Endocrine

Pituitary adenoma: prolactinoma, acromegaly, Cushing disease

Clinical Overview and When to Suspect Pituitary Adenoma

— Prolactinoma (~40–50% of functioning adenomas): galactorrhea, amenorrhea, infertility, low libido, erectile dysfunction

— Acromegaly (GH-secreting, ~10–15%): acral/soft-tissue overgrowth, sweating, OSA, glucose intolerance

— Cushing disease (ACTH-secreting, ~5%): central obesity, striae, proximal myopathy, hypertension, hyperglycemia

— Young woman with secondary amenorrhea + galactorrhea → check prolactin

— Adult with new ring/shoe size increase, jaw prognathism, or new diabetes + hypertension + OSA cluster → IGF-1

— Patient with refractory HTN, hypokalemia, weight gain, easy bruising, new-onset DM under age 40 → screen for hypercortisolism

— Any patient with bitemporal hemianopsia, new headache pattern, or hypopituitarism (fatigue, cold intolerance, hypogonadism)

Pituitary adenomas are benign monoclonal tumors of the anterior pituitary, accounting for ~15% of intracranial neoplasms. Classified by size (microadenoma <1 cm, macroadenoma ≥1 cm) and function (hormone-secreting vs nonfunctioning).

Three hypersecretory syndromes dominate Step 3:

When to suspect in outpatient practice:

Incidentalomas: ~10% of MRIs show pituitary lesions; most are nonfunctioning microadenomas requiring hormonal screen + visual fields if ≥1 cm.

Board pearl: Always check prolactin, IGF-1, and a cortisol screen (late-night salivary cortisol or 1-mg dexamethasone suppression) on any newly discovered pituitary mass — plus TSH/free T4, LH/FSH, testosterone or estradiol, and morning cortisol to assess for hypopituitarism from stalk compression.

Step 3 management: The outpatient internist's role is recognition + initial biochemical screen + referral to endocrinology; neurosurgery is engaged for macroadenomas with mass effect, Cushing disease, acromegaly, or dopamine-agonist–resistant prolactinomas.

Presentation Patterns and Key History

— Premenopausal women: oligomenorrhea/amenorrhea, galactorrhea, infertility — typically presents as microadenoma because symptoms appear early

— Men and postmenopausal women: decreased libido, ED, gynecomastia, infertility — often presents as macroadenoma with mass-effect symptoms (headache, visual loss) because hypogonadism is recognized late

— Always ask about medications that elevate prolactin: antipsychotics (risperidone, haloperidol), metoclopramide, methyldopa, verapamil, SSRIs, opioids, estrogens

— Enlarging hands/feet (ring tightening, increased shoe size), coarsening facial features, frontal bossing, prognathism, macroglossia, widely spaced teeth

— Hyperhidrosis, oily skin, deepening voice, skin tags (associated with colon polyps)

— Headache, arthralgias, carpal tunnel syndrome, OSA, new HTN, diabetes (~25%), cardiomyopathy

— Compare old photos — most useful single history item

— Weight gain (central), moon facies, dorsocervical fat pad ("buffalo hump"), supraclavicular fullness

— Wide purple striae (>1 cm), easy bruising, proximal muscle weakness (difficulty rising from chair, climbing stairs), thin skin

— Hypertension, hyperglycemia, hypokalemia, osteoporosis/fragility fractures, mood lability, psychosis

— Menstrual irregularity, hirsutism, acne from adrenal androgen excess

— Headache (dural stretch), bitemporal hemianopsia ("bumping into things, car accidents"), diplopia from cavernous sinus invasion (CN III, IV, VI, V1/V2)

— Symptoms of hypopituitarism: fatigue, cold intolerance, weight loss, hypotension, loss of axillary/pubic hair

Prolactinoma:

Acromegaly (insidious, ~10-year diagnostic delay):

Cushing disease:

Mass-effect history (any subtype):

Key distinction: Galactorrhea + amenorrhea in a woman on risperidone — rule out drug-induced hyperprolactinemia first (prolactin usually <100 ng/mL) before imaging.

Physical Exam Findings and Visual Field Assessment

— Confrontation visual fields with each eye separately — look for bitemporal hemianopsia from optic chiasm compression

— Cranial nerves III, IV, VI, V1/V2 — cavernous sinus extension causes ophthalmoplegia, ptosis, facial sensory loss

— Fundoscopy: optic atrophy in long-standing chiasmal compression

— Expressible galactorrhea (bilateral, milky), breast exam for masses

— Tanner staging in adolescents with delayed puberty

— Testicular volume in men (small, soft testes from hypogonadism)

— Large, doughy, sweaty hands; "spade-like" appearance

— Frontal bossing, prognathism, malocclusion, increased interdental spacing, macroglossia with tooth indentations

— Tinel/Phalen sign for carpal tunnel

— Skin tags (acrochordons), oily skin, deep nasolabial folds

— Cardiac: displaced PMI, S3/S4, signs of CHF; auscultate for OSA-related pulmonary HTN

— Acanthosis nigricans (insulin resistance)

— Centripetal obesity with thin extremities, supraclavicular fat pads, dorsocervical hump

— Plethoric moon facies

— Wide violaceous striae on abdomen, thighs, breasts, axillae (>1 cm distinguishes from simple obesity)

— Easy bruising, thin "cigarette paper" skin

— Proximal myopathy: have patient rise from chair without using arms — most specific clinical sign

— Hirsutism, acne, hyperpigmentation (hyperpigmentation suggests very high ACTH — favors ectopic ACTH or Nelson syndrome)

— BP elevation; check for hypokalemic alkalosis stigmata

General exam priorities in any suspected pituitary adenoma:

Prolactinoma-specific:

Acromegaly-specific:

Cushing disease-specific:

Hemodynamic note: Acromegaly causes biventricular hypertrophy and diastolic dysfunction; Cushing causes volume-expanded hypertension. Both require BP measurement in both arms and assessment for OSA.

Board pearl: Proximal muscle weakness + wide purple striae + spontaneous ecchymoses is the most specific clinical triad for endogenous Cushing — push for biochemical testing even if BMI is "normal."

Diagnostic Workup — Initial Labs and Imaging

— Serum prolactin (fasting, midmorning, non-stressed draw)

— Normal <25 ng/mL (women), <20 (men). >200 ng/mL → almost always prolactinoma; 25–200 → broad differential

— Confirm with repeat sample. Check TSH (primary hypothyroidism elevates prolactin via TRH), β-hCG (pregnancy), BUN/Cr (CKD reduces clearance), medication review

— Hook effect: in very large prolactinomas, assay saturation gives falsely low prolactin — request 1:100 dilution if macroadenoma but prolactin appears modestly elevated

— Macroprolactin: biologically inactive aggregate; asymptomatic patient with elevated prolactin → request PEG precipitation

— Serum IGF-1 — best initial screening test; age- and sex-matched reference range

— Random GH is unreliable (pulsatile)

— If IGF-1 elevated → 75-g oral glucose tolerance test with GH measurement: failure of GH to suppress <1 ng/mL (or <0.4 with ultrasensitive assay) confirms diagnosis

— Late-night salivary cortisol (×2 — easiest outpatient)

— 24-hour urine free cortisol (×2)

— 1-mg overnight dexamethasone suppression test (cortisol should suppress <1.8 µg/dL)

— Once hypercortisolism confirmed → plasma ACTH:

– ACTH suppressed (<5 pg/mL) → ACTH-independent (adrenal) → adrenal CT

– ACTH normal/elevated → ACTH-dependent → next step is pituitary MRI

Prolactinoma:

Acromegaly:

Cushing disease — requires two positive first-line tests:

Imaging: Pituitary MRI with and without gadolinium, dedicated thin-cut sellar protocol — for any confirmed hormonal abnormality or suspected mass effect

Visual field testing: formal Humphrey perimetry for any macroadenoma or chiasm-abutting lesion

Step 3 management: Don't order MRI before biochemistry in suspected Cushing — incidentalomas in 10% of normals will mislead you. Confirm hypercortisolism first, then ACTH, then image.

Diagnostic Workup — Advanced and Confirmatory Studies

— Once ACTH-dependent hypercortisolism confirmed and MRI shows adenoma ≥6 mm → Cushing disease likely

— MRI negative or adenoma <6 mm → inferior petrosal sinus sampling (IPSS) with CRH stimulation is the gold standard

– Central:peripheral ACTH ratio ≥2 (baseline) or ≥3 (post-CRH) confirms pituitary source

— High-dose dexamethasone suppression test (8 mg): suppression >50% suggests pituitary; no longer first-line but appears on exams

— CRH stimulation test: rise in ACTH/cortisol favors pituitary

— If ectopic ACTH suspected: CT chest/abdomen/pelvis, somatostatin receptor PET (Ga-68 DOTATATE) for small-cell lung, bronchial carcinoid, medullary thyroid, pancreatic NET

— OGTT with GH suppression is confirmatory after elevated IGF-1

— Pituitary MRI localizes adenoma (>75% are macroadenomas at diagnosis)

— Screen for comorbidities: echocardiogram (cardiomyopathy), sleep study (OSA in 60%), colonoscopy at diagnosis (increased colon polyp/cancer risk), HbA1c, lipid panel, DEXA

— MRI to characterize size, cavernous sinus invasion, chiasm contact

— If macroadenoma → check all pituitary axes (cortisol, TSH/FT4, LH/FSH, testosterone/estradiol, IGF-1) for hypopituitarism

— Formal visual fields if tumor touches/abuts chiasm

— 8 AM cortisol + ACTH (cosyntropin stim if borderline)

— Free T4 (TSH unreliable in central hypothyroidism)

— LH/FSH + sex steroids

— IGF-1 (GH deficiency)

— Posterior pituitary rarely affected pre-op; post-op DI is common

Cushing disease — distinguishing pituitary from ectopic ACTH (critical Step 3 pathway):

Acromegaly confirmatory:

Prolactinoma confirmatory:

Hypopituitarism evaluation (any macroadenoma):

Board pearl: IPSS is invasive and operator-dependent — reserve for ACTH-dependent Cushing with negative/equivocal MRI or discordant biochemistry. Don't order it first.

Risk Stratification and First-Line Management Logic

— Microadenoma without symptoms (e.g., menses preserved, no infertility goal) → may observe with serial prolactin/MRI

— Symptomatic micro- or any macroadenoma → dopamine agonist (cabergoline preferred)

— Surgery reserved for: dopamine-agonist intolerance, resistance, CSF leak, apoplexy, patient preference, pregnancy planning with macroadenoma

— Transsphenoidal surgical resection by high-volume neurosurgeon is definitive

— Cure rates: 80–90% for microadenomas, 40–50% for macroadenomas

— Persistent disease post-op → medical therapy (somatostatin analogs, pegvisomant, cabergoline) ± radiation

— Transsphenoidal selective adenomectomy by experienced surgeon

— Remission rates 70–90% for microadenomas

— Failure or recurrence → repeat surgery, radiation, medical therapy (ketoconazole, metyrapone, osilodrostat, mifepristone, pasireotide), or bilateral adrenalectomy (risk of Nelson syndrome)

— Microadenoma, no mass effect, no hormone deficits → observe with MRI at 1 year, then every 1–2 years

— Macroadenoma → surgery if visual compromise, hypopituitarism, growth, or chiasm contact

— Replace cortisol first if adrenal insufficiency present (stress-dose hydrocortisone perioperatively)

— Treat hypothyroidism, control hyperglycemia, optimize BP, screen for OSA

— Anesthesia consult for acromegaly (difficult airway from macroglossia, prognathism)

Prolactinoma — medical therapy is first-line (unique among pituitary adenomas):

Acromegaly — surgery is first-line:

Cushing disease — surgery is first-line:

Nonfunctioning adenoma decision tree:

Pre-op considerations for all:

Step 3 management: The classic exam trap — prolactinoma macroadenoma with visual field defect. Don't rush to surgery. Start cabergoline; tumors typically shrink within weeks and vision often recovers. Surgery only if no response.

Pharmacotherapy — First-Line Drug Regimens

— Cabergoline 0.25 mg PO twice weekly, titrated to 0.5–1 mg twice weekly based on prolactin and tumor response (preferred: better efficacy, tolerability, less nausea)

— Bromocriptine 1.25 mg PO qHS, titrated to 2.5–15 mg/day (preferred in pregnancy planning due to longer safety record)

— Adverse effects: nausea, orthostatic hypotension, headache, nasal congestion, psychiatric (impulse control disorders — gambling, hypersexuality), cardiac valvulopathy (cabergoline at high doses — echo if >2 mg/week)

— Monitor prolactin q1month until normal, then q3–6 months; MRI at 3–6 months and 1 year

— Attempt taper/withdrawal after ≥2 years of normal prolactin and no MRI tumor

— Somatostatin receptor ligands: octreotide LAR 20 mg IM monthly, lanreotide 90 mg SQ monthly, pasireotide LAR (potent but causes hyperglycemia)

– SE: gallstones, bradycardia, GI upset, hyperglycemia

— GH receptor antagonist: pegvisomant SQ daily — normalizes IGF-1 but doesn't shrink tumor; monitor LFTs and tumor MRI

— Cabergoline: modest efficacy if IGF-1 only mildly elevated

— Steroidogenesis inhibitors (block cortisol synthesis):

– Ketoconazole 200–400 mg PO BID-TID (hepatotoxicity, QT prolongation, drug interactions via CYP3A4)

– Metyrapone 250 mg–1 g PO q6h (hirsutism, hypokalemia, HTN from mineralocorticoid precursors)

– Osilodrostat — newer 11β-hydroxylase inhibitor

— Pituitary-directed: pasireotide SQ BID (hyperglycemia in 70%)

— Glucocorticoid receptor antagonist: mifepristone — used when DM/HTN dominant; can't follow cortisol (blocks receptor, ACTH/cortisol rise)

— Adrenolytic: mitotane (rare for Cushing disease; mostly adrenocortical carcinoma)

Prolactinoma — dopamine agonists:

Acromegaly medical therapy (post-op residual or non-surgical candidate):

Cushing disease medical therapy:

Board pearl: Always counsel cabergoline patients about impulse control disorders — failure to disclose is a tested informed-consent issue.

Procedures — Transsphenoidal Surgery and Radiation

— Indications: acromegaly, Cushing disease, dopamine-agonist–resistant prolactinoma, any macroadenoma with mass effect, apoplexy

— Cure rates depend on surgeon volume — refer to centers performing >50/year

— Microadenoma cure: Cushing 70–90%, acromegaly 80–90%, prolactinoma 80–90%

— Macroadenoma cure rates drop to 40–60%

— Pre-op: stress-dose hydrocortisone (50–100 mg IV at induction) if adrenal axis suppressed or unknown

— Post-op day 1–3: monitor for diabetes insipidus (polyuria >300 mL/hr, hypernatremia, dilute urine) — DDAVP as needed

— Post-op day 7–10: watch for SIADH (hyponatremia from delayed ADH release) — fluid restrict

— Triphasic response: DI → SIADH → permanent DI possible

— Check morning cortisol POD 2–3: <3 µg/dL suggests cure (in Cushing) AND requires glucocorticoid replacement; >18 µg/dL suggests persistent disease

— Free T4 at 6 weeks; full axis re-evaluation at 6–12 weeks

— CSF rhinorrhea (5%), meningitis, epistaxis, sinusitis

— New hypopituitarism (5–15%), permanent DI (1–3%)

— Carotid injury (rare), visual loss (<1%)

— Stereotactic radiosurgery (gamma knife) preferred for well-defined residual tumor away from chiasm (>3–5 mm)

— Fractionated radiotherapy for larger residual disease near chiasm

— Biochemical control takes 5–10 years; high rate of subsequent hypopituitarism (50% at 10 years)

— Small risks: secondary tumors, cerebrovascular disease, optic neuropathy

Transsphenoidal surgery (TSS) — endoscopic endonasal approach is standard:

Perioperative management (CCS-flavored):

Complications of TSS:

Radiation therapy:

Bilateral adrenalectomy: salvage for refractory Cushing — rapid cure but risk of Nelson syndrome (aggressive ACTH-secreting tumor growth, hyperpigmentation) — requires lifelong steroid replacement + pituitary surveillance

CCS pearl: After transsphenoidal surgery, order strict I/O, daily weights, serum Na, urine specific gravity — don't forget stress-dose steroids continued until POD 2 cortisol checked.

Special Populations — Elderly and Renal/Hepatic Impairment

— Pituitary incidentalomas more common — most are nonfunctioning and stable

— Threshold for surgery higher; weigh frailty, comorbidity, life expectancy

— Cushing disease in elderly often presents as osteoporotic fractures, refractory HTN, new DM, or proximal weakness — easily attributed to "aging"

— Acromegaly diagnosis delayed average 10 years — many elderly patients present with cardiomyopathy, colon cancer, or arthropathy as the unmasking event

— Prolactinoma in postmenopausal women lacks menstrual clue → often presents with macroadenoma and visual loss

— Start lower dose in elderly (cabergoline 0.25 mg weekly) due to orthostasis, fall risk

— Screen for cognitive issues before prescribing (impulse control disorders harder to detect)

— Annual echo if cumulative dose high (mainly relevant in Parkinson dosing, but be aware)

— Cabergoline and bromocriptine are hepatically metabolized — minimal renal adjustment

— Octreotide/lanreotide: dose adjustment in severe renal impairment; monitor more closely

— Pegvisomant: minimal renal clearance, generally safe

— Hyperprolactinemia of CKD: prolactin elevation from reduced clearance, typically <100 ng/mL; don't treat as prolactinoma unless symptomatic and MRI confirms

— Ketoconazole contraindicated in active hepatic disease; baseline + serial LFTs mandatory (boxed warning)

— Pegvisomant: monitor LFTs monthly initially — discontinue if ALT >5× ULN

— Cabergoline/bromocriptine: use cautiously, reduce dose

— Mitotane and metyrapone require hepatic monitoring

— Ketoconazole/osilodrostat strong CYP3A4 inhibitors — review warfarin, statins, DOACs, antifungals

— Cabergoline with antihypertensives: additive orthostasis

Elderly considerations:

Dopamine agonist dosing:

Renal impairment:

Hepatic impairment:

Polypharmacy and drug interactions:

Board pearl: An elderly patient with mildly elevated prolactin (40–80 ng/mL) and CKD stage 4–5 — don't image, don't treat unless symptomatic; it's clearance-mediated.

Special Populations — Pregnancy and Fertility

— Fertility restored within weeks of dopamine agonist initiation — counsel about immediate contraception decisions

— Bromocriptine has the most pregnancy safety data and is traditionally preferred for conception

— Cabergoline increasingly used; no clear teratogenicity signal

— Once pregnancy confirmed → stop dopamine agonist for microadenomas (tumor growth risk <3%); continue for macroadenomas with chiasm proximity (growth risk ~20–30%)

— Don't check prolactin during pregnancy — physiologic rise is normal

— Monitor visual fields each trimester for macroadenomas; MRI without gadolinium if symptoms develop

— Breastfeeding is permitted post-delivery if asymptomatic; resume DA after weaning if needed

— Fertility often impaired (hypogonadism, hyperprolactinemia from stalk effect)

— Stop somatostatin analogs and pegvisomant before conception when possible (limited safety data)

— Most tumors stable during pregnancy; placental GH variant interferes with assays — don't monitor IGF-1 during pregnancy

— Watch for gestational diabetes, hypertension, cephalopelvic disproportion

— Rare; cortisol naturally rises in pregnancy → diagnosis challenging

— Use 24-hour urine free cortisol (>3× ULN suggestive); late-night salivary cortisol less reliable

— Untreated hypercortisolism → high rates of preeclampsia, GDM, prematurity, fetal loss

— Transsphenoidal surgery in second trimester is preferred treatment

— Metyrapone has been used; ketoconazole and mifepristone contraindicated

— Rare; consider MEN1 (parathyroid, pancreatic NET, pituitary), Carney complex, familial isolated pituitary adenoma

— Prolactinomas most common in adolescent girls

— GH-secreting tumors before epiphyseal closure → gigantism, not acromegaly

— Growth chart deviation is the key screen

Prolactinoma and pregnancy:

Acromegaly and pregnancy:

Cushing disease and pregnancy:

Pediatric pituitary adenomas:

Step 3 management: Woman with prolactinoma wanting pregnancy → use bromocriptine, switch from cabergoline if she's on it; stop at first positive pregnancy test for microadenoma; perimetry each trimester for macroadenoma.

Complications and Adverse Outcomes

— Bitemporal hemianopsia from chiasm compression — can become permanent if delayed >6 months

— Cavernous sinus syndrome: CN III/IV/VI palsy, V1/V2 sensory loss

— Hydrocephalus (rare, from third ventricle obstruction)

— Hypopituitarism from compression/destruction: secondary adrenal insufficiency, central hypothyroidism, hypogonadism, GH deficiency, central DI

— Sudden hemorrhage/infarction into adenoma → thunderclap headache, ophthalmoplegia, vision loss, altered mental status

— Triggers: anticoagulation, hypertension, surgery, dopamine agonist therapy, dynamic testing, pregnancy

— Treatment: stress-dose hydrocortisone immediately, urgent MRI, neurosurgery consultation; surgical decompression for visual deficits

— Cardiovascular: biventricular hypertrophy, diastolic dysfunction, HTN, arrhythmia

— Metabolic: DM, dyslipidemia

— OSA (60%), pulmonary hypertension

— Colon polyps and colorectal cancer — increased incidence

— Thyroid nodules, arthropathy, carpal tunnel

— Venous thromboembolism risk markedly elevated — peri-op DVT prophylaxis critical

— Osteoporosis, vertebral fractures

— DM, HTN, hypokalemia, dyslipidemia

— Infections (immunosuppression), poor wound healing

— Psychiatric: depression, psychosis, suicide risk

— Mortality 2–4× general population if untreated

— Hypogonadism → infertility, osteoporosis, decreased lean mass

— Macroadenoma mass effect

— Post-op DI/SIADH, hypopituitarism, CSF leak, meningitis

— Radiation: hypopituitarism, secondary tumors, optic neuropathy

— DA: impulse control disorders, valvulopathy at high doses, CSF leak from rapid macroadenoma shrinkage

Mass-effect complications:

Pituitary apoplexy — neurosurgical emergency:

Acromegaly-specific morbidity (increases mortality 2–3×):

Cushing-specific morbidity:

Prolactinoma-specific:

Treatment-related:

Board pearl: Pituitary apoplexy = give hydrocortisone before MRI. Don't wait for cortisol levels — adrenal crisis is the immediate killer, not the hemorrhage itself.

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Pituitary apoplexy: thunderclap headache + visual loss/ophthalmoplegia → ICU, hydrocortisone 100 mg IV, neurosurgery, neuro-ophthalmology

— Adrenal crisis in known/suspected hypopituitarism: hypotension, hyponatremia, hypoglycemia → hydrocortisone 100 mg IV bolus, then 50 mg q6h, aggressive IV fluids

— Severe hypercortisolism (random cortisol >40 µg/dL, UFC >5× ULN, hypokalemia, psychosis, infection): admit for rapid block-and-replace with metyrapone/ketoconazole, VTE prophylaxis, infection screening

— Severe acute visual loss from macroadenoma: urgent neurosurgical decompression

— Any newly diagnosed hormone-secreting adenoma

— Cushing syndrome workup (complex biochemistry)

— Acromegaly with cardiac/respiratory comorbidity needing pre-op optimization

— Macroprolactinoma with visual deficit (DA may avert surgery — get endo input first)

— Macroadenoma with mass effect or chiasm contact

— All Cushing disease and acromegaly cases

— DA-resistant or intolerant prolactinoma

— Apoplexy

— Neuro-ophthalmology: formal perimetry, OCT

— Anesthesia pre-op consult for acromegaly (difficult airway algorithm)

— Cardiology: pre-op echo in acromegaly and severe Cushing

— Sleep medicine: OSA screening in acromegaly

— Psychiatry: Cushing-related mood disorders, DA-induced ICDs

— Symptomatic hyponatremia (post-op SIADH) or hypernatremia (DI)

— Hemodynamic instability suggesting adrenal insufficiency

— Severe hypokalemia, uncontrolled diabetes, hypertensive urgency in new Cushing

— VTE in Cushing patient (high recurrence — extended anticoagulation often needed)

Immediate ED/ICU triage:

Urgent endocrinology consultation:

Neurosurgery consultation:

Multidisciplinary inputs:

Admission triggers:

CCS pearl: In any acutely ill patient with pituitary disease, order hydrocortisone before the cortisol level returns — it's the only step where empiric treatment beats diagnostic certainty.

Key Differentials — Same-Category (Sellar/Hormonal) Causes

— Pituitary adenoma (most common)

— Craniopharyngioma: suprasellar, calcified, cystic with motor oil fluid; bimodal age (children, 50–70); causes panhypopituitarism and DI

— Rathke cleft cyst: incidental, smooth cystic, between anterior/posterior pituitary

— Meningioma: dural-based, homogeneous enhancement

— Germinoma: midline, young patients, often with DI as first sign; β-hCG/AFP positive

— Metastasis: breast, lung most common; often presents with DI (posterior pituitary preferentially affected) — distinguishes from adenoma which rarely causes DI

— Lymphocytic hypophysitis: peripartum women or autoimmune; pituitary stalk thickening; central adrenal insufficiency

— Sarcoidosis, tuberculosis, IgG4-related disease, Langerhans cell histiocytosis: granulomatous infiltration

— Pituitary carcinoma: rare; CSF/distant metastasis required for diagnosis

— Pregnancy (always rule out first)

— Medications: antipsychotics (risperidone highest), metoclopramide, methyldopa, verapamil, opioids, estrogens, SSRIs

— Primary hypothyroidism (TRH stimulates prolactin)

— Chronic kidney disease

— Stalk effect: any non-prolactinoma sellar mass compressing stalk → mild hyperprolactinemia (usually <100 ng/mL)

— Macroprolactin: biologically inactive

— Cirrhosis, chest wall stimulation, stress, exercise, nipple stimulation

— Pituitary somatotroph adenoma (>95%)

— Ectopic GHRH secretion (rare carcinoid, pancreatic NET)

— Ectopic GH (extraordinarily rare)

— McCune-Albright syndrome (mosaic GNAS mutation)

Differential for sellar/parasellar mass:

Differential for hyperprolactinemia:

Differential for GH/IGF-1 excess:

Key distinction: DI as a presenting feature of a sellar mass argues against pituitary adenoma and points to craniopharyngioma, germinoma, hypophysitis, metastasis, or infiltrative disease — adenomas rarely cause DI pre-op.

Key Differentials — Other-Category Causes

— Exogenous (iatrogenic) glucocorticoid use — by far most common; ask about inhalers, joint injections, topical/inhaled/nasal steroids, herbal supplements; ACTH suppressed, low DHEA-S

— Cushing disease (pituitary ACTH adenoma): 70% of endogenous Cushing

— Ectopic ACTH syndrome: small-cell lung carcinoma, bronchial carcinoid, pancreatic NET, medullary thyroid, pheochromocytoma — rapid onset, severe hypokalemia, hyperpigmentation, weight loss

— Adrenal adenoma/carcinoma: ACTH suppressed; adrenal CT for unilateral mass

— Bilateral macronodular hyperplasia / PPNAD (Carney complex)

— Pseudo-Cushing states: severe depression, alcohol use disorder, obesity, poorly controlled DM, pregnancy — biochemistry overlaps; dexamethasone-CRH test or repeat testing after stressor resolution

— Acromegaly (GH/IGF-1 elevated)

— Pachydermoperiostosis (primary hypertrophic osteoarthropathy) — normal IGF-1

— Acromegaloidism (severe insulin resistance with acanthosis nigricans — normal IGF-1)

— Phenytoin gingival hyperplasia, hypothyroidism (myxedema features)

— Prolactinoma vs primary hypothyroidism vs PCOS vs hypothalamic amenorrhea vs premature ovarian insufficiency vs Asherman syndrome

— Always check β-hCG, TSH, prolactin, FSH as first-pass workup

— Bitemporal hemianopsia → chiasm (sellar mass)

— Homonymous hemianopsia → retrochiasmal (stroke, tumor)

— Junctional scotoma → optic nerve-chiasm junction

— Altitudinal defect → anterior ischemic optic neuropathy

Differential for Cushing syndrome (broader than pituitary):

Differential for acromegaloid features:

Differential for amenorrhea-galactorrhea:

Differential for visual field defects:

Board pearl: A patient with classic Cushing features and low ACTH, low cortisol, low DHEA-S has been on exogenous glucocorticoids — including unrecognized intra-articular, inhaled, or topical sources. Always re-take a steroid history.

Secondary Prevention, Discharge, and Long-Term Plan

— Stress-dose hydrocortisone taper or maintenance dosing until POD 2–3 cortisol assessment

— Strict precautions: no nose blowing, straws, heavy lifting, or air travel for 2–4 weeks (CSF leak risk)

— Saline nasal irrigation

— DDAVP prn for documented DI; daily weights and serum Na checks at 1 week post-discharge

— Return precautions: clear nasal drainage (CSF leak), severe headache, fever, neck stiffness (meningitis), polyuria/polydipsia (DI), nausea/weakness (adrenal crisis), hyponatremia symptoms (delayed SIADH at POD 7–10)

— Cushing disease: morning cortisol POD 2–3 (<3 µg/dL = remission); repeat 24-hr UFC and late-night salivary cortisol at 3, 6, 12 months; lifelong annual surveillance (10–25% recurrence over 10 years)

— Acromegaly: IGF-1 at 12 weeks, then every 6–12 months; OGTT with GH at 12 weeks for confirmation of cure

— Prolactinoma: prolactin q3–6 months; MRI at 6–12 months; attempt DA withdrawal after ≥2 years of normal prolactin

— Hydrocortisone 15–25 mg/day in divided doses + sick-day rules (double dose for febrile illness, IM injection for vomiting); medical alert bracelet

— Levothyroxine dosed to free T4 mid-upper-normal (NOT TSH — central hypothyroidism)

— Testosterone or estrogen/progesterone for hypogonadism (after fertility considerations)

— GH replacement in adults with documented deficiency and symptoms

— DDAVP for permanent DI; monitor sodium

— Acromegaly: continue colonoscopy every 5–10 years (more frequent if polyps), annual echocardiogram for those with cardiomyopathy, OSA reassessment, DEXA, lipids, HbA1c

— Cushing: bone health (calcium, vitamin D, bisphosphonate if needed), cardiovascular risk reduction, VTE risk reassessment, mental health follow-up

Post-transsphenoidal discharge planning:

Long-term post-op surveillance:

Hormone replacement (lifelong if hypopituitarism):

Comorbidity management:

Step 3 management: Every patient on chronic glucocorticoid replacement needs written sick-day rules, an injectable hydrocortisone kit, and a medical alert ID — this is a tested transition-of-care item.

Follow-Up, Monitoring Parameters, and Counseling

— Prolactinoma on DA: prolactin at 1 month, then q3 months until normal; MRI at 3–6 months and 1 year; annual MRI for macroadenomas. After 2 years of biochemical and radiographic remission → attempt DA taper/withdrawal; monitor prolactin q3 months for 1 year post-withdrawal

— Acromegaly post-op/medical therapy: IGF-1 q3–6 months until controlled, then annually; MRI at 12 weeks post-op, then annually; annual screening for DM, HTN, OSA, cardiomyopathy, colon cancer (per surveillance schedule), thyroid nodules

— Cushing disease post-op: cortisol off hydrocortisone q3–6 months for first year; UFC and late-night salivary cortisol annually; MRI at 3 months then annually; lifelong surveillance due to late recurrence

— Prolactinoma: contraception planning (rapid fertility return), DA side effects (impulse control disorders — specifically ask about gambling, hypersexuality, compulsive shopping at every visit), bone health if hypogonadism persists

— Acromegaly: lifestyle (weight, OSA CPAP adherence, glycemic control), colon cancer surveillance, joint protection

— Cushing: bone density follow-up, psychiatric support, DM/HTN management even after biochemical cure (cardiovascular risk persists)

— Standard adult schedule, plus annual influenza

— Pneumococcal and zoster particularly important if chronic glucocorticoid replacement

— Quality of life often impaired even after biochemical cure (especially Cushing) — screen for depression, cognitive issues, fatigue at each visit

— Rehab and physical therapy for myopathy, deconditioning

— Annual multidisciplinary review for complex cases (endocrine, neurosurgery, radiation oncology, neuro-ophthalmology)

Follow-up cadence after diagnosis or treatment:

Counseling priorities:

Vaccinations:

Patient-reported outcomes:

Pituitary tumor registry/MDT:

Board pearl: Cushing patients have persistent cardiovascular and psychiatric morbidity even years after cure — don't stop antihypertensives, lipid therapy, or mood monitoring just because cortisol is normal.

Ethical, Legal, and Patient Safety Considerations

— Cabergoline/bromocriptine can trigger pathological gambling, hypersexuality, compulsive shopping, binge eating — affecting up to 17% of patients

— Mandatory pre-prescription disclosure of ICDs at every prescribing encounter; document the conversation

— Include family members in counseling — patients often lack insight; spouses report first

— Failure to disclose has been the basis for malpractice claims

— Post-transsphenoidal patients are at risk for adrenal crisis if discharge instructions are unclear — ensure stress-dose steroid education, written sick-day plan, MedicAlert bracelet, and a clear point of contact

— Delayed SIADH at POD 7–10 is a major readmission cause — schedule sodium check at 1 week post-discharge

— Hand-off communication between neurosurgery and endocrinology must include cortisol axis status

— Patients with bitemporal hemianopsia may not meet state vision requirements for driving

— Document counseling; some states have mandatory physician reporting of vision-impaired drivers (varies by state)

— Rapid fertility return with DA therapy → contraception conversation before initiation

— Acromegaly/Cushing pregnancy planning is high-risk — co-management with MFM

— Cushing disease can have remission rates that differ dramatically by surgeon experience — refer to high-volume centers (>50/year)

— Patients have right to know institutional/surgeon-specific outcomes

— Young patient (<30) with pituitary adenoma, family history, or features of MEN1/Carney/AIP → offer genetic counseling and testing; consent for implications to family members

— Many novel agents (pasireotide, osilodrostat) come from clinical trials — discuss eligibility for trials at academic centers

Informed consent — dopamine agonist impulse control disorders (ICDs):

Transition-of-care safety:

Driving and visual field defects:

Fertility and reproductive counseling:

Surgical decision-making and shared decision-making:

Genetic testing:

Research participation:

Step 3 management: Document at each DA visit: "Patient/family counseled re: impulse control disorders including gambling, hypersexuality, compulsive shopping. Denies symptoms." This is a tested medico-legal safety net.

High-Yield Associations and Rapid-Fire Clinical Facts

— MEN1 (menin gene, 11q13): 3 P's — Parathyroid hyperplasia, Pancreatic NETs (gastrinoma, insulinoma), Pituitary adenomas (prolactinoma most common)

— MEN4 (CDKN1B): similar to MEN1, rare

— Carney complex (PRKAR1A): pituitary (GH), cardiac myxomas, spotty pigmentation, PPNAD

— McCune-Albright: GNAS mosaic mutation, café-au-lait, polyostotic fibrous dysplasia, precocious puberty, GH excess

— Familial isolated pituitary adenoma (FIPA): AIP gene

— Prolactin >200 ng/mL → prolactinoma until proven otherwise

— Macroadenoma + prolactin 30–100 → suspect stalk effect from nonfunctioning adenoma, not prolactinoma

— Acromegaly + colon polyps → colonoscopy at diagnosis

— Acromegaly + skin tags → marker for colon polyps

— Acromegaly + sudden death → undiagnosed cardiomyopathy or OSA

— Cushing + hypokalemia + hyperpigmentation + rapid onset → ectopic ACTH (small-cell lung)

— Cushing + DI + visual loss → think non-adenoma (craniopharyngioma, metastasis)

— Bitemporal hemianopsia + amenorrhea-galactorrhea → macroprolactinoma

— Post-TSS polyuria with dilute urine → DI (POD 1–3)

— Post-TSS hyponatremia at week 1–2 → SIADH

— Pregnancy + headache + visual loss in known prolactinoma → tumor expansion

— Anticoagulated patient + thunderclap headache + ophthalmoplegia → pituitary apoplexy

— Sheehan syndrome: postpartum hemorrhage → pituitary infarction → failure to lactate is earliest sign

— Cushing screening = late-night salivary cortisol, 24-hr UFC, or 1-mg DST (need 2 positive)

— Acromegaly screening = IGF-1, confirmation = OGTT with GH suppression

— Cushing localization = plasma ACTH → MRI → IPSS if needed

Genetic syndromes:

Rapid-fire associations:

Testing pearls:

Board pearl: Sheehan syndrome = postpartum panhypopituitarism from pituitary infarction; first clue is inability to lactate, then amenorrhea, fatigue, hypotension — classic Step 3 stem.

Board Question Stem Patterns

— 28-year-old woman with 9 months amenorrhea, milky nipple discharge, headaches. Prolactin 280 ng/mL, β-hCG negative, TSH normal. MRI: 1.4-cm sellar mass with chiasm contact, bitemporal hemianopsia on perimetry.

— Best next step: cabergoline (NOT surgery) — macroprolactinomas typically shrink with DA, vision recovers

— Woman on risperidone, prolactin 65, no MRI findings. Best next step: review medications, consider antipsychotic switch with psychiatry — don't image

— 45-year-old with new diabetes, hypertension, OSA, increasing ring size, sweating, headaches. Coarse features.

— Best initial test: IGF-1

— Confirmatory: OGTT with GH suppression

— Next: pituitary MRI

— Treatment: transsphenoidal surgery; somatostatin analog for residual disease; colonoscopy and echo at diagnosis

— Woman with weight gain, purple striae, proximal weakness, new HTN/DM.

— Best initial test: late-night salivary cortisol (×2) or 24-hr UFC or 1-mg DST

— Cortisol elevated, ACTH normal/high → pituitary MRI; if <6 mm → IPSS

— Cortisol elevated, ACTH suppressed → adrenal CT

— Hypertensive patient on warfarin with sudden severe headache, ophthalmoplegia, vision loss.

— First step: IV hydrocortisone 100 mg (NOT MRI first)

— Then: MRI, neurosurgery consult, reverse anticoagulation

— POD 1 after TSS, urine output 400 mL/hr, urine sg 1.002, Na 148.

— Diagnosis: central DI → DDAVP

— Postpartum woman with PPH, now unable to lactate, fatigue, amenorrhea, hypotension.

— Diagnosis: panhypopituitarism → replace cortisol first, then thyroid

Classic stem 1 — Prolactinoma:

Classic stem 2 — Drug-induced hyperprolactinemia:

Classic stem 3 — Acromegaly:

Classic stem 4 — Cushing workup:

Classic stem 5 — Pituitary apoplexy:

Classic stem 6 — Post-op DI:

Classic stem 7 — Sheehan syndrome:

Step 3 management: When the stem gives "vision is worsening" in a macroprolactinoma, the answer is almost always start cabergoline, not "urgent surgery" — recheck the answer choices for a DA option.

One-Line Recap

Pituitary adenomas demand a stepwise approach: confirm hormone excess biochemically before imaging, treat prolactinomas medically with dopamine agonists, treat acromegaly and Cushing disease surgically, and replace hypopituitary axes lifelong — with cortisol always replaced first.

Prolactinoma: prolactin >200 → image → cabergoline first-line (even for macroadenomas with visual loss); surgery for resistance/intolerance; bromocriptine for pregnancy; counsel on impulse control disorders at every visit

Acromegaly: screen with IGF-1, confirm with OGTT-GH suppression, image with pituitary MRI, treat with transsphenoidal surgery; medical therapy (somatostatin analogs, pegvisomant, cabergoline) for residual disease; screen for colon cancer, OSA, cardiomyopathy, diabetes at diagnosis and longitudinally

Cushing disease: screen with two of three (late-night salivary cortisol, 24-hr UFC, 1-mg dexamethasone suppression), then plasma ACTH to localize, then MRI, then IPSS if MRI negative/equivocal; treat with transsphenoidal selective adenomectomy; medical therapy (ketoconazole, metyrapone, osilodrostat, pasireotide, mifepristone) for refractory disease; bilateral adrenalectomy as salvage with Nelson syndrome risk

Pituitary emergencies and safety: apoplexy → IV hydrocortisone before MRI; post-TSS DI on day 1–3, SIADH at week 1–2; lifelong cortisol replacement with sick-day rules, injectable kit, MedicAlert bracelet; bitemporal hemianopsia mandates driving counseling; MEN1 screening in young or familial cases

Step 3 management: The single most-tested concept across this topic is giving stress-dose hydrocortisone empirically in any pituitary patient with hemodynamic instability, apoplexy, or perioperative stress — adrenal insufficiency kills faster than the underlying tumor ever will.