Cabergoline is an ergot-derived dopamine type 2 receptor agonist with significantly higher dopamine type 2 receptor affinity and selectivity than bromocriptine and a substantially longer elimination half-life of approximately 63 to 68 hours, enabling twice-weekly oral dosing. Typical starting dose is 0.25 milligrams twice weekly, titrated upward by 0.25 to 0.5 milligram increments every 4 weeks based on serum prolactin response; most patients achieve normoprolactinemia at 1 milligram per week or less, with an effective dose range of 0.5 to 2 milligrams per week. Cabergoline undergoes extensive first-pass hepatic metabolism primarily via cytochrome P450 3A4, with predominantly fecal elimination. Drug interactions are modest: strong cytochrome P450 3A4 inhibitors (azole antifungals, macrolide antibiotics) can increase cabergoline levels, and dopamine antagonists (antipsychotics, metoclopramide) pharmacodynamically oppose its prolactin-lowering effect.

The most important long-term safety consideration for cabergoline is cardiac valvulopathy — fibrotic thickening of cardiac valve leaflets, predominantly tricuspid and mitral, with regurgitation. This was first described in Parkinson disease patients receiving high cumulative doses (3 to 6 milligrams per day), far exceeding prolactinoma doses. At typical prolactinoma doses (0.5 to 3.5 milligrams per week), large clinical series have not demonstrated significantly elevated risk of clinically significant valve disease compared with the general population. However, baseline echocardiography is recommended before starting cabergoline and periodic surveillance is appropriate, particularly when doses exceed 2 milligrams per week. The valvulopathy risk is mediated by cabergoline's agonist activity at serotonin 5-hydroxytryptamine 2B receptors on cardiac valve fibroblasts — a non-dopaminergic effect unrelated to the therapeutic mechanism.

Drug withdrawal after sustained normoprolactinemia is an important management decision. Approximately 65 to 70% of patients who achieve sustained normoprolactinemia on cabergoline and have no visible tumor on magnetic resonance imaging remain normoprolactinemic at 1 year after withdrawal. Candidates for withdrawal include patients with normalized prolactin for at least 2 consecutive years and no visible tumor or at most minimal residual changes on magnetic resonance imaging. Recurrence rates reach approximately 30 to 35% within 1 year and up to 70% at 5 years; recurrence is managed by restarting cabergoline.

Bromocriptine is an older ergot dopamine agonist with a shorter half-life (approximately 6 to 8 hours) requiring twice or three times daily oral dosing, and with substantially higher rates of nausea, vomiting, orthostatic hypotension, and nasal stuffiness than cabergoline. Despite inferior tolerability, bromocriptine retains two important advantages. First, it has the longest and largest safety record in pregnancy — over four decades of data with reassuring first-trimester exposure outcomes. Current practice in many centers is to switch women planning pregnancy from cabergoline to bromocriptine before conception, or to discontinue dopamine agonists entirely once pregnancy is confirmed in patients with microadenomas. Second, bromocriptine is substantially less expensive than cabergoline, an important consideration in resource-limited settings. Rare but serious adverse effects with long-term high-dose bromocriptine use include pleuropulmonary fibrosis and retroperitoneal fibrosis.

Ketoconazole is an imidazole antifungal that inhibits multiple adrenal cytochrome P450 enzymes — principally cytochrome P450 11A1 (cholesterol side-chain cleavage), cytochrome P450 11B1 (11-beta-hydroxylase), and cytochrome P450 17A1 (17-alpha-hydroxylase/17,20-lyase) — collectively reducing cortisol biosynthesis across multiple steps. It reduces urinary free cortisol in 50 to 60% of patients with Cushing disease at doses of 400 to 1,200 milligrams daily in divided doses. The principal clinical liabilities are hepatotoxicity (elevated liver enzymes in up to 20% of patients; severe hepatotoxicity in up to 3%), corrected QT interval prolongation via potassium channel (hERG channel) inhibition, and potent cytochrome P450 3A4 inhibition producing numerous drug interactions — dramatically increasing plasma concentrations of cyclosporine, tacrolimus, statins, calcium channel blockers, midazolam, and many others. Liver function test monitoring every 2 to 4 weeks during initiation and monthly thereafter is required.

Metyrapone is a selective inhibitor of cytochrome P450 11B1 (11-beta-hydroxylase), blocking the final step in cortisol synthesis. The upstream intermediate 11-deoxycortisol accumulates and is measurable as a surrogate marker of drug action. Oral bioavailability exceeds 80%, with peak effect within 2 hours. Usual dosing is 750 milligrams to 6 grams daily in three to four divided doses, titrated to normalize urinary free cortisol. Because the block is proximal to cytochrome P450 11B2 (aldosterone synthase), mineralocorticoid precursors accumulate, particularly 11-deoxycorticosterone, which can cause hypokalemia and hypertension. Additional adverse effects include hirsutism and acne in women (from androgenic precursor accumulation driven by increased adrenocorticotropic hormone stimulation above the block), nausea, dizziness, and headache. Metyrapone has limited significant cytochrome P450 drug interactions, differentiating it from ketoconazole.

Osilodrostat (Isturisa) is a newer oral cytochrome P450 11B1 inhibitor with additional cytochrome P450 11B2 (aldosterone synthase) inhibitory activity, approved for Cushing disease. Phase 3 trials demonstrated urinary free cortisol normalization in approximately 53 to 79% of patients at 12 weeks. Dosing starts at 2 milligrams twice daily, titrated upward by 1 to 2 milligram increments based on urinary free cortisol. Unlike metyrapone, osilodrostat also inhibits aldosterone synthesis, which can cause hypotension and hypokalemia through aldosterone deficiency; electrolyte and blood pressure monitoring is essential at each dose titration. Osilodrostat is metabolized by cytochrome P450 3A4 and is a moderate inhibitor of cytochrome P450 2D6, which can increase plasma concentrations of tricyclic antidepressants and certain beta-blockers. Corrected QT interval prolongation occurs at therapeutic doses and requires electrocardiogram monitoring.

Mitotane (o,p'-DDD) is an adrenolytic agent derived from the insecticide DDT that produces selective destruction of the adrenal cortex through cytotoxic mechanisms (formation of reactive acyl chloride intermediates that alkylate adrenocortical cell proteins), in addition to inhibiting multiple steroidogenic enzymes. Indicated primarily for adrenocortical carcinoma, it is also used in refractory Cushing disease. Administered orally in doses of 2 to 6 grams daily in three to four divided doses with fatty food (which substantially increases absorption). The effective plasma concentration range is 14 to 20 milligrams per liter and plasma level monitoring is required. Mitotane is a potent inducer of cytochrome P450 3A4 and cytochrome P450 2B6, accelerating metabolism of warfarin (requiring dose increases of 50% or more), glucocorticoids (requiring doubled or tripled replacement doses), and oral contraceptives. Because mitotane produces adrenal destruction, all patients require lifelong glucocorticoid and mineralocorticoid replacement therapy. Neurotoxic adverse effects at therapeutic concentrations include cerebellar ataxia, cognitive impairment, somnolence, and confusion.

Serum prolactin is measured every 3 months during cabergoline dose titration, then every 6 to 12 months once stable. Pituitary magnetic resonance imaging is performed every 1 to 2 years during active medical therapy (more frequently for macroprolactinomas during initial treatment). Gonadal function assessment — testosterone in men, menstrual regularity and estradiol in women — confirms resolution of hypogonadism. Bone mineral density by dual-energy X-ray absorptiometry is appropriate at baseline in patients with established hypogonadism, as hyperprolactinemia-driven sex steroid deficiency causes bone loss that reverses with successful treatment. Echocardiography is recommended at baseline before cabergoline initiation, particularly when doses are expected to exceed 2 milligrams per week.

Urinary free cortisol or late-night salivary cortisol is measured every 4 to 6 weeks during steroidogenesis inhibitor dose titration to guide dosing and detect over-treatment (adrenal insufficiency). Liver function tests are required every 2 to 4 weeks for ketoconazole during initiation, then monthly. Electrolytes (potassium and sodium) and blood pressure are monitored at each visit for all steroidogenesis inhibitors, with particular attention to hypokalemia (metyrapone, due to mineralocorticoid precursor accumulation) and to both hypokalemia and hypotension (osilodrostat, due to aldosterone synthase inhibition). Hemoglobin A1c and fasting glucose are monitored closely for pasireotide. Electrocardiogram is required for ketoconazole and osilodrostat. Pituitary magnetic resonance imaging every 6 to 12 months in active Cushing disease tracks tumor behavior during medical management. For all patients on steroidogenesis inhibitors: regular assessment of adrenal insufficiency symptoms and confirmation that stress-dose hydrocortisone prescription and injectable hydrocortisone are available.