JC41 (Medicine) - Pituitary tumors and hypopituitarism Flashcards
Pituitary gland
- Location
- Borders
- Anatomical division and secretions
Site: enclosed in sella turcica (normally <0.8cm deep)
Superior → diaphragm sellae
Anterosuperior → optic chiasm
Inferior → sphenoidal sinus
Lateral → cavernous sinus
Anterior lobe secretes prolactin, LH/FSH, TSH, ACTH, GH
Posterior lobe secretes oxytocin and ADH
Anatomical connection between pituitary and hypothalamus
Connected to hypothalamus via infundibular stalk
- Portal vessel carrying blood from median
eminence of hypothalamus to anterior lobe
- Nerve fibres from PVN and SON to posterior lobe (neurohypophysis)
List non-functional tumors of pituitary
Non-functional tumours:
→ Pituitary adenoma (most common)
→ Craniopharyngioma
→ Metastatic tumours
List pituitary diseases with hormone excess/ deficiency
Hormone excess:
→ Hyperprolactinemia
→ Acromegaly
→ Cushing’s disease
→ SIADH
→ TSH-/LH-/FSH-secreting adenomas (rare)
Hormone deficiency:
→ Hypopituitarism
→ Diabetes insipidus
→ GnRH deficiency (Kallmann’s syndrome)
Approach to ascertain type of pituitary disease
Approach to pituitary diseases:
- Hormonal secretion: depends on mode of secretion
→ Pulsatile secretion: GH, ACTH → requires suppression/stimulation tests
→ Constant secretion: prolactin, TSH, LH/FSH → direct measurement of its level - Perimetry for visual defects due to compression on optic pathways
- MRI pituitary if pituitary tumour suspected
- Intra-op biopsy for histological Dx
Tests for ACTH excess/ Deficiency
ACTH Excess:
Low-dose dexamethasone suppression test
Late-night salivary cortisol
24h urine free cortisol
ACTH Deficiency:
Low 9am serum cortisol
Short synacthen test (SST)
Insulin tolerance test (ITT)
Tests for Growth hormone excess/ deficiency
GH excess:
Oral glucose tolerance test (OGTT)
High serum IGF-1
GH deficiency:
Low serum IGF-1
Insulin tolerance test (ITT)
Glucagon stimulation test
Arginine-GHRH stimulation test
Tests for FSH/ LH deficiency
Random serum LH/FSH
Random serum testosterone in M
GnRH (LHRH) stimulation test
Tests for TSH excess/ deficiency
Random serum T4, TSH
Tests for prolactin excess/ deficiency
Random serum prolactin
Test for ADH excess/ deficiency
ADH excess - Diagnosis of exclusion
ADH deficiency - Water deprivation test
Outline clinical presentation of Pituitary tumor
Local compressive symptoms:
- Headache, Visual field defect, Diplopia, Disconnection hyperprolactinaemia, Pituitary apoplexy
Hormonal symptoms:
- Hypersecretion: acromegaly, Cushing’s, hyperprolactinaemia
- Hyposecretion: hypopituitarism
Local compressive symptoms of pituitary tumor
- Headache (Stretching diaphragma sellae)
- Visual field defect (optic chiasm involvement)
- Diplopia (Cavernous sinus involvement)
- Acute infarction/ expansion (pituitary apoplexy, sudden hemorrhage)
- Disconnection hyperprolactinaemia
S/S of hypopituitarism
- Growth hormone deficiency:
Growth retardation, Lethargy
- Gonadotrophin deficiency:
Lethargy, Loss of libido, Hair loss, Amenorrhea
- ACTH deficiency:
Lethargy, Pallor, Postural hypotension, Hair loss
- TSH deficiency:
Hypothyroidism S/S
- Vasopressin deficiency:
Thirst, polydipsia, polyuria
S/S hyperpituitarism
Cushing’s disease
Acromegaly
Hyperprolactinemia: Galactorrhea, Amenorrhea, Hypogonadism
Characteristic sign of pituitary tumor on Cranial XR?
Skull XR: double-flooring due to asymmetrical enlargement
Ddx sellar masses
□ Pituitary adenomas
□ Pituitary carcinomas: very rare
→ Types: germ cell tumours, chordoma, lymphoma, metastatic
□ Craniopharyngiomas: majority in children/young adulthood
□ Other tumours: meningioma, pituicytoma, lymphoma, germ cell tumour, metastatic tumours (esp CA breast, lung)
□ Non-neoplastic masses: Rathke’s cleft cyst, arachnoid cyst, pituitary abscess, carotid-cavernous fistula, hypophysitis
Craniopharyngioma
- Site
- Morphology
- Age of onset
- Presentation, S/S
Site: commonly in suprasellar region but can occur intrasellarly
Nature: often cystic, 50% calcified (visible on XR/CT)
Onset:
→ 50% present in childhood
(more common than pituitary adenoma in young people)
→ 25% presents between 20-40y
→ 25% presents >40y
Presentation:
- Hypopituitarism, eg. growth retardation
- Central DI due to stalk compression
- Visual field defects due to chiasmal compression
- ↑ICP due to 3rd ventricle compression
- Hypothalamic damage, eg. hyperphagia, obesity, loss of thirst sensation, disturbance of temperature regulation
Pituitary adenoma
Site
Size cut-off
Subtypes
Site: usually within sella turcica
Size: microadenoma (<1cm) vs macroadenoma (>1cm)
Functional adenomas:
Prolactinoma
GH-secreting
ACTH-secreting
Glycoprotein-secreting: FSH, LH, TSH
Non-functional adenomas: Hypopituitarism
Clinical presentation of functioning pituitary adenomas
- Prolactinoma: Galactorrhea, Hypogonadotropic hypogonadism - Amenorrhea and Impotence
- GH-secreting adenoma: Acromegaly in adults, Gigantism in children
- ACTH-secreting adenoma: Cushing’s disease
- Glycoprotein-secreting tumors: Secondary hyperthyroidism, Precocious puberty, Ovarian Hyperstimulation syndrome, Hypopituitarism, Local compressive symptoms
Clinical presentation of non-functioning pituitary adenomas
Hypopituitarism (classically GH → FSH/LH → ACTH → TSH)
Local symptoms including headache and visual loss
Clinical diagnosis of functional pituitary adenoma
Dx:
Hormonal hypersecretion in functional adenomas
→ Prolactinoma: ↑serum prolactin >200ng/mol (usu >10× ULN)
→ Acromegaly: ↑serum IGF-1, non-suppressible GH on OGTT
→ Cushing’s disease: ↑ACTH + ↑cortisol (by ≥2× diagnostic tests)
→ 2o hyperthyroidism: ↑TSH, ↑fT4
→ Gonadotroph tumour: seldom hypersecretes
Radiological diagnosis:
→ Contrast MRI: modality of choice
→ CT: better for calcified tumour (meningioma, craniopharyngioma)
Pituitary apoplexy
S/S
Diagnosis
Management
□ S/S: sudden onset of excruciating headache (stretching of sella) + diplopia (pressure on CNIII) + hypopituitarism (esp adrenal crisis)
□ Dx: acute blood in pituitary seen on CT/MRI
□ Mx: steroid cover + urgent surgical decompression if
→ Signs of ↑ICP
→ Change in conscious state
→ Evidence of compression on neighbouring structures
Management options of pituitary tumors (functional and non-functional)
Non-functional microadenoma - Observe and FU
Functional adenoma and Non-functional Macroadenoma:
→ Surgical Tx: first-line for all
→ RT: usually as adjunct to surgery
→ Medical Tx: first-line only to prolactinoma
Surgery for pituitary tumor
- Indication
- Approach
- Advantages
- Disadvantages
- F/U
□ Indication: all functioning tumours (except prolactinoma) and all macroadenomas
□ Approach:
→ Trans-sphenoidal (route of choice): transnasal endoscopic or sublabial
- Unresectable if compresses/abuts optic pathway or invades cavernous sinus → maximal debulking instead
→ Transfrontal if very large suprasellar extension or severe chiasmal compression
□ Advantages: rapid ↓secretion and ↓size → remission >85% for micro-, 40-50% for macroadenoma
□ Disadvantages:
→ Residual or recurrence esp if macroadenomas (2-8%)
→ Hypopituitarism
→ DI due to surgical injury to stalk or posterior pituitary (may be transient)
□ F/U:
→ Monitor pituitary function for 4-6w for hypopituitarism
→ Post-op imaging at 1y, 2y, 5y, 10y for any recurrence
Radiotherapy for pituitary tumor
- Modalities
- Indication
- Advantages
- Disadvantages
□ Modalities: conventional EBRT or stereotactic radiosurgery (SRS) by gamma/X-knife
□ Use:
→ Usually as adjunct to surgery (for residual tumours)
→ May be primary therapy for macroprolactinoma
□ Advantages: restrains tumour growth
□ Disadvantages:
→ Delayed effect on secretion (not used in acute setting)
→ Higher incidence of hypopituitarism
→ Risk of damage to other structures (NOT used if <5mm from optic chiasma)
Medical treatment for pituitary adenoma
- Indication
- Efficacy
- Drug options
□ Use: 1st line for prolactinomas and as adjunct to surgery/RT in others
□ Efficacy:
→ Usually reversible on drug withdrawal
→ No reduction in size except for prolactinomas (by dopamine agonists); 50% of GH/TSH-producing tumours (by somatostatin analogues)
Options:
Dopamine agonists, eg. bromocriptine, cabergoline
Somatostatin analogues, eg. octreotide LAR, lanreotide, pasireotide
GH receptor antagonists, eg. pegvisomant
Dopamine agonists for pituitary tumors
Efficacy
Examples
S/E
F/U
Dopamine agonists, eg. bromocriptine, cabergoline
Effect:
- Prolactinoma: >90% achieve normal prolactin, tumour shrinkage
- Acromegaly: IGF-1 normalized in 10% pt
- FSH-producing tumours: ↓FSH but no effect on tumour size
S/E: constipation, nausea and headaches. hallucinations, peripheral edema, gastrointestinal ulcers, pulmonary fibrosis and psychosis.
F/U:
- Monitor tumour size by serial MRI
- Monitor prolactin level → taper off after dropping to normal
Somatostatin analogues for pituitary tumors
Efficacy
Examples
S/E
Somatostatin analogues, eg. octreotide LAR, lanreotide, pasireotide
Use as adjunct to surgery/RT
Octreotide LAR/lanreotide: predominantly act on sstr
→ ↓size and secretion of GH and TSH-producing tumours
→ 60% acromegaly pt achieve normal GH/IGF-1
Pasireotide: high affinity for sstr5,
→ Effective for ACTH-producing tumours
→ more effective for some GH-producing tumours
S/E: 3Gs
- GI side-effects: nausea/vomiting, steatorrhoea, abdominal cramps
- Gallstones due to ↓gallbladder motility
- ↓glucose tolerance due to ↓insulin secretion (hyperGly more common for pasireotide)
GH receptor antagonists for pituitary tumor
Example
Efficacy
S/E
GH receptor antagonists, eg. pegvisomant
Effect:
- 90% normalize IGF-1 in 12mo, 76% in long-term
- No ↓tumour size, no ↓GH level (-ve feedback)
S/E: ↑liver transaminases (5%)
Causes of Hyperprolactinemia
Clinical presentation of hyperprolactinemia
Hypogonadotropic hypogonadism due to inhibition on GnRH secretion
→ Female: secondary amenorrhoea, anovulation with infertility, climacteric symptoms, ↓BMD
→ Male: ↓libido, lethargy, erectile dysfunction, infertility
Galactorrhoea due to ↑breast milk production (NOT breast development – due to oestrogen!)
→ Female: can present with milk discharge
→ Male: rarely occur unless gynaecomastia already induced (oestrogen-mediated)
Serum prolactin levels and associated conditions at each level
Define Macroprolactin
Levels:
- <500mU/L → normal
- 500-1000mU/L → stress, drugs
- 1000-5000mU/L → drugs, microprolactinoma, disconnection prolactinoma
- >5000mU/L → highly suggestive of macroprolactinoma
- >100000mU/L → potential for high-dose hook effect and thus false -ve
Macroprolactin: prolactin bound to IgG Ab
- Cannot cross blood vessel walls → NOT physiologically active
- May cause interference! → use assays that are known not to cross-react
Investigations for Hyperprolactinemia
- Exclude pregnancy if female and child-bearing age
- Serum prolactin levels
- MRI/CT pituitary for pituitary adenoma
- Pituitary hormones: IGF-1, ACTH, FSH/LH/sex hormones
- T4, TSH to exclude 1o hypothyroidism
Treatment of hyperprolactinemia
Dopamine agonist as 1st line, treat if symptomatic or macroadenoma
→ Efficacy: ↓prolactin secretion, ↓size of adenoma in >90%
→ Termination: taper off DA if prolactin normalized + no adenoma by MRI for ≥2y (off when pregnant)
→ S/E: nausea, postural hypotension, mental fogginess, impulse control disorders (hypersexuality, compulsion)
Surgery ± adjuvant RT if failed medical Tx or very large adenoma planning pregnancy
Acromegaly
Cause
Clinical features
Cause: GH-secreting pituitary adenoma (most), GHRH-secreting hypothalamic tumours, ectopic GHRH/GH secretion by neuroendocrine tumours
Clinical features:
- Pituitary local compressive symptoms: headache, VF defects, CN palsies, hypopituitarism
- GH-excess:
- Soft tissue overgrowth: Coarse facial features, Macroglossia, Malocclusion, OSA, Prognathism
- Acral overgrowth: Large hands with board palms, spatulate fingers, sweaty palms; Large feet with thick heel pads
- Skin changes: Hyperhidrosis, Hirsutism
- Bone: Hypertrophic arthropathy, increase BMD
- Visceromegaly: Goiter, Testiculomegaly
Complications of Acromegaly
Complications: overall mortality 1.72× to general population (mainly due to CVS risk)
- Cardiovascular: HTN, LVH, cardiomyopathy with diastolic HF, CV mortality, VHD
- Metabolic: IGT (40%), T2DM (20%), ↑lipids, ↑Ca, ↑PO4
- Colon: ↑risk of colon CA, polyp, diverticulosis
- Others: ↑risk of other malignancy, renal stones (hypercalciuria)
- hyperprolactinemia (30%) (due to interference with hypothalamic/pituitary blood flow or from cosecretion of PRL)
Investigations for acromegaly
□ Serum IGF-1: elevated
□ OGTT: inadequate GH suppression
Normal → adequate suppression to <1ng/L after 2h
Acromegaly → no suppression or paradoxical increase (30%)
□ Pituitary MRI and pituitary hormone profile
□ Colonoscopy for any colonic tumours
Treatment options for acromegaly
Transsphenoidal surgery (1st line)
→ Postop evaluation: IGF-1 + random GH and MRI at postop 12w
→ Residual disease: repeat OT if resectable or compresses vital structures, otherwise medical or SRS
Medical Rx if not a surgical candidate or incomplete clearance
→ Somatostatin analogues, eg. octreotide, lanreotide
→ GH receptor antagonist, eg. pegvisomant
→ Dopamine agonist if co-secrete prolactin
Stereotactic RT if refractory to medical therapy
Structural causes of hypopituitarism
Structural damage involving hypothalamus, pituitary or stalk
→ Tumours: large pituitary or hypothalamic tumours
→ Trauma: surgery, RT, head injury
→ Infarction: post-partum necrosis (Sheehan’s syndrome), pituitary apoplexy
→ Infiltration: haemosiderosis/haemochromatosis, histiocytosis, sarcoidosis
→ Infection: TB, syphilis, mycosis, toxoplasmosis (in AIDS)
→ Immunological: lymphocytic hypophysitis (spontaneous or induced by cancer immunotherapy), isolated ACTH deficiency (due to anti-ACTH secreting cell Ab)
Congenital causes of hypopituitarism
→ Congenital panhypopituitarism
→ Isolated GH deficiency
→ Isolated LH/FSH deficiency, eg. in Kallmann’s syndrome (may be a/w anosmia)
Functional causes of hypopituitarism
→ Emotional deprivation (GH insufficiency)
→ Anorexia nervosa (LH/FSH ± TSH insufficiency)
Panel of tests for hypopituitarism
GH:
- IGF-1, ITT, GST, Arginine- GHrH stimulation test
ACTH:
- Short synacthen test, ITT, 9am serum cortisol
TSH: Thyroid function test
FSH/ LH: Random serum levels
Basal non-stressed prolactin
Treatment of Growth hormone deficiency
GH replacement in children ± adults
Route: SC injection of recombinant GH daily
Indications in adult: impaired QoL + severe GH deficiency → reassess symptoms at 9mo
(defined as peak GH <9mU/L during a stimulation test)
Treatment of Gonadotropin deficiency
Testosterone in M
- Route: usually long-acting IM injections every few weeks
- S/E: CA prostate (screen before starting and at 3mo, 1y), BPH, erythrocytosis, VTE, ?↑CVD risk
Oestrogen ± progestogen in Female in the form of COCP
Gonadotropins for ovulation induction
- Eg. human menopausal gonadotropin (HMG): mainly FSH
- Eg. human chorionic gonadotropin (hCG): mimics LH action
- Eg. recombinant FSH/LH, i.e. follitropin + lutropin α
Treatment for TSH deficiency
T4 replacement (start at 1.6μg/kg) → Should be deferred until cortisol replaced as treatment of hypothyroidism may ↑cortisol clearance → Should aim serum T4 in upper 1/2-2/3 of normal range
Treatment of ACTH deficiency
ACTH deficiency: hydrocortisone replacement (15-25mg/d)
→ Mineralocorticoid NOT required (independent of ACTH)
Diabetes Insipidus
Definition
2 subtypes
Diabetes insipidus (DI): characterized by persistent excretion of excessive quantities of dilute urine
□ Cranial DI: deficient ADH production/secretion by pituitary
□ Nephrogenic DI: renal tubules unresponsive to ADH
→ More common, often asymptomatic
→ Only presents during episodes of water deprivation (eg. solute diuresis, ↓water intake)
Familial causes of Diabetes insipidus
Central DI
- Vasopressin prohormone mutation (AD)
- Wolfram syndrome
- PCSK1 deficiency
Nephrogenic DI
- V2 receptor mutation (X-linked)
- Aquaporin 2 mutation (AR)
- Sickle cell trait
Acquired causes of central DI
Traumatic – accidental, surgical
Neoplasm causing damage to pituitary stalk
- Primary – craniopharyngioma, dysgerminoma, meningioma, adenomal
- Secondary – metastasis
Granulomas – TB, sarcoidosis, Langerhans’ histiocytosis, toxoplasmosis…
Infections – meningitis, encephalitis
Vascular – Sheehan’s syndrome, aneurysm, hypoxic encephalopathy
Idiopathic or congenital – Congenital hypopituitarism, septo-optic dysplasia
Acquired causes of nephrogenic DI
Renal tubular damage - Chronic pyelonephritis, APCKD, obstruction…
Metabolic – hypoK, hyperCa
Drugs
- Lithium carbonate for bipolar disorder
- Drugs causing tubular damage – eg. cisplatin, amphotericin B
- Others: cidofovir, foscarnet, demeclocycline, ifosfamide, ofloxacin, orlistat, didanosine
Gestational DI
Clinical presentation of Diabetes insipidus
Clinical presentation:
□ Polyuria + polydipsia: suspect if >50mL/kg/d (>3000mL for 60kg female)
→ May be masked by associated cortisol deficiency (impairment of diuresis)
□ ± hyperNa: usu high-normal except in impaired thirst mechanism (eg. unconscious, hypothalamic lesion)
Ddx of polyuria + polydipsia
Polyuria as primary defect: urine output > water intake, ↑plasma osmolality
- Solute (osmotic diuresis): DM (esp if hyperGly or on SGLT-2), urea diuresis (post AKI), mannitol, sodium diuresis (post volume expansion, post-obstructive)
- Water diuresis: diabetes insipidus
- Early CKD
- Diuretics
Excessive drinking as primary defect: water intake > urine output, ↓plasma osmolality
→ Primary polydipsia: excessive drinking in pt with psychiatric disease or hypothalamic lesions
Investigations for Diabetes Insipidus
- Chart I/O to document polyuria and rule out obvious alternative causes
- Paired plasma/urine osmolality + plasma electrolytes
- Water deprivation test
Differentiate plasma osm, urine osm, Paired urine/plasma osmolality ratio results between:
Diabetes insipidus
Primary polydipsia
Osmotic diuresis
Water deprivation test
- Indication
- MoA
- Procedure
- Findings
Indication: Suspected* DI
(already diagnostic if Urine: Plasma osmolality ratio <1 or Na conc. >145 + Urine osmolality <300)
Principle: to induce ↑ADH by creating hyperosmolar state and to detect response to ↑ADH
Procedure:
- No fluid intake for 8h (only dry food allowed)
- During test, measure hourly body weight, urine volume and U/P osmolality
- Stop when end-point reached (U/P osmo ratio ≤2 with Plasma osmo > 300) or lose 3% body weight)
- *- Give DDAVP 2μg IM**
Findings:
- Normal/primary polydipsia = adequate concentration of urine (U/P ratio ≥2)
- DI = plasma osmolality >300, U/P osmo ratio still ≤1.9 (cannot concentrate urine) (i.e. U < 600)
- Cranial DI = ↑ ≥50% urine osmo (adequate urine concentration) after DDAVP
- Nephrogenic DI = no change in urine osmo after DDAVP
Management of cranial DI
Route of administration
S/E
Cranial DI: desmopressin (DDAVP)
→ RoA: usually intranasal, PO/sublingual also available
→ S/E: excessive Tx (water intoxication, hypoNa), inadequate Tx (hyperNa)
Management of nephrogenic DI
Route of administration
S/E
Nephrogenic DI:
→ Treat underlying cause, eg. stop offending medication
→ Low Na/protein diet + thiazide diuretics ± amiloride
→ NSAIDs (inhibit prostaglandin production (antagonist of ADH action) and thus increase concentrating ability)
→ Consider DDAVP if refractory
Acute post-operative/ Traumatic DI
Clinical presentation
Clinical presentation: follows classical triphasic pattern
→ Polyuric phase (phase I) due to transient DI from hypothalamic dysfunction leading to inhibition of ADH release
- Time frame: begins ≤24h and lasts till 4-5d
→ Antidiuretic phase (phase II) due to release of stored ADH from degenerating posterior pituitary → SIADH
- Time frame: usually d6-11, lasts 2-14d
→ Return of DI (phase III) due to depletion of stored ADH → may be permanent
Management of Acute post-operative/ traumatic DI
Monitor: Chart I/O, Body weight, serum Na, urine osmolality
- Oral hydration or IV hydration with oral DDAVP
- Allow some polyuria between doses and give next dose if previously urine output >200mL/h in successive hours
- Target urine output 1-2L/ Day
- Advise drug holiday if appropriate
