Pituitary and adrenal glands
Hypothalamus, pituitary and adrenal glands: feedback, hormones and disorders
Hypothalamic, pituitary and adrenal physiology for FCPS Part 1: nuclei, portal system, feedback, prolactin, GH, cortisol and aldosterone. It shows how to locate a lesion from a hormone pattern and how Cushing and Addison disease are tested and imaged.
Hypothalamic nuclei
| Nucleus or area | Function | Effect of a lesion |
|---|---|---|
| Suprachiasmatic | Circadian clock (retinal input) | Loss of daily rhythms |
| Ventromedial | Satiety | Hyperphagia, obesity |
| Lateral | Feeding centre | Refusal to eat, weight loss |
| Anterior (preoptic, OVLT) | Heat loss; osmoreceptors for ADH and thirst | Hyperthermia |
| Posterior | Heat conservation (shivering) | Temperature drifts with the environment |
| Supraoptic | Mainly ADH | Cranial diabetes insipidus |
| Paraventricular | Mainly oxytocin; CRH and TRH (parvocellular) | Loss of milk ejection |
| Arcuate | Dopamine, GnRH, GHRH | Raised prolactin |
| Periventricular | Somatostatin (inhibits GH and TSH) |
- Kisspeptin neurons drive GnRH pulses. Prostaglandins raise the hypothalamic set point (fever).
Hypothalamic–pituitary connections
- Anterior pituitary: releasing hormones travel down the hypophyseal portal system. It secretes GH, prolactin, ACTH, TSH, LH and FSH.
- Posterior pituitary: ADH and oxytocin are made in hypothalamic neurons, carried down axons bound to neurophysin and released into blood: true neurosecretion. ADH (V1 receptors) is also a powerful vasoconstrictor.
- The median eminence, stalk and pituitary lack a blood–brain barrier and enhance strongly. On T1 MRI the posterior lobe is a bright spot (stored granules).
- Normal enlargement: puberty, pregnancy (lactotroph hyperplasia), untreated primary hypothyroidism (thyrotroph hyperplasia).
- A pituitary mass growing upwards presses the chiasm: bitemporal hemianopia.
Feedback and lesion localisation
- Negative feedback is the commonest and most important control: the end hormone suppresses its releasing and trophic hormones.
- Positive feedback amplifies: the LH surge (rising oestradiol), and the Ferguson reflex, where cervical stretch releases oxytocin, which strengthens contractions and stretches the cervix further. Others: clotting cascade, action potential upstroke.
- Low target hormone with high trophic hormone: primary (gland) failure. Low with low or normal trophic hormone: pituitary or hypothalamus. A rise after the releasing hormone points to the hypothalamus.
- Stress: CRH rises first; parvocellular vasopressin on V1b receptors amplifies ACTH. CRH, cortisol and energy deficit suppress GnRH pulsatility, so exam stress, weight loss and heavy exercise give amenorrhoea with low LH, FSH and oestrogen (functional hypothalamic amenorrhoea).
Prolactin
- The only anterior pituitary hormone under tonic inhibition: dopamine on D2 receptors. TRH stimulates.
- Stalk section lowers every other anterior hormone but raises prolactin.
- Causes of hyperprolactinaemia: pregnancy and suckling, prolactinoma, D2 blockers (antipsychotics, metoclopramide), primary hypothyroidism (TRH excess), stalk compression by a non-functioning adenoma, stress, chronic kidney disease, chest wall lesions. A level above about 1000 mU/L with headache and visual loss is usually a prolactinoma.
- Prolactin disrupts GnRH pulses: amenorrhoea, galactorrhoea, low libido.
- Dopamine agonists (cabergoline) shrink prolactinomas. If a giant tumour has eroded the sellar floor, rapid shrinkage can unplug the defect and cause CSF rhinorrhoea (beta-2 transferrin positive), which needs repair because of meningitis risk.
Growth hormone
- Pulsatile, highest in deep sleep; rises with fasting, hypoglycaemia, exercise, stress and arginine; falls with hyperglycaemia and obesity. Acts through JAK–STAT.
- Direct actions: lipolysis and anti-insulin effects (hyperglycaemia in acromegaly).
- Via IGF-1 (liver): bone and soft tissue growth. Growth also needs insulin and thyroid hormone (permissive), so a hypothyroid child is short even with normal GH.
- Excess before epiphyseal fusion gives gigantism; after fusion, acromegaly (large hands, feet, jaw, impaired glucose tolerance). Diagnosis: high IGF-1 and GH not suppressed by oral glucose.
- Ectopic GHRH (bronchial or pancreatic neuroendocrine tumour): acromegaly with diffuse pituitary enlargement, no adenoma and high plasma GHRH; pituitary surgery does not cure it.
- Laron syndrome: GH receptor defect, high GH with low IGF-1.
Adrenal cortex
| Zone | Product | Main control |
|---|---|---|
| Glomerulosa | Aldosterone | Angiotensin II and K⁺ |
| Fasciculata | Cortisol | ACTH |
| Reticularis | Androgens (DHEA-S) | ACTH |
- Rate-limiting step: cholesterol entry into mitochondria (StAR) for side-chain cleavage. Steroids are not stored.
- Cortisol acts on an intracellular receptor. It drives gluconeogenesis (its main metabolic action), is permissive for catecholamines, lowers eosinophils and lymphocytes and raises neutrophils. It peaks early in the morning around waking and is lowest near midnight; loss of the midnight trough (late-night salivary cortisol) is an early sign of Cushing syndrome.
- Skin in Cushing syndrome: cortisol reduces fibroblast collagen synthesis, so the dermis thins: wide purple striae and easy bruising.
- Thrombosis in Cushing syndrome: raised clotting factors (VIII, fibrinogen) and reduced fibrinolysis (high PAI-1); risk persists for weeks after surgery.
- Renal 11β-HSD2 inactivates cortisol to protect the mineralocorticoid receptor; ectopic ACTH overwhelms it, causing hypokalaemic alkalosis.
- Aldosterone acts mainly on principal cells of the late distal tubule and collecting duct: opens ENaC and increases Na⁺–K⁺ ATPase, so Na⁺ is reabsorbed and K⁺ and H⁺ are secreted. In dehydration, renin, angiotensin II and aldosterone rise. Secondary hyperaldosteronism in heart failure, cirrhosis or nephrotic syndrome is driven by renin from an underperfused kidney.
- Adrenal medulla: cortisol in intra-adrenal portal blood induces PNMT (noradrenaline to adrenaline). Phaeochromocytoma: headache, palpitations, sweating, raised metanephrines and VMA. Neuroblastoma (neural crest, under 4 years) is the commonest adrenal medullary tumour of children.
- Fetal adrenal makes DHEA-S, the precursor of placental oestriol.
Cushing syndrome: testing and treatment
- Screening (obesity versus Cushing): overnight 1 mg dexamethasone suppression test, 24-hour urinary free cortisol or late-night salivary cortisol.
| Pattern | Low-dose dexamethasone | High-dose | ACTH | CRH test |
|---|---|---|---|---|
| Pituitary adenoma (Cushing disease) | No suppression | Suppresses | High; adrenals smoothly thickened | ACTH and cortisol rise |
| Ectopic ACTH | No | No | Very high | No rise |
| Adrenal tumour | No | No | Undetectable; other adrenal atrophies | No rise |
- Up to half of corticotroph microadenomas are invisible on MRI, so a CRH-responsive ACTH rise with a normal scan still points to the pituitary (confirmed by inferior petrosal sinus sampling).
- Ketoconazole lowers cortisol by blocking cytochrome P450 steroid-synthesis enzymes (side-chain cleavage, 11β-hydroxylase); it is hepatotoxic and inhibits CYP3A4. Metyrapone blocks 11β-hydroxylase.
Adrenal insufficiency
| Feature | Primary (Addison) | Secondary (pituitary) |
|---|---|---|
| ACTH | High (POMC also yields MSH: pigmentation) | Low (pale skin) |
| Aldosterone and K⁺ | Low aldosterone, high K⁺, high renin | Aldosterone preserved, K⁺ normal |
| Hyponatraemia | Salt loss | ADH released without cortisol restraint |
- Waterhouse–Friderichsen syndrome: bilateral adrenal haemorrhage in meningococcal septicaemia (sore throat, purpura, sudden death).
- After bilateral adrenalectomy both glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) must be replaced for life.
- Long-term steroids suppress ACTH and atrophy fasciculata and reticularis; glomerulosa is spared. In hypopituitarism start hydrocortisone before thyroxine.
Adrenal imaging and sampling
- Lipid-rich adenoma: 10 HU or less unenhanced; lipid-poor adenoma: rapid washout. Carcinoma: large, heterogeneous, necrotic, may invade the IVC.
- Adrenal vein sampling in primary aldosteronism lateralises the source. Cortisol is measured in each sample to confirm the catheter is in the adrenal vein (cortisol much higher than in the IVC) and to correct aldosterone for dilution (aldosterone/cortisol ratio). The short right adrenal vein entering the IVC directly is often missed.
Remember Low target hormone with high trophic hormone: the gland has failed; with low trophic hormone: the problem lies above it.
Exam trap Hyperkalaemia and pigmentation belong to primary adrenal failure only; angiotensin II, not ACTH, runs the glomerulosa.
Exam trap Stalk section raises prolactin while every other anterior pituitary hormone falls.
How FCPS asks about this
- Cortisol peak: early morning around waking; main metabolic action gluconeogenesis.
- Example of positive feedback: Ferguson reflex in labour, LH surge.
- Neurosecretory hormone: ADH (also a vasoconstrictor).
- Stress or weight-loss amenorrhoea with low LH, FSH and oestrogen: suppressed GnRH pulsatility.
- Why measure cortisol in adrenal vein sampling: to confirm catheter position and correct for dilution.
- Acromegaly with diffuse pituitary enlargement and bronchial mass: ectopic GHRH from a carcinoid.
- Purple striae in Cushing syndrome: reduced collagen synthesis by fibroblasts.
Test yourself on this topic
5 of the 123 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 55-year-old man with a 4 cm left adrenal mass found on CT is referred for CT-guided biopsy. Before the radiologist will proceed, plasma metanephrines must be checked. Why?
Answer: Needling a phaeo can cause a catecholamine crisis
A phaeochromocytoma can look like any other adrenal mass on CT. Puncturing or handling it can release large amounts of catecholamines, causing a hypertensive crisis, arrhythmia, haemorrhage or death. Biochemical testing for phaeochromocytoma is therefore done before any adrenal biopsy, and biopsy is avoided if the result is positive. Biopsy is now rarely needed for adrenal masses, except to confirm metastasis in a patient with known cancer.
Before adrenal biopsy
- Phaeo can look like any adrenal mass
- Needle can trigger catecholamine crisis
- Check metanephrines first
- Biopsy rarely needed
Remember Always exclude phaeochromocytoma before touching an adrenal mass.
Exam trap Do not biopsy a suspected adrenocortical carcinoma either, because of tumour seeding.
Why the other options are wrong
- Metanephrines show whether the mass is benign Metanephrines do not tell benign from malignant cortical lesions.
- Biopsy is contraindicated in adrenal adenomas Biopsy is unnecessary for adenomas but is not dangerous for that reason.
- Metanephrines predict bleeding from the needle Metanephrines do not predict bleeding risk.
- Contrast reacts with high metanephrines Modern contrast does not react with metanephrines.
After surgery for a large pituitary macroadenoma, a 50-year-old man is found to have deficiencies of TSH and ACTH. Why must hydrocortisone be started before levothyroxine?
Answer: Thyroxine speeds cortisol clearance and need
Thyroid hormone raises the metabolic rate and increases the hepatic clearance of cortisol, so the body's cortisol requirement rises. If thyroxine is given to a patient with untreated ACTH deficiency, the little cortisol available is used up faster, which can precipitate an adrenal crisis. Glucocorticoid replacement is therefore started first, followed by levothyroxine. Monitoring in central hypothyroidism uses free T4, not TSH.
Steroid before thyroxine
- Thyroxine raises metabolic rate
- Speeds cortisol clearance
- Can trigger adrenal crisis
- Start hydrocortisone first
Remember In hypopituitarism, cortisol first, thyroxine second.
Exam trap In central hypothyroidism TSH is useless for monitoring; free T4 guides the dose.
Why the other options are wrong
- Hydrocortisone is needed to absorb thyroxine Thyroxine absorption does not depend on hydrocortisone.
- Thyroxine blocks the cortisol receptor Thyroxine does not block cortisol receptors.
- Hydrocortisone converts T4 to T3 Deiodinases convert T4 to T3; hydrocortisone is not needed.
- Thyroxine suppresses residual ACTH Thyroxine has no major effect on residual ACTH in this setting.
Hypothalamic releasing hormones pass freely into portal capillaries at the median eminence, and pituitary hormones pass freely into the blood, although capillaries in the rest of the hypothalamus are tightly sealed. What explains this?
Answer: These areas lack a blood-brain barrier
Most brain capillaries have tight junctions, forming the blood-brain barrier that keeps large and polar molecules out. The median eminence, pituitary stalk and posterior pituitary belong to the circumventricular organs, which have fenestrated capillaries without a barrier. This lets hypothalamic hormones enter the portal blood and pituitary hormones enter the circulation; the anterior pituitary also lies outside the barrier. Other circumventricular organs, such as the area postrema (vomiting centre) and the organum vasculosum (osmoreceptors), sample the blood directly.
No blood-brain barrier
- Fenestrated capillaries
- Median eminence, stalk, posterior pituitary
- Also area postrema, OVLT
- Hormones in and out freely
Remember Where hormones must cross, the barrier is absent.
Exam trap The area postrema lacks a barrier so that it can detect toxins in the blood and trigger vomiting.
Why the other options are wrong
- They contain the most neurones in the brain Neuronal density does not affect capillary permeability.
- They are lined by choroid plexus Choroid plexus makes CSF and is not what lines these structures.
- They have high CSF flow around them CSF flow does not affect capillary permeability.
- They take up gadolinium actively Passage is passive through fenestrations, not active uptake.
Plasma free metanephrines are preferred over plasma catecholamines for diagnosing phaeochromocytoma, even in a patient who has no symptoms on the day of the test. What explains the better sensitivity?
Answer: Tumour cells convert catecholamines to metanephrines continuously
Phaeochromocytoma cells contain catechol-O-methyltransferase (COMT), which converts adrenaline and noradrenaline into metanephrine and normetanephrine inside the tumour. This happens all the time, whether or not the tumour is releasing a burst of catecholamines, so metanephrine levels stay raised even between attacks. Catecholamines themselves are released episodically and have short half-lives, so a level taken between attacks can be normal.
Metanephrines
- Tumour COMT makes metanephrines
- Produced continuously
- Catecholamines released in bursts
- Metanephrines more sensitive
Remember Measure the steady by-product, not the bursting hormone.
Exam trap Tricyclic antidepressants and some other drugs can raise normetanephrine falsely.
Why the other options are wrong
- Metanephrines are released only during attacks They are produced continuously, not only in attacks.
- Metanephrines are made by the liver from dietary tyrosine They are made from catecholamines by COMT, not from dietary tyrosine in the liver.
- Catecholamines are too stable to change with tumour activity Catecholamines are unstable and short-lived.
- Metanephrines come mainly from sympathetic nerve endings Sympathetic nerves mainly use reuptake and MAO, not COMT, so they contribute little.
A 30-year-old woman with Cushing syndrome has wide purple stretch marks over her abdomen and thighs and bruises easily. Which action of cortisol mainly explains these skin changes?
Answer: Reduced fibroblast collagen synthesis
Cortisol inhibits fibroblasts, reducing the synthesis of collagen and ground substance, so the dermis becomes thin and weak. Under stretch from central fat, the thin dermis tears to form wide striae, which look purple because blood in the underlying vessels shows through. The weak connective tissue around small vessels also explains easy bruising. Healing is slow for the same reason.
Cushing skin
- Cortisol inhibits fibroblasts
- Thin dermis, less collagen
- Wide purple striae
- Easy bruising, poor healing
Remember Cortisol thins the skin from the inside.
Exam trap Pale, narrow striae of pregnancy or growth spurts are common and are not a sign of Cushing syndrome.
Why the other options are wrong
- Stimulation of skin melanocytes Melanocyte stimulation causes pigmentation, not striae.
- Raised capillary hydrostatic pressure Capillary pressure is not the cause of striae or bruising.
- Excess adrenal androgen production Androgens cause hirsutism and acne, not wide purple striae.
- Increased skin blood flow overall Skin blood flow is not the cause.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: Endocrine and reproductive physiology, Hypothalamus, pituitary and adrenal glands; endocrine regulation
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