Chapter 32 · Module 4 Visual Summary
Pituitary Adenoma Pharmacotherapy
Prolactinoma, Cushing disease, and acromegaly adjunct pharmacology
UFC = urinary free cortisol  ·  ACTH = adrenocorticotropic hormone  ·  GR = glucocorticoid receptor  ·  SSTR = somatostatin receptor subtype  ·  INR = international normalized ratio  ·  GLP-1 = glucagon-like peptide-1
Prolactinoma — Dopamine Agonists
Cabergoline (First-Line)
Ergot D2R Agonist — High Selectivity
  • t½ 63–68 h; twice-weekly oral dosing
  • Start 0.25 mg twice weekly; titrate q4 weeks based on prolactin
  • Usual effective dose: 0.5–2 mg/week
  • Prolactin normalization: 85–95% microadenomas; 70–85% macroprolactinomas
  • Tumor volume reduction: 80–90% of patients
  • Cardiac valvulopathy risk (5-HT2B): echocardiogram at baseline; periodically if >2 mg/week
  • CYP3A4 substrate; dopamine antagonists oppose effect
  • Withdrawal possible after 2 years of normoprolactinemia + no tumor on MRI
Bromocriptine (Alternative)
Ergot D2R Agonist — Shorter Acting
  • t½ 6–8 h; twice or three times daily dosing
  • Higher rates of nausea, vomiting, orthostatic hypotension
  • Advantages over cabergoline:
  • Longest pregnancy safety record (>40 years) — preferred when fertility is the goal
  • Substantially less expensive — preferred in resource-limited settings
  • Rare: pleuropulmonary fibrosis and retroperitoneal fibrosis with long-term high-dose use
Cushing Disease — Pharmacotherapy by Level of Action
Drug Level of Action Mechanism Key Toxicity / Interaction Monitor
Pasireotide Pituitary (ACTH) Pan-SSTR agonist → ↓ ACTH from corticotrophs (SSTR5 > SSTR2) Hyperglycemia 57–73%; prefer GLP-1 agonist or insulin UFC q4–6 weeks; HbA1c; glucose
Cabergoline Pituitary (ACTH) D2R agonist → ↓ ACTH; UFC normalization in ~25–40% Resistance develops in 12–24 months; cardiac valvulopathy at higher doses UFC; prolactin; echocardiogram if >2 mg/week
Ketoconazole Adrenal (steroidogenesis) Inhibits CYP11A1, CYP11B1, CYP17A1 → ↓ cortisol Hepatotoxicity (LFTs q2–4 weeks); strong CYP3A4 inhibitor; QTc prolongation UFC; LFTs; ECG; avoid QT drugs
Metyrapone Adrenal (steroidogenesis) Selective CYP11B1 inhibitor → 11-deoxycortisol accumulates Mineralocorticoid precursor accumulation (hypertension, hypokalemia); hirsutism; nausea UFC; BP; potassium; 11-deoxycortisol
Osilodrostat Adrenal (steroidogenesis) CYP11B1 + CYP11B2 inhibitor → ↓ cortisol and ↓ aldosterone Hypotension and hypokalemia (aldosterone deficiency); QTc prolongation; CYP2D6 inhibitor UFC; electrolytes; BP; ECG
Mitotane Adrenal (cytotoxic) Adrenocortical cell destruction + multi-enzyme inhibition CYP3A4/2B6 inducer (warfarin, glucocorticoids); neurotoxicity; requires lifelong steroid replacement Plasma mitotane level 14–20 mg/L; INR q2 weeks; cortisol and fludrocortisone replacement
Mifepristone Target tissue (GR block) GR antagonist → blocks cortisol action; cortisol and ACTH RISE (expected) Cortisol NOT useful for monitoring; endometrial thickening in women; strong CYP3A4 inhibitor Clinical endpoints (glucose, BP, weight); annual endometrial ultrasound in women
High-Yield Clinical Pearls
Hook Effect
Large Tumor, Falsely Low Prolactin
  • Very high prolactin saturates immunometric assay antibodies
  • Result: falsely normal or low prolactin on standard assay
  • Risk: large mass misclassified as non-functioning adenoma → unnecessary surgery
  • Fix: request 1:100 serum dilution
  • Values that fall further on dilution confirm hook effect → treat with dopamine agonist
Nelson Syndrome
Post-Adrenalectomy ACTH Excess
  • Develops after bilateral adrenalectomy for Cushing disease
  • Loss of cortisol negative feedback → unchecked ACTH hypersecretion
  • Corticotroph tumor enlarges rapidly: visual field loss, cavernous sinus invasion
  • ACTH levels often >500 pg/mL
  • Hyperpigmentation: ACTH-driven melanocyte-stimulating hormone activity
  • Prevention: pituitary radiotherapy after bilateral adrenalectomy reduces risk
  • Treatment: repeat surgery, radiotherapy, temozolomide, pasireotide, cabergoline
Mifepristone Monitoring Rule — Cortisol Is Not Informative
Mifepristone blocks the glucocorticoid receptor at target tissues. Cortisol and ACTH rise during therapy because negative feedback is abolished — this is expected, not treatment failure.  •  Do NOT use serum cortisol, UFC, or ACTH to assess mifepristone efficacy or diagnose adrenal insufficiency.  •  Use clinical endpoints: blood glucose, blood pressure, weight, and resolution of cushingoid features.  •  Adrenal insufficiency diagnosis on mifepristone: use clinical signs (hypotension, fatigue, hyponatremia); treat empirically with high-dose hydrocortisone if suspected; discontinue mifepristone to restore normal feedback axis.