Anterior pituitary
A pea-sized block of hormone-secreting cells sitting in a bony pocket under the brain, told what to do by blood-borne signals from the hypothalamus, which then drives the thyroid, the adrenal cortex, the gonads, growth and lactation — so one small lesion can switch off four organ systems at once.
What it normally does
The anterior pituitary has no secretory nerve supply from the hypothalamus (unlike the posterior lobe, which is neural tissue). It is controlled entirely by blood: hypothalamic neurons empty their hormones into a capillary bed in the median eminence, and portal veins running down the stalk carry that blood straight to the pituitary cells (hypothalamic-hypophyseal portal system). Most of those signals are releasers — GnRH, TRH, CRH, GHRH — but two are inhibitory: somatostatin restrains growth hormone, and dopamine holds prolactin down all day. Growth hormone is therefore under dual control (GHRH on, somatostatin off), while prolactin is the one hormone whose net hypothalamic control is inhibitory.
cut, compress or infarct the stalk and every anterior pituitary hormone falls except prolactin, which rises because the dopamine brake has been removed. A modestly raised prolactin with a big pituitary mass therefore does not prove the mass makes prolactin — it may just be sitting on the stalk, and that single asymmetry decides whether the patient gets a tablet or an operation. The same stalk also carries the posterior pituitary axons, so a stalk lesion can add cranial diabetes insipidus (arginine vasopressin deficiency) — polyuria and thirst — which an adenoma confined to the anterior lobe almost never does. The dual control of GH is what somatostatin analogues exploit.
Five cell types make six hormones. Somatotrophs make growth hormone and are about half the gland. Lactotrophs make prolactin. Corticotrophs make ACTH. Gonadotrophs make LH and FSH. Thyrotrophs make TSH and are the smallest population, around 5%. The cells are not scattered evenly, and the trophic hormones are released in pulses rather than as a steady stream — GH mostly in overnight bursts during slow-wave sleep, ACTH and cortisol in an early-morning peak.
adenomas take their syndrome from the cell they arise in. The two commonest are the clinically non-functioning adenoma (usually gonadotroph lineage, secreting nothing measurable) and the prolactinoma; which of them leads depends on the series, since non-functioning tumours dominate surgical series while population-based studies usually put prolactinomas first. Among secreting tumours the prolactinoma is clearly commonest, followed by GH- and ACTH-secreting tumours. When a mass compresses the gland the hormones fail in a fairly reproducible order — GH first, then the gonadotrophs, then TSH, then ACTH — but this reflects how sensitive each cell line is and how much reserve each axis holds, not how numerous the cells are (thyrotrophs are the fewest cells yet TSH outlasts the gonadotrophs). Pulsatility explains why a single random GH or ACTH level is close to useless, and why testing uses dynamic tests or a stable downstream marker instead.
Each axis is a loop. The pituitary hormone drives a target gland, and the target gland's product feeds back to shut off both the pituitary and the hypothalamus: cortisol on ACTH, thyroid hormone on TSH, testosterone and oestradiol on LH and FSH (with inhibin B selectively restraining FSH), and IGF-1 (made by the liver in response to GH) on growth hormone. Feedback is negative and continuous, with one physiological exception — sustained high oestradiol in the late follicular phase flips to positive feedback and generates the mid-cycle LH surge that triggers ovulation.
you never interpret a pituitary hormone alone — you read the pair. Low thyroid hormone with a high TSH is a sick thyroid; low thyroid hormone with a normal or low TSH is a sick pituitary, because a healthy pituitary facing a low T4 is obliged to produce a high TSH. The same logic explains why months of prednisolone suppress the corticotrophs so that cortisol cannot be raised on demand, and why IGF-1, which is stable across the day, is the practical screening test for growth hormone excess.
The gland sits in a bony hollow in the sphenoid (sella turcica) with the optic chiasm immediately above it and a cavernous sinus on each side carrying cranial nerves III, IV, V1 and VI (V2 runs in the lower lateral wall) plus the internal carotid artery. The roof is only a fold of dura (diaphragma sellae), so an enlarging gland takes the path of least resistance and grows upward into the chiasm. The floor is a thin plate of bone above the sphenoid sinus and the nose.
the first neurological sign of a pituitary tumour is loss of the outer visual fields — classically a superior bitemporal quadrant defect first, because compression from below hits the inferonasal crossing fibres, progressing to a full bitemporal hemianopia. Lateral growth into the cavernous sinus is common on imaging but often silent, since the nerves are pushed rather than infiltrated; an acute cranial nerve palsy (most often the third) therefore suggests apoplexy or an aggressive lesion rather than ordinary slow growth. And the thin floor is why surgeons reach the gland up through the nose (transsphenoidal) rather than opening the skull.
What goes wrong
A benign clone of lactotrophs escapes dopamine control and secretes prolactin autonomously. Prolactin then does two things. It acts on the breast to produce milk, and it suppresses hypothalamic GnRH pulses (via kisspeptin neurons), which drops LH and FSH and therefore oestradiol or testosterone. So the patient gets a lactation problem plus a hypogonadism problem from one hormone. This is the commonest hormone-secreting pituitary tumour.
Amenorrhoea, galactorrhoea, infertility in women; late presentation with mass effect in men. Prolactin broadly scales with tumour size — a big tumour with only a mildly raised prolactin is stalk effect, not a prolactinoma. First-line treatment is a tablet (dopamine agonist), with surgery reserved for intolerance, resistance or a mass still threatening vision.
You would find: A woman in her twenties or thirties with periods that stopped, milky discharge from both nipples, and infertility — she presents early because the periods stop, so the tumour is usually small (microadenoma, under 10 mm). A man presents late with low libido, erectile dysfunction and a headache or visual field defect, because nothing forced him in earlier, so his tumour is usually large. Interpret the number, not just the flag: a prolactin in the hundreds to low thousands (roughly 700-2000 mIU/L) beside a large mass is usually stalk compression, whereas a macroprolactinoma typically runs well above 5000 mIU/L. Before chasing a tumour, exclude the everyday causes — pregnancy, lactation, hypothyroidism (raised TRH also drives prolactin), chronic kidney disease, and dopamine-blocking drugs such as risperidone and metoclopramide. If a very large mass sits beside a surprisingly modest prolactin, ask the laboratory to repeat the assay diluted: enormous prolactin levels can saturate the assay and read falsely low (hook effect).
A somatotroph adenoma secretes growth hormone continuously instead of in overnight pulses. GH drives the liver to make IGF-1, and IGF-1 does the growing. After the growth plates have fused bone can only thicken, not lengthen, so the jaw, brow, hands and feet enlarge. Soft tissue and cartilage swell everywhere — including the tongue, the airway and the carpal tunnel. GH also opposes insulin, so glucose rises. If the same tumour appears before the growth plates fuse, the child gets gigantism instead.
Screen with age-adjusted IGF-1, confirm with failure of GH suppression on OGTT, then MRI. Transsphenoidal surgery is first-line treatment. Excess mortality is mainly cardiovascular and respiratory — hypertension, cardiomyopathy, sleep apnoea — rather than from the tumour itself, and it falls towards normal once the biochemistry is controlled.
You would find: Rings that no longer fit, shoes gone up two sizes, a jaw that has come forward with teeth spreading apart (prognathism, interdental separation), coarse features, greasy sweaty skin, carpal tunnel syndrome, snoring and obstructive sleep apnoea, new hypertension and new type 2 diabetes. The change is so slow that nobody notices — reported delay to diagnosis is usually several years, commonly quoted as 5-10 — so ask for a driver licence photo from ten years ago. Screen with IGF-1, interpreted against an age-matched reference range because IGF-1 falls with age; confirm with failure of GH to suppress during an oral glucose tolerance test, since glucose normally switches GH off.
- Mass effect and pituitary apoplexy← from “The gland sits in a bony hollow in the sphenoi…”
A non-functioning adenoma makes nothing measurable, so it announces itself only by size. Growing upward it lifts and stretches the optic chiasm; growing sideways it extends into the cavernous sinus. Apoplexy is the emergency version: the adenoma suddenly bleeds into itself or infarcts, the sella contents swell in a box that cannot expand, and the chiasm and cavernous sinus nerves are compressed within hours. Corticotroph function is lost in roughly two thirds of cases, so the patient may lose cortisol acutely — which is why cortisol deficiency is assumed until disproved rather than waited for.
Bitemporal hemianopia = chiasm compressed from below. Apoplexy = thunderclap headache plus ophthalmoplegia plus hypotension; hydrocortisone first, imaging second, urgent surgery if vision is threatened or consciousness is falling.
You would find: Slow version: bitemporal field loss the patient has not noticed, found on confrontation testing or formal perimetry, sometimes with headache. Apoplexy: thunderclap headache, vomiting, sudden visual loss, a droopy dilated eye with a down-and-out gaze (third nerve palsy in the cavernous sinus), and hypotension that responds poorly to fluids because there is no cortisol. Parenteral hydrocortisone is given on suspicion — before imaging and before endocrine results are back — after a cortisol and ACTH sample is drawn if that causes no delay. Separately, remember pituitary incidentalomas are found on roughly one in ten brain MRIs and most need nothing but a hormone panel, a visual field check if they abut the chiasm, and a repeat scan.
- Hypopituitarism← from “Five cell types make six hormones. Somatotroph…”
The gland is destroyed or compressed — most often by an adenoma or its treatment (surgery, radiotherapy), sometimes by infarction, infiltration (haemochromatosis, sarcoidosis, hypophysitis) or traumatic brain injury. Axes fail in a fairly reproducible order of vulnerability: growth hormone first, then the gonadotrophs, then TSH, and ACTH last. Because the failure is above the target gland, ACTH deficiency loses cortisol but keeps aldosterone, which is driven by renin-angiotensin and potassium rather than by the pituitary. Sheehan syndrome is the obstetric version: the lactotroph-enlarged pituitary of late pregnancy outgrows its blood supply and infarcts when severe postpartum haemorrhage drops the blood pressure.
Secondary adrenal insufficiency: cortisol low, aldosterone normal, so pale skin, low sodium, normal potassium. Order of loss GH, then LH/FSH, then TSH, then ACTH. Failure to lactate after postpartum haemorrhage is Sheehan until proven otherwise.
You would find: Vague and easily missed — exhaustion, loss of libido, amenorrhoea, loss of axillary and pubic hair, pale sallow skin, and hyponatraemia (cortisol is needed to excrete free water, and cortisol deficiency also releases vasopressin). The skin is pale, not pigmented: without ACTH there is no melanocortin drive on melanocytes, the reverse of primary adrenal failure. There is no hyperkalaemia and no salt craving, because aldosterone is intact. Sheehan classically presents as a woman who cannot breastfeed after a haemorrhagic delivery, then never resumes periods. It is rare in Australia but tracks obstetric haemorrhage care, and Aboriginal and Torres Strait Islander women — who face substantially higher rates of severe maternal morbidity and of birthing far from a tertiary centre — carry more of that risk.
- Cushing disease← from “Each axis is a loop. The pituitary hormone dri…”
A corticotroph adenoma — usually a microadenoma — secretes ACTH with only partial sensitivity to cortisol feedback. Cortisol rises and stays high overnight instead of falling, and the excess ACTH also drives adrenal androgens. Because the tumour retains some feedback, high-dose dexamethasone suppresses most pituitary tumours while most ectopic ACTH sources such as small cell lung cancer do not — but the test is far from clean (bronchial carcinoids often suppress like a pituitary tumour), so it no longer stands alone. Note the honest denominator: the commonest cause of Cushing syndrome by far is prescribed glucocorticoids, and that form has a suppressed ACTH.
Exclude exogenous steroids, confirm cortisol excess with two tests, then measure ACTH. ACTH suppressed means adrenal or exogenous steroid; ACTH normal or high means pituitary or ectopic, and petrosal sinus sampling is the reference standard for telling those apart. Proximal myopathy, wide purple striae and easy bruising are the discriminating signs, not obesity.
You would find: Weight gain that is central with thin arms and legs, a round plethoric face, purple stretch marks wider than a centimetre, skin that bruises and tears, and weakness getting out of a chair or off the floor (proximal myopathy from cortisol catabolising muscle). Add new hypertension, new diabetes, osteoporotic fractures and mood change; hypokalaemia occurs but marked hypokalaemic alkalosis points more to ectopic ACTH than to a pituitary tumour. Screening exploits the loss of the daily rhythm — late-night salivary cortisol, a 1 mg overnight dexamethasone suppression test, or 24-hour urinary free cortisol, with two abnormal tests before proceeding — then ACTH tells you whether the driver is pituitary or adrenal. When ACTH is not suppressed, MRI plus (where the imaging and the biochemistry disagree) inferior petrosal sinus sampling is what actually separates pituitary from ectopic.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- The D2 dopamine receptor on the lactotroph cell membrane
- Which does
- D2 is Gi-coupled. Agonism drops intracellular cAMP, which shuts down prolactin gene transcription and secretion and also shrinks the cell itself, so the tumour physically involutes.
- So you see
- Prolactin falls within days and the tumour shrinks over weeks to months. Periods and fertility return, galactorrhoea stops, and visual fields recover — which is why a prolactinoma compressing the chiasm is one of the few large intracranial tumours treated with a tablet rather than an operation.
- And the same mechanism causes
- D2 receptors are not confined to the pituitary. In the area postrema (the vomiting trigger zone, outside the blood-brain barrier) they cause nausea. Peripherally, D2 agonism on sympathetic nerve terminals reduces noradrenaline release and dopamine receptors on vascular smooth muscle vasodilate, so first doses cause postural dizziness. In the mesolimbic reward pathway D2 and D3 stimulation produces impulse control disorders — gambling, compulsive shopping, hypersexuality — which patients will not volunteer, so you ask directly at every review. Both are ergot alkaloids and can cause vasospastic and, rarely, fibrotic reactions.
- Handling
- Nausea and postural drop are dose- and titration-dependent, so treatment starts low, is taken with food in the evening, and is escalated slowly — cabergoline once or twice weekly (better tolerated, more effective, the usual Australian first choice), bromocriptine daily. Bromocriptine is preferred where a large evidence base in pregnancy matters. Cabergoline also stimulates 5-HT2B receptors on heart valve fibroblasts, which can drive valve thickening; the demonstrated risk sits at the far higher continuous doses used in Parkinson disease, which is why cardiac valve disease is asked about and echocardiography considered for long-term high-dose use.
Catches people out: Fertility returns before periods do, so a woman who does not want to conceive needs contraception from the day she starts. Run the reverse logic before diagnosing anything: dopamine antagonists raise prolactin by the identical mechanism, so check for antipsychotics (risperidone especially), metoclopramide and prochlorperazine first — and never simply stop an antipsychotic to prove the point without the prescriber.
- Binds
- Somatostatin receptors, chiefly SSTR2 with some SSTR5, on the adenoma cell surface
- Which does
- These are Gi-coupled too: cAMP falls, calcium influx falls, and secretory granules are not released. GH output drops and the tumour usually shrinks modestly.
- So you see
- GH and IGF-1 fall, and with them the sweating, headache, soft tissue swelling, joint pain and carpal tunnel symptoms. Ring and shoe size stop changing. Bone that has already thickened does not reverse.
- And the same mechanism causes
- Somatostatin is a universal inhibitor of secretion across the gut, so the same receptors deliver the same off-switch elsewhere. Gallbladder contraction and CCK release are inhibited, bile stagnates, and gallstones or sludge form. Insulin secretion from the beta cell is inhibited, so glucose can rise even as acromegaly improves. Pancreatic enzyme output and gut motility fall, producing bloating, cramps and steatorrhoea in the first weeks. Sinus bradycardia also occurs, reflecting the same inhibitory signalling in cardiac tissue.
- Handling
- Given by injection — typically a monthly depot, octreotide LAR deep intramuscular or lanreotide deep subcutaneous, often after a trial of short-acting subcutaneous octreotide to check tolerance and response — because a peptide of this kind is not reliably absorbed if swallowed.
Catches people out: The effect on glucose runs in two directions: less growth hormone improves insulin sensitivity, less insulin secretion worsens it. Which one wins varies by patient, so glucose is monitored rather than assumed to improve. Pasireotide, a multi-receptor analogue with strong SSTR5 activity, is the same drug family aimed at the corticotroph in Cushing disease — and it worsens hyperglycaemia far more, for exactly the reason above.
- Binds
- The growth hormone receptor on hepatocytes and peripheral tissues
- Which does
- It is a pegylated, mutated GH molecule that binds one site of the receptor dimer but cannot engage the second properly, so the receptor pair never adopts the active conformation and JAK2-STAT5 is not triggered. The signal stops at the cell surface and the liver stops making IGF-1.
- So you see
- IGF-1 normalises in the large majority of patients and symptoms resolve, even though circulating GH is unchanged or higher.
- And the same mechanism causes
- Blocking the receptor removes IGF-1 feedback onto the pituitary, so GH secretion rises and the adenoma loses that restraint — tumour enlargement is uncommon in practice but real, so the tumour is imaged periodically. Because GH rises on treatment, and because the drug cross-reacts with some GH assays, measuring GH to judge control is meaningless; IGF-1 is the only valid marker. Liver transaminases rise in some patients and are monitored. Lipohypertrophy can develop at injection sites, since GH signalling normally restrains local fat.
- Handling
- Daily subcutaneous injection after a loading dose, titrated against IGF-1.
Catches people out: This is the clearest example on the page of a drug named for a pituitary disease that never touches the pituitary. It fixes the biochemistry and the symptoms while leaving the tumour in place — so it does not replace surgery or imaging follow-up.
- Binds
- The intracellular glucocorticoid receptor, present in almost every nucleated cell
- Which does
- The steroid crosses the membrane, binds its receptor in the cytoplasm, and the complex moves into the nucleus and switches gene transcription on and off over hours — which is why the clinical effect is not instant.
- So you see
- Blood vessels regain their responsiveness to catecholamines so blood pressure recovers, gluconeogenesis resumes, free water is excreted so sodium normalises, and the profound fatigue lifts. Oral hydrocortisone is divided across the day, weighted to the morning, to imitate the natural cortisol rhythm; prednisolone is a once-daily alternative.
- And the same mechanism causes
- The same receptor in the same tissues at higher occupancy is simply Cushing syndrome — thin skin, bruising, proximal muscle wasting, hyperglycaemia, osteoporosis. Over-replacement does not cause a new disease; it causes the disease from earlier on this page. That is the argument for using the lowest dose that abolishes symptoms, since there is no blood test that reliably confirms adequate replacement.
- Handling
- Mineralocorticoid replacement is not needed here. Aldosterone is driven by renin-angiotensin and potassium, not ACTH, so the zona glomerulosa is intact — the point of difference from primary adrenal failure, where fludrocortisone is required.
Catches people out: Order matters. If a patient needs both hydrocortisone and thyroxine, hydrocortisone goes first: thyroid hormone speeds cortisol clearance and raises metabolic demand, and starting thyroxine into an unreplaced cortisol deficit can precipitate an adrenal crisis. Every replaced patient also needs sick day rules — an increased oral dose during intercurrent illness, a parenteral hydrocortisone ampoule and a written emergency plan for vomiting or trauma, and medical identification — because the axis cannot mount its own stress response. The specific doses are set by the treating endocrinologist and written into the patient's plan; the examinable point is that the dose must go up under stress, never down or stopped abruptly.
Two habits carry most pituitary questions. First, always read the pair. A low target hormone with a trophic hormone that is merely normal is a pituitary lesion, because a working pituitary facing a low T4, low cortisol or low testosterone is obliged to produce a high TSH, ACTH or LH. Second, remember the two inhibitory hypothalamic signals — dopamine on prolactin and somatostatin on GH — because both are where the drugs act. Anything that interrupts the stalk pushes prolactin up while dragging everything else down, and any drug blocking D2 does the same thing pharmacologically. From there the treatments sort themselves: prolactinoma is medical first (dopamine agonist), almost every other secreting adenoma is surgical first (transsphenoidal), with somatostatin analogues and pegvisomant as later lines in acromegaly. In Cushing disease, note the site of action of the medical options — the steroidogenesis inhibitors (metyrapone, which blocks adrenal 11-beta-hydroxylase) work on the adrenal, not the pituitary, while pasireotide and cabergoline act on the corticotroph itself; all are adjuncts to surgery, and oral ketoconazole is no longer routinely available in Australia for this purpose. And in any acutely unwell patient with a pituitary mass, hydrocortisone goes in before the diagnosis is complete.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.