol = 11β-hydroxylase deficiency
📌 ACTH stimulation differentiates late-onset CAH from PCOS
📌 Memory framework: 21 loses salt, 11 gains pressure, 17 loses sex.
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Board Question Stem Patterns
📣 Newborn with ambiguous genitalia + hyponatremia + hyperkalemia → 21-hydroxylase deficiency
📣 Virilized girl + hypertension + hypokalemia → 11β-hydroxylase deficiency
📣 Teenager with absent puberty + hypertension → 17α-hydroxylase deficiency
📣 Woman with hirsutism + elevated 17-hydroxyprogesterone after ACTH → late-onset 21-hydroxylase deficiency
📣 CAH patient with fever + hypotension + hypoglycemia → adrenal crisis requiring IV hydrocortisone
📣 Precocious puberty + advanced bone age + elevated 17-hydroxyprogesterone → untreated CAH
📣 XX karyotype + ambiguous genitalia + normal internal female organs → assign female gender
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One-Line Recap
🔸 Congenital adrenal hyperplasia results from enzyme deficiencies in cortisol synthesis causing ACTH-driven adrenal hyperplasia with precursor shunting, presenting as three main patterns: 21-hydroxylase deficiency (salt wasting + virilization), 11β-hydroxylase deficiency (hypertension + virilization), and 17α-hydroxylase deficiency (hypertension + sexual infantilism), diagnosed by elevated precursor hormones and treated with hormone replacement to restore deficiencies and suppress androgen excess.
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