Pituitary tumours, hypopituitarism and dynamic pituitary tests (insulin tolerance test)

Overview

The pituitary sits in the sella turcica, below the optic chiasm and between the cavernous sinuses. Most pituitary disease comes from benign adenomas, which cause problems by pressing on nearby structures, by secreting too much of one hormone, or by destroying the normal gland (hypopituitarism). PGET questions test the visual field defects, prolactin interpretation, acromegaly testing, emergencies such as apoplexy, and the logic of dynamic tests.

Anatomy and control (just what you need)

• Posterior pituitary stores ADH and oxytocin made in the supraoptic and paraventricular nuclei of the hypothalamus.
• Prolactin is the only hormone held down by the hypothalamus. Damage to the stalk (stalk effect) or hypothalamus therefore raises prolactin but lowers everything else.
• Pituitary disease alone rarely causes diabetes insipidus, because ADH can still leak from the cut ends of hypothalamic axons. DI with a pituitary mass suggests a hypothalamic or stalk lesion (craniopharyngioma, metastasis, hypophysitis, sarcoidosis, histiocytosis).

Pituitary tumours

Classification

• Microadenoma: below 10 mm; macroadenoma: 10 mm or more.
• Functioning: prolactinoma (commonest), somatotroph (GH, acromegaly), corticotroph (ACTH, Cushing disease), rare TSH- or gonadotrophin-secreting.
• Non-functioning (often gonadotroph origin): present late with pressure effects and hypopituitarism.
• Small incidental adenomas on MRI ("incidentalomas") are common.

Pressure (mass) effects

• Headache.
• Visual field loss from chiasmal compression: bitemporal superior quadrantanopia first (tumour pushes up from below on the lower crossing fibres), progressing to bitemporal hemianopia. A craniopharyngioma pressing from above usually causes inferior quadrant loss first.
• Lateral spread into the cavernous sinus: palsies of III, IV, VI (diplopia, ptosis).
• Upward: hypothalamic dysfunction, obstructive hydrocephalus.
• Downward: erosion of the sella floor, CSF rhinorrhoea (may appear when a prolactinoma shrinks on cabergoline).
• Hypopituitarism of the remaining gland.

Assessment of any pituitary mass

1. MRI pituitary (better than CT).
2. Formal visual fields (perimetry) and acuity.
3. Basal 9 am bloods: cortisol, TSH and FT4, LH, FSH with testosterone or oestradiol, prolactin, IGF-1, plus plasma and urine osmolality and sodium.
4. Dynamic tests where basal results are equivocal (see below).
5. Always measure prolactin before surgery: a prolactinoma is treated with drugs, not an operation.

Treatment options

Prolactinoma and hyperprolactinaemia

Causes of raised prolactin

• Physiological: pregnancy, breastfeeding, stress (including venepuncture), sleep, exercise, coitus.
• Drugs (dopamine blockers and others): antipsychotics (risperidone, haloperidol, phenothiazines), metoclopramide, domperidone, methyldopa, oestrogens, SSRIs, tricyclics, verapamil, opioids, cimetidine.
• Pathological: prolactinoma, stalk compression by other masses, primary hypothyroidism (high TRH), PCOS, renal failure (reduced clearance), liver failure, chest wall injury or herpes zoster, after seizures.
• Macroprolactinaemia: prolactin bound to IgG; biologically inactive; normal periods and no symptoms. Detected by polyethylene glycol precipitation.

Clinical features

• Women: galactorrhoea, oligomenorrhoea or amenorrhoea, infertility; usually microadenomas found early.
• Men: low libido, erectile dysfunction; often macroadenomas with headache and visual loss because they present late.
• Both: osteoporosis from sex hormone deficiency (prolactin suppresses GnRH pulses).

Interpreting the level

• Mildly raised (about 400–600 mU/L) may be stress-related: repeat through a cannula after rest.
• Above about 5000 mU/L with a macroadenoma, or above about 2000 mU/L with a microadenoma, strongly suggests prolactinoma.
• A large tumour with only a modest rise (e.g. under about 2000–3000 mU/L) is usually a non-functioning adenoma causing stalk compression: it will not shrink with cabergoline and may need surgery.
• Hook effect: a giant prolactinoma can give a falsely low result in some immunoassays because the antibody is swamped. Ask the lab to dilute the sample (e.g. 1 in 100) when a large tumour has an unexpectedly low prolactin.

Treatment

• Cabergoline (dopamine D2 agonist, once or twice weekly) is first line, even for macroadenomas with visual field defects: it lowers prolactin and shrinks the tumour quickly.
• Bromocriptine has a longer safety record in pregnancy; it is taken daily and causes more nausea, vomiting and postural dizziness.
• Side effects: nausea, postural hypotension, impulse-control disorders (gambling, hypersexuality), and at high (Parkinson) doses fibrosis and cardiac valve disease (echo monitoring).
• Pregnancy: usually stop the agonist once pregnant (microadenoma); monitor visual fields in macroadenomas, which can grow.
• Surgery is for drug intolerance or resistance; radiotherapy is rarely needed.
• Microprolactinomas may stay in remission after 2–3 years of treatment; postmenopausal women with microadenomas may need no treatment.

Acromegaly and gigantism

• GH excess from a somatotroph adenoma (rarely ectopic GHRH from a carcinoid). Before epiphyseal fusion → gigantism; after → acromegaly. May be part of MEN 1 or McCune–Albright syndrome.

Features

• Coarse face, prominent supraorbital ridges, prognathism, widely spaced teeth, large tongue, deep voice.
• Spade-like hands and feet, increasing ring and shoe size, carpal tunnel syndrome, arthropathy.
• Excessive sweating, oily skin, headache, skin tags.
• Complications: diabetes / impaired glucose tolerance (GH opposes insulin), hypertension, cardiomyopathy and heart failure, obstructive sleep apnoea, colonic polyps and cancer, visual field loss, hypopituitarism; mildly raised prolactin in some.

Diagnosis

1. IGF-1: raised in almost all; best screening test (reflects average daily GH).
2. Oral glucose tolerance test with GH measurement: in health GH suppresses to very low levels; in acromegaly GH fails to suppress (and may rise paradoxically). This confirms the diagnosis.
3. MRI pituitary, visual fields, other pituitary hormones.

Treatment

• Trans-sphenoidal surgery first line (cure in most microadenomas, about half of macroadenomas).
• Somatostatin analogues (octreotide, lanreotide, monthly depot): lower GH and IGF-1, shrink some tumours; side effects gallstones, GI upset.
• Pegvisomant: GH receptor antagonist; normalises IGF-1 but GH levels and tumour size are unchanged.
• Cabergoline: helpful in mild disease or mixed GH/prolactin tumours.
• Radiotherapy for residual disease.
• Aim: normal IGF-1 and a low mean GH; treat diabetes, BP, sleep apnoea; colonoscopy screening.

Other tumours and masses

• Non-functioning adenoma: visual loss, headache, hypopituitarism, mild stalk-effect hyperprolactinaemia; surgery if pressure effects, observation if small.
• Cushing disease (ACTH adenoma): see the chapter on adrenal disorders.
• TSH-secreting adenoma: high FT4 with non-suppressed TSH and goitre.
• Craniopharyngioma: from Rathke pouch; often cystic and calcified; commonest sellar tumour in children (short stature, headache, visual loss, DI).
• Others: meningioma, metastases (often with DI), lymphocytic hypophysitis (late pregnancy or postpartum), carotid aneurysm (must be excluded before surgery), Rathke cleft cyst.

Pituitary apoplexy

• Sudden haemorrhage or infarction of a pituitary tumour (often previously unknown).
• Sudden severe headache, vomiting, visual loss, ophthalmoplegia (III, IV, VI), meningism, reduced consciousness, hypotension and hyponatraemia from acute ACTH deficiency.
• Can mimic subarachnoid haemorrhage or meningitis.
• Give IV hydrocortisone (100 mg) immediately, fluids, urgent MRI, neurosurgical review. Urgent decompression if vision is worsening or consciousness falls; otherwise many settle with steroids and observation.

Sheehan syndrome

• Infarction of the pituitary after severe postpartum haemorrhage and hypotension (the gland enlarges in pregnancy and is vulnerable).
• Still seen in Pakistan where obstetric care is limited.
• Earliest sign: failure of lactation (prolactin loss), then no return of periods, loss of pubic and axillary hair, tiredness, hypothyroidism and adrenal insufficiency, which may appear years later.

Hypopituitarism

Causes

• Tumours (adenoma, craniopharyngioma, metastases) and their treatment (surgery, radiotherapy): commonest.
• Vascular: Sheehan syndrome, apoplexy.
• Inflammatory/infiltrative: hypophysitis, sarcoidosis, TB meningitis, Langerhans cell histiocytosis, haemochromatosis.
• Trauma: head injury, skull base fracture.
• Congenital: Kallmann (isolated GnRH), PROP1 or POU1F1 mutations, septo-optic dysplasia.
• Functional: anorexia nervosa, starvation, severe illness.
• Drugs: immune checkpoint inhibitors; long-term high-dose steroids (suppress ACTH).

Order of hormone loss with a growing mass

GH → LH/FSH → TSH → ACTH, while prolactin rises (stalk effect). Posterior pituitary function is usually spared.

Clinical features

• Classic long-standing picture: pale "alabaster" skin, fine wrinkles, loss of body hair.

Replacement

• Sick-day rules: double the hydrocortisone during fever or illness; IM hydrocortisone 100 mg if vomiting; carry a steroid card and bracelet.
• Give hydrocortisone before levothyroxine; thyroxine first can trigger adrenal crisis.
• Steroid replacement can unmask diabetes insipidus, because cortisol is needed to excrete a water load.

Testing pituitary function

Basal tests (9 am)

• Cortisol: a value above about 400 nmol/L usually means adequate reserve; below about 100 nmol/L means deficiency; in between needs a dynamic test.
• TSH with FT4, LH/FSH with testosterone or oestradiol, prolactin, IGF-1. In a menstruating woman, regular cycles show the gonadal axis is intact.

Insulin tolerance test (ITT, insulin stress test)

The gold standard for ACTH (cortisol) and GH reserve, because hypoglycaemia is a powerful stress that stimulates both.

Before the test

• Only in specialist units, with a doctor present, IV glucose and hydrocortisone ready.
• Contraindications: ischaemic heart disease (do an ECG), epilepsy or unexplained blackouts, basal 9 am cortisol below about 100 nmol/L, untreated hypothyroidism, the elderly and young children.
• Overnight fast; start about 08:00–09:00.

Procedure

• Soluble insulin 0.15 unit/kg IV (higher in insulin resistance such as acromegaly or Cushing).
• Measure glucose, cortisol and GH at 0, 30, 45, 60, 90 and 120 minutes.
• Adequate stress requires glucose below 2.2 mmol/L with symptoms (sweating, tachycardia). If glucose does not fall that low, the result cannot be read.
• If severe neuroglycopenia occurs, give IV glucose (and continue sampling).

Interpretation (lab cut-offs vary)

• Normal cortisol response: peak above about 550 nmol/L.
• Normal GH response: peak above about 7 µg/L; below about 3 µg/L means severe GH deficiency.

Alternatives to the ITT

Quick revision

• Micro <10 mm, macro ≥10 mm; prolactinoma commonest.
• Upward growth → bitemporal superior quadrantanopia → hemianopia; craniopharyngioma → inferior first.
• Prolactin >5000 mU/L with macroadenoma = prolactinoma; modest rise with large mass = stalk effect; dilute if hook effect suspected.
• Cabergoline first for prolactinoma, even with visual loss.
• Acromegaly: IGF-1 screen; GH not suppressed on OGTT; surgery first; octreotide, pegvisomant.
• Apoplexy: IV hydrocortisone first. Sheehan: no lactation after PPH.
• Loss order GH, LH/FSH, TSH, ACTH; secondary adrenal failure: no pigment, normal K+.
• Hydrocortisone before thyroxine; monitor FT4 not TSH.
• ITT: insulin 0.15 unit/kg; glucose <2.2; normal cortisol >550, GH >7; not in IHD or epilepsy.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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