Hypothalamus

What it normally does

• The hypothalamus talks to the front of the pituitary by chemistry, not by nerve. Small (parvocellular) neurons drip releasing hormones — GnRH, TRH, CRH, GHRH — into a private set of veins running down the stalk (hypophyseal portal system), so the signal arrives at the anterior pituitary concentrated instead of diluted in the whole circulation. Two of the signals are brakes rather than accelerators: dopamine holds prolactin down continuously, and somatostatin holds growth hormone down. And pulsatility matters, most sharply for GnRH, which must arrive roughly every 60 to 90 minutes. A steady, unvarying level first over-stimulates, then downregulates the GnRH receptor and switches the pituitary off.

  Explains why a lesion of the stalk drops every anterior pituitary hormone except prolactin, which goes up once the dopamine brake is cut; why a continuous GnRH agonist is used to shut the gonadal axis down rather than drive it — and why it causes a testosterone or oestrogen FLARE for the first one to two weeks before it works, which is why anti-androgen cover is given when starting one for prostate cancer; and why hypothalamic disease and pituitary disease look identical on a single blood test — in both, the target hormone is low and the trophic hormone fails to rise.

• ADH (vasopressin) and oxytocin are not made in the pituitary at all. Large (magnocellular) neurons in the supraoptic and paraventricular nuclei make them and run their axons down the stalk to the posterior pituitary, which is really just a field of nerve endings storing hormone — no portal veins, no second cell. Nearby, osmoreceptor neurons in circumventricular organs (the OVLT and subfornical organ) sit outside the blood-brain barrier and shrink when plasma gets salty: a rise of about 1 to 2% above a threshold near 280 to 285 mosmol/kg switches on ADH, and a slightly higher threshold near 290 to 295 switches on thirst. A big fall in blood volume or pressure overrides osmolality altogether and releases ADH regardless.

  Explains why damage high in the hypothalamus or stalk causes permanent diabetes insipidus while surgery on the pituitary itself often causes only a transient one — cut the axon low down and the cell bodies survive and regrow terminals. It also explains why an alert patient with intact thirst and a water jug can pass 8 litres a day and keep a nearly normal sodium, while the same patient nil by mouth overnight becomes dangerously hypernatraemic. Thirst, not ADH, is the last line of defence.

• The preoptic area at the front of the hypothalamus is the thermostat. It compares blood temperature and skin sensor traffic against a set point and drives the effectors: sweating and skin vasodilation to lose heat, shivering, skin vasoconstriction and brown fat to make it. Infection does not heat the body directly. Bacterial products make white cells release IL-1, IL-6 and TNF; these (together with direct action on the local vasculature) trigger prostaglandin E2 production at the leaky vascular window at the front of the hypothalamus, and PGE2 acting on EP3 receptors in the preoptic area raises the set point. The body then heats itself to the new number.

  Explains why a patient piles on blankets and shivers while the temperature is climbing — they are cold relative to the new set point — and sweats when the pyrogen clears and the set point drops. It also explains why paracetamol and NSAIDs lower a fever (they block the cyclo-oxygenase making PGE2) and why they do nothing in heat stroke, where the set point was never raised and the problem is heat that cannot be shed.

• Appetite is set in the arcuate nucleus at the base of the hypothalamus, beside the median eminence where the blood-brain barrier is leaky, so the neurons can sample the blood directly: leptin from fat, insulin, ghrelin from the empty stomach, GLP-1 and PYY from the fed gut. Two populations argue. POMC neurons release alpha-MSH, which acts on melanocortin-4 receptors (MC4R) on second-order neurons downstream (notably in the paraventricular nucleus) and says stop eating. AgRP/NPY neurons block those same receptors and say eat. Leptin rises with fat mass, stimulates POMC and inhibits AgRP.

  Explains why leptin failed as an obesity drug — people with obesity already have high leptin and are resistant to it, because the system evolved to defend against starvation, not excess. It explains why MC4R mutations are the commonest single-gene cause of obesity, why a tumour or surgery near this nucleus produces relentless hunger that no diet fixes, and why the GLP-1 drugs work: they feed a signal into this circuit rather than fighting it from outside.

What goes wrong

• Hypothalamic and stalk failure (central hypopituitarism)← from “The hypothalamus talks to the front of the pit…”

  The releasing hormones never reach the pituitary. Causes worth knowing: craniopharyngioma in a child, tumours pressing up from the sella, cranial radiotherapy, severe traumatic brain injury, infiltration (sarcoidosis, Langerhans cell histiocytosis, tuberculosis) and hypophysitis from immune checkpoint inhibitors. The axes usually fail in order — growth hormone and gonadotrophins first, TSH and ACTH later. Because the dopamine brake travels down the same stalk, prolactin goes UP modestly while everything else goes down: the stalk effect. Two consequences follow from where the block is. Cortisol is low but aldosterone is intact, because aldosterone is driven by renin and potassium, not ACTH — so there is no hyperkalaemia and no severe salt wasting. And the skin is pale rather than pigmented, because ACTH (which is cut from the same POMC precursor as the melanocyte-stimulating pigment signal) is low, not high.

  Every axis down with prolactin UP means the stalk — image it, do not reach for cabergoline. Low free T4 with a non-raised TSH is central hypothyroidism. Hydrocortisone before thyroxine, always. The common outpatient version has no lesion at all: functional hypothalamic amenorrhoea, where low energy availability from restrictive eating, heavy training or illness slows the GnRH pulse generator — amenorrhoea with LOW LH, FSH and oestradiol (the opposite of PCOS), plus bone loss. The treatment is restoring energy availability and rest, not the pill.

  You would find: A child with a headache, falling height velocity, bitemporal hemianopia and polyuria — craniopharyngioma until proven otherwise. An adult with fatigue, loss of libido, amenorrhoea, loss of body and axillary hair, pale skin and hyponatraemia. The lab pattern is the diagnosis: a LOW target hormone with a trophic hormone that is low or unhelpfully normal. Free T4 low with a TSH of 1.2 is not normal, it is central hypothyroidism. A 9 am cortisol of 90 nmol/L with an unremarkable ACTH is central adrenal insufficiency. Mildly raised prolactin alongside all of that points at the stalk.

• Cranial diabetes insipidus (arginine vasopressin deficiency)← from “ADH (vasopressin) and oxytocin are not made in…”

  The magnocellular neurons or their axons are destroyed — pituitary surgery, head injury, tumour, infiltration, autoimmune infundibuloneurohypophysitis. With no ADH the collecting duct keeps no aquaporin-2 in its apical membrane, so filtered water is not reclaimed and pours out. Plasma osmolality and sodium rise, thirst switches on, and the patient drinks to keep up. The mirror problem is nephrogenic DI (arginine vasopressin resistance), where ADH is present but the kidney cannot hear it — lithium, chronic hypercalcaemia, hypokalaemia.

  Large volumes of dilute urine plus a rising sodium plus thirst. Concentrates with desmopressin means cranial. The patient who dies of this is the one who cannot ask for water: unconscious, post-operative, elderly, or a small child.

  You would find: Three to twenty litres a day, nocturia, and a craving for iced water. Urine osmolality under 300 mosmol/kg (often under 200) while plasma osmolality is over 295 and sodium is high-normal or high. Give desmopressin and cranial DI concentrates the urine by more than half; nephrogenic barely moves. After pituitary surgery expect the triphasic pattern: DI for a few days, then a phase around days 5 to 10 where stored hormone leaks out of dying terminals and behaves like SIADH — this is when the sodium crashes if desmopressin and fluids are continued — then permanent DI if enough neurons died.

• SIADH (too much ADH)← from “ADH (vasopressin) and oxytocin are not made in…”

  ADH is released when plasma osmolality is already low — the opposite of the rule the osmoreceptor is meant to follow. It comes either from the hypothalamus itself (stroke, subarachnoid haemorrhage, meningitis, pain, nausea, the post-operative state, and drugs including SSRIs, carbamazepine and tramadol) or from a tumour making it ectopically, classically small cell lung cancer. Water is retained while sodium handling stays normal, so the patient dilutes: hyponatraemia with a normal blood volume, not a swollen one.

  SIADH is a diagnosis of exclusion. Check cortisol and TSH before you commit, because a hypothalamic lesion causes cortisol deficiency and hyponatraemia at the same time, and steroid replacement fixes that sodium while fluid restriction alone will not. First-line treatment is fluid restriction and removing the cause.

  You would find: Sodium under 135 with a LOW plasma osmolality, but a urine osmolality above 100 mosmol/kg and urine sodium above 30 mmol/L — the kidney concentrating when it should be pouring out water. Patient euvolaemic, not on diuretics, thyroid and adrenal function normal. Symptoms track the speed of the fall, not the number: nausea and headache, then confusion, then seizures below about 120 mmol/L if it fell fast. Correcting faster than 8 to 10 mmol/L in 24 hours risks osmotic demyelination — the patient improves, then deteriorates days later.

• Hypothalamic obesity, and why body weight defends itself← from “Appetite is set in the arcuate nucleus at the …”

  Damage to the arcuate and ventromedial region — resection or radiotherapy for a suprasellar tumour — removes the stop signal while the hunger drive continues, and also removes the sympathetic outflow that burns energy. Intake rises and expenditure falls at the same time. A rare genetic version breaks the same circuit without a lesion: an MC4R mutation leaves the downstream receptor deaf to alpha-MSH. In common obesity there is no lesion, but the same machinery defends the old weight: lose weight and leptin falls, ghrelin rises, measured energy expenditure drops below what the new body size predicts, and hunger climbs. The hypothalamus reads weight loss as starvation and pushes back.

  Appetite is a defended feedback loop with a set point of its own. Drugs that work on weight work by feeding into that loop, and weight returns when they stop, because the defence was suppressed rather than removed.

  You would find: A child treated for a craniopharyngioma who gains weight relentlessly under supervised care, alongside pituitary hormone deficiencies. In the clinic, the far commoner version: weight regain after a successful diet, which is physiology doing its job, not a failure of willpower. Around two in three Australian adults sit above a healthy weight, and obesity and type 2 diabetes fall disproportionately on Aboriginal and Torres Strait Islander communities, where diabetes is diagnosed younger and drives kidney and cardiovascular disease earlier.

• Fever versus hyperthermia← from “The preoptic area at the front of the hypothal…”

  Two different problems that produce the same number on the thermometer. In fever the thermostat has been reset upwards by PGE2, and the body actively defends the new set point — vasoconstriction, shivering, feeling cold, then sweating when the pyrogen clears. In hyperthermia the set point is normal and heat production or heat load simply overwhelms the ability to lose it: heat stroke (exertional in young workers and athletes, classic in older people during a heatwave), serotonin toxicity (an SSRI plus tramadol or a MAOI), neuroleptic malignant syndrome (dopamine blockade, including in the hypothalamus itself), and malignant hyperthermia after a volatile anaesthetic or suxamethonium.

  An antipyretic moves the set point, not the temperature. If the set point was never the problem, paracetamol is useless and physical cooling plus stopping the offending drug is the treatment.

  You would find: Fever: temperature climbing with rigors and a patient asking for blankets, settling with paracetamol. Heat stroke: core temperature above 40 degrees with altered mental state after exertion or a run of hot days, skin that may be dry or drenched, and no response to paracetamol because the set point was never raised — cool immediately (cold water immersion for exertional heat stroke) and look for rhabdomyolysis and acute kidney injury. Separate the drug causes by tone: clonus and hyperreflexia, worse in the legs, with onset over hours, suggest serotonin toxicity; lead-pipe rigidity and hyporeflexia developing over days after an antipsychotic suggest neuroleptic malignant syndrome. Heatwaves have killed more Australians than any other natural hazard, and remote communities and outdoor workers carry the load.

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.