A 6-day-old infant who was born via uncomplicated vaginal delivery at 39 weeks of gestation is brought to the family physician for poor feeding. The mother received adequate prenatal care throughout the pregnancy, and has no medical conditions. On physical exam, the infant's temperature is 36.5°C (97.7°F), blood pressure is 70/45 mmHg, pulse is 170/min, and respirations are 40/min. The infant has dry mucous membranes, capillary refill of 4 seconds, and a depressed anterior fontanelle. No abdominal masses are noted. Genital exam shows enlargement of the clitoris with fusion of the labioscrotal folds. Serum chemistry is remarkable for hyponatremia and hyperkalemia. The infant's karyotype is 46,XX. Which of the following findings are most likely to be discovered upon further workup?

Increased sex hormones, increased 17-hydroxyprogesterone

Increased aldosterone, decreased cortisol

Decreased aldosterone, increased 11-deoxycorticosterone

Increased sex hormones, decreased renin activity

Decreased cortisol, decreased sex hormones

A 6-year-old boy is brought to the physician by his mother who is concerned about his early sexual development. He has no history of serious illness and takes no medications. He is at the 99th percentile for height and 70th percentile for weight. His blood pressure is 115/78 mm Hg. Examination shows greasy facial skin and cystic acne on his forehead and back. There is coarse axillary and pubic hair. Serum studies show: Cortisol (0800 h) 4 μg/dL Deoxycorticosterone 2.5 ng/dL (N = 3.5–11.5) Dehydroepiandrosterone sulfate 468 mcg/dL (N = 29–412) Which of the following is the most likely underlying cause of this patient's symptoms?

Idiopathic overproduction of GnRH

Constitutive activation of adenylyl cyclase

A newborn female is found to have ambiguous genitalia and hypotension. Laboratory workup reveals hyperkalemia, hyperreninemia, and elevated levels of 17-hydroxyprogesterone in the patient's urine. Which of the following enzymes would you expect to be deficient in this patient?

3β-hydroxysteroid dehydrogenase

11β-hydroxysteroid dehydrogenase

A 6-day-old newborn girl is brought into the hospital by her mother because of excessive vomiting and poor feeding. The mother did not have antenatal care. Her temperature is 36.8°C (98.2°F), blood pressure is 50/30 mm Hg, and pulse is 150/min. On examination, the infant is dehydrated and demonstrates signs of shock. Her genitalia are ambiguous, with fused labia and an enlarged clitoris. Laboratory results are shown: Serum sodium (Na) 125 mEq/L Serum potassium (K) 6 mEq/L Serum 17-hydroxyprogesterone 100,000 ng/dL (normal level is 1,000–3,000 ng/dL) Which of the following is the most likely cause of this infant's condition?

Deficiency of 11-beta-hydroxylase

Deficiency of 5-alpha reductase

Deficiency of placental aromatase

Deficiency of 17-alpha-hydroxylase

A newborn is delivered at term to a 38-year-old woman after an uncomplicated pregnancy and delivery. The newborn's blood pressure is 142/85 mm Hg. Examination shows clitoral enlargement and labioscrotal fusion. Serum studies show a sodium of 151 mg/dL and a potassium of 3.2 mg/dL. Karyotype analysis shows a 46, XX karyotype. The patient is most likely deficient in an enzyme that is normally responsible for which of the following reactions?

11-deoxycorticosterone to corticosterone

Progesterone to 17-hydroxyprogesterone

Testosterone to dihydrotestosterone

Progesterone to 11-deoxycorticosterone

An 8-year-old boy is brought to the pediatrician by his mother with nausea, vomiting, and decreased frequency of urination. He has acute lymphoblastic leukemia for which he received the 1st dose of chemotherapy 5 days ago. His leukocyte count was 60,000/mm3 before starting chemotherapy. The vital signs include: pulse 110/min, temperature 37.0°C (98.6°F), and blood pressure 100/70 mm Hg. The physical examination shows bilateral pedal edema. Which of the following serum studies and urinalysis findings will be helpful in confirming the diagnosis of this condition?

Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and urate crystals in the urine

Hyperuricemia, hyperkalemia, hyperphosphatemia, and urinary monoclonal spike

Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, urine supernatant pink, and positive for heme

Hyperkalemia, hyperphosphatemia, hypocalcemia, and extremely elevated creatine kinase (MM)

Hyperuricemia, hyperkalemia, hyperphosphatemia, lactic acidosis, and oxalate crystals

Steroid hormone synthesis for USMLE Step 3: High-Yield Biochemistry Lessons

Steroidogenesis - Cholesterol's Makeover

Steroid Hormone Synthesis Pathway with Key Enzymes

Foundation: All steroid hormones are synthesized from cholesterol, primarily in the adrenal cortex, gonads, and placenta.
Rate-Limiting Step: Cholesterol → Pregnenolone, via cholesterol desmolase (P450scc) in the mitochondria. This step is stimulated by ACTH.
📌 Mnemonic for adrenal cortex zones (from outside-in) & products: "Salt, Sugar, Sex... the deeper you go, the sweeter it gets."
- Zona Glomerulosa → Aldosterone (Salt)
- Zona Fasciculata → Cortisol (Sugar)
- Zona Reticularis → Androgens (Sex)

⭐ Enzyme deficiencies are a high-yield topic. A $21$-hydroxylase deficiency shunts all precursors towards androgen production, leading to virilization.

Synthesis Pathway - The Adrenal Axis

Regulation: Hypothalamic CRH → Pituitary ACTH → Adrenal cortex stimulation.
Rate-Limiting Step: Cholesterol → Pregnenolone, catalyzed by Cholesterol Desmolase (CYP11A1) in mitochondria.

Adrenal Steroid Synthesis Pathway

Adrenal Cortex Zones (superficial to deep):
- Glomerulosa → Aldosterone (mineralocorticoids)
- Fasciculata → Cortisol (glucocorticoids)
- Reticularis → Androgens (sex hormones)
- 📌 Mnemonic: "Goes Faster with Red And Caffeine" (Salt, Sugar, Sex...the deeper you go, the sweeter it gets).

⭐ 21-Hydroxylase Deficiency (CYP21A2) is the most common form of Congenital Adrenal Hyperplasia (CAH). It leads to ↓cortisol, ↓aldosterone, and ↑androgens. Presents with virilization in females, salt wasting (hyponatremia, hyperkalemia), and hypotension. Classic finding: ↑17-hydroxyprogesterone.

Congenital Adrenal Hyperplasia - Enzyme Glitches

Autosomal recessive disorders leading to cortisol synthesis defects. ACTH stimulation ↑, causing adrenal hyperplasia.

Steroid hormone synthesis pathway

21-Hydroxylase Deficiency (Most Common, >90%)
- ↓ Aldosterone & Cortisol, ↑ Sex Hormones.
- Presents with salt wasting (hyponatremia, hyperkalemia, hypotension) & virilization in XX females.
- 💡 ↑ 17-hydroxyprogesterone is diagnostic.
11β-Hydroxylase Deficiency
- ↓ Aldosterone & Cortisol, ↑ Sex Hormones.
- ↑ 11-deoxycorticosterone (weak mineralocorticoid) → Hypertension.
- Virilization in XX females.
17α-Hydroxylase Deficiency
- ↑ Aldosterone, ↓ Cortisol & Sex Hormones.
- Hypertension, hypokalemia.
- XY: Ambiguous genitalia. XX: Lacks secondary sexual development.

⭐ Newborn Screening: All states screen for CAH by measuring 17-hydroxyprogesterone levels to detect 21-hydroxylase deficiency early and prevent life-threatening adrenal crises.

High‑Yield Points - ⚡ Biggest Takeaways

All steroid hormones are derived from cholesterol.

The rate-limiting enzyme is desmolase (CYP11A1), converting cholesterol to pregnenolone; this step is stimulated by ACTH.

StAR protein is essential for transporting cholesterol into the mitochondria.

21-hydroxylase deficiency is the most common CAH, presenting with virilization and salt wasting.

17α-hydroxylase deficiency causes hypertension and hypogonadism.

Hormone production is dictated by the unique enzymes within each adrenal cortex layer.

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