JC41 (Medicine) - Pituitary tumors and hypopituitarism Flashcards

Question

Surgery for pituitary tumor * Indication * Approach * Advantages * Disadvantages * F/U

Answer 1

□ 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

Answer 2

□ 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)

Answer 3

□ 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

Answer 4

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

Answer 5

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)

Answer 6

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%)

Answer 7

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)

Answer 8

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

Answer 9

1. Exclude pregnancy if female and child-bearing age 2. Serum prolactin levels 3. MRI/CT pituitary for pituitary adenoma 4. Pituitary hormones: IGF-1, ACTH, FSH/LH/sex hormones 5. T4, TSH to exclude 1o hypothyroidism

Answer 10

**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

Answer 11

Cause: GH-secreting pituitary adenoma (most), GHRH-secreting hypothalamic tumours, ectopic GHRH/GH secretion by neuroendocrine tumours Clinical features: 1. Pituitary local compressive symptoms: headache, VF defects, CN palsies, hypopituitarism 2. 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

Answer 12

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)

Answer 13

□ **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

Answer 14

**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

Answer 15

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)

Answer 16

→ Congenital panhypopituitarism → Isolated GH deficiency → Isolated LH/FSH deficiency, eg. in Kallmann’s syndrome (may be a/w anosmia)

Answer 17

→ Emotional deprivation (GH insufficiency) → Anorexia nervosa (LH/FSH ± TSH insufficiency)

Answer 18

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

Answer 19

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)

Answer 20

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

Answer 21

``` 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 ```

Answer 22

ACTH deficiency: hydrocortisone replacement (15-25mg/d) → Mineralocorticoid NOT required (independent of ACTH)

Answer 23

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)

Answer 24

Central DI * Vasopressin prohormone mutation (AD) * Wolfram syndrome * PCSK1 deficiency Nephrogenic DI * V2 receptor mutation (X-linked) * Aquaporin 2 mutation (AR) * Sickle cell trait

Answer 25

**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

Answer 26

**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**

Answer 27

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)

Answer 28

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**

Answer 29

1. **Chart I/O** to document polyuria and rule out obvious alternative causes 2. **Paired plasma/urine osmolality + plasma electrolytes** 3. **Water deprivation test**

Answer 30

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**

Answer 31

Cranial DI: desmopressin (DDAVP) → RoA: usually intranasal, PO/sublingual also available → S/E: excessive Tx (water intoxication, hypoNa), inadequate Tx (hyperNa)

Answer 32

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

Answer 33

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

Answer 34

**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