A 32-year-old woman from Delhi presents with a 6-month history of progressive proximal muscle weakness, easy bruising, and amenorrhea. On examination, she has central obesity with supraclavicular fat pads, purple striae, and hypertension (160/100 mmHg). 24-hour urinary free cortisol is elevated at 250 µg/day (normal <50). High-dose dexamethasone suppression test (8 mg overnight) shows cortisol of 45 ng/mL (suppressed <50% from baseline). Which corticosteroid would be most appropriate for initial management of her underlying condition?

Explanation

## Clinical Diagnosis This patient presents with classic Cushing syndrome (proximal weakness, striae, hypertension, amenorrhea, central obesity) with biochemical confirmation (elevated 24-hour UFC, inadequate suppression on high-dose dexamethasone). The high-dose dexamethasone suppression test result (45 ng/mL, <50% suppression) is consistent with **adrenal Cushing syndrome** (ACCS), not pituitary-dependent disease (which would suppress >50%). **Key Point:** In adrenal Cushing syndrome, the adrenal gland autonomously produces excess cortisol independent of ACTH; therefore, suppressing ACTH with dexamethasone or other agents is ineffective. ## Role of Metyrapone in Adrenal Cushing Metyrapone is a **11β-hydroxylase inhibitor** that blocks the final step of cortisol synthesis, reducing circulating cortisol levels acutely while allowing ACTH-driven precursor accumulation. It is the **preferred medical agent** for: - Rapid symptomatic relief of severe hypercortisolism (within 24–48 hours) - Bridge therapy before definitive surgery (adrenalectomy) - Patients unfit for surgery or awaiting surgical intervention **High-Yield:** Metyrapone works in **both pituitary and adrenal Cushing**, but is particularly valuable in adrenal disease because it does not rely on ACTH suppression. ## Why Metyrapone Over Alternatives | Agent | Mechanism | Onset | Adrenal Cushing Use | Notes | |-------|-----------|-------|-------------------|-------| | **Metyrapone** | 11β-hydroxylase inhibitor | 24–48 hrs | ✓ Preferred | Rapid symptom relief; bridge to surgery | | **Mitotane** | Adrenolytic (cytotoxic) | 3–6 weeks | ✓ Second-line | Slow onset; reserved for adrenocortical carcinoma or refractory cases | | **Dexamethasone** | Glucocorticoid (ACTH suppression) | N/A | ✗ Ineffective | Adrenal tumour produces cortisol autonomously; ACTH suppression does not help | | **Prednisone** | Glucocorticoid replacement | N/A | ✗ Worsens disease | Adds exogenous steroid; does not address autonomous adrenal production | **Clinical Pearl:** Metyrapone may cause a transient rise in ACTH and precursors (11-deoxycortisol), which can be monitored to guide dosing. Hypokalemia and hypertension should be managed concurrently. ## Management Algorithm ```mermaid flowchart TD A["Cushing Syndrome Confirmed"]:::outcome --> B{"High-dose DST Result?"}:::decision B -->|"Suppression >50%"| C["Pituitary Cushing"]:::outcome B -->|"Suppression <50%"| D["Adrenal Cushing"]:::outcome C --> E["Pituitary MRI + Surgery Planning"]:::action D --> F{"Urgent Symptom Control Needed?"}:::decision F -->|"Yes"| G["Metyrapone 750 mg TDS"]:::action F -->|"No"| H["Plan Adrenalectomy"]:::action G --> I["Bridge to Adrenalectomy"]:::outcome H --> J["Definitive Surgical Cure"]:::outcome ``` **Mnemonic:** **MAD** — **M**etyrapone for **A**drenal **D**isease (acute control); **M**itotane for **M**alignant adrenocortical tumours.