Endocrine system

An almond-sized block of nuclei under the thalamus that runs the endocrine system by remote control: releasing hormones dripped down a private set of portal veins into the anterior pituitary, ADH and oxytocin built here and stored in the posterior lobe hanging below it, plus the body thermostat, the thirst sensor and the appetite switch — which is why damage in one small place breaks several unrelated systems at once.

What it 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.

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.

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.

What goes wrong

Hypothalamic and stalk failure (central hypopituitarism)Cranial diabetes insipidus (arginine vasopressin deficiency)SIADH (too much ADH)Hypothalamic obesity, and why body weight defends itselfFever versus hyperthermia

What we give

Desmopressin (synthetic ADH analogue)Vasopressin V2 receptor antagonists (vaptans)Glucocorticoid replacementGLP-1 receptor agonists

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 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.

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.

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.

What goes wrong

ProlactinomaAcromegalyMass effect and pituitary apoplexyHypopituitarismCushing disease

What we give

Dopamine agonistsSomatostatin analoguesGrowth hormone receptor antagonistGlucocorticoid replacement

Not a gland at all — it is the nerve endings of the hypothalamus, dripping ADH and oxytocin straight into the blood, so it sets body water and clamps the uterus after birth.

What it does

It is not a glandular tissue. It is the far end of nerve cells whose bodies sit in the hypothalamus (supraoptic and paraventricular nuclei). They make ADH (vasopressin) and oxytocin, carry them down their own axons through the stalk, and release them into capillaries here.

ADH is released when the blood becomes too concentrated — hypothalamic osmoreceptors start firing above about 280-285 mOsm/kg. ADH binds V2 receptors on the last stretch of the nephron (collecting duct) and pushes water channels (aquaporin-2) into the membrane facing the urine. Water is pulled back and the urine ends up small and concentrated.

ADH's main job is to move water, not salt — so the plasma sodium is really a measure of body water. And a big fall in blood volume or pressure overrides osmolality: baroreceptors drive ADH out even when the plasma is already dilute.

What goes wrong

Central diabetes insipidus (arginine vasopressin deficiency, AVP-D)Nephrogenic diabetes insipidus (AVP resistance, AVP-R)SIADH (syndrome of inappropriate ADH)Hyponatraemia from low effective circulating volumeUterine atony and postpartum haemorrhage

What we give

Desmopressin (DDAVP) — synthetic vasopressin analogueAmiloride (potassium-sparing diuretic)Tolvaptan (vaptan — V2 receptor antagonist)Oxytocin (and the longer-acting analogue carbetocin)

A butterfly of iodine-trapping follicles across the front of the trachea that stores months of hormone outside its own cells and releases it under pituitary control to set the metabolic rate of every tissue in the body.

What it does

The follicular cell traps iodide from blood against a steep gradient using the sodium-iodide symporter (NIS) on its basolateral membrane, powered by the sodium gradient from the Na/K ATPase. Iodide moves to the apical membrane (pendrin and other channels), where thyroid peroxidase (TPO) — a membrane-bound enzyme sitting on the apical surface and facing the colloid — uses hydrogen peroxide to oxidise it and attach it to tyrosine residues on thyroglobulin (organification), then couples the iodinated tyrosines together: DIT + DIT gives T4, MIT + DIT gives T3. The finished hormone stays stuck to thyroglobulin in the colloid, outside the cell, and is only chopped free when the cell endocytoses colloid and digests it. The store is large: roughly two to three months of hormone sits in the colloid at any time.

The gland secretes mostly T4 — around 85 to 100 micrograms a day against only about 5 micrograms of T3. T4 is a prohormone. Deiodinase enzymes in liver, kidney, muscle, pituitary and elsewhere strip an outer-ring iodine to make T3, the form that actually binds the nuclear receptor with roughly ten times the affinity; stripping an inner-ring iodine instead makes inactive reverse T3. Most circulating T3 is made this way in the tissues, not secreted. Over 99% of circulating hormone is bound to thyroxine-binding globulin, transthyretin and albumin, so only the tiny free fraction is active. T4 has a half-life near seven days, T3 about one day.

The pituitary thyrotroph releases TSH under hypothalamic TRH drive. TSH binds a Gs-coupled receptor on the follicular cell and raises cAMP, which turns up iodide trapping, hormone synthesis, colloid uptake and release — and also makes the cells grow and divide. T3 generated inside the pituitary from T4 by type 2 deiodinase feeds back and shuts TSH off. The relationship is log-linear: a small movement in free T4 produces a large, inverse movement in TSH.

What goes wrong

Graves diseaseHashimoto thyroiditis and primary hypothyroidismDestructive thyroiditisThyroid nodules and thyroid cancerIodine supply, pregnancy and the thyroid

What we give

Thionamides (antithyroid drugs)Beta blockersLevothyroxineRadioactive iodine (iodine-131)

Four glands the size of rice grains, stuck on the back of the thyroid, doing one job: holding the free calcium in blood inside a narrow band — the ionised fraction moves only about a tenth to a fifth of a millimole across the whole normal range. They read that calcium with a receptor wired backwards — calcium ON means hormone OFF — so nearly everything on this page is that switch stuck on, stuck off, or cut out with the thyroid.

What it does

The hormone-making cells of the parathyroid (chief cells) read blood calcium directly, through a G-protein coupled receptor sitting on their surface [calcium-sensing receptor, CaSR]. It is wired the opposite way to most hormone loops: when calcium binds the receptor, parathyroid hormone (PTH) secretion is switched OFF. Let calcium fall a few hundredths of a millimole and the receptor empties and PTH is released from preformed granules within seconds to minutes. Only the free, unbound fraction counts [ionised calcium, roughly half the total; about 40% is bound to albumin and about 10% complexed to citrate, phosphate and bicarbonate], so the gland is blind to a total calcium that is low only because albumin is low. Binding to albumin is pH-dependent: alkalosis drives calcium onto albumin and drops the ionised fraction without changing the total.

PTH raises calcium by three routes at once. Bone: it binds PTH1 receptors on osteoblasts and osteocytes, not on osteoclasts, and makes them release RANKL, which recruits and activates osteoclasts to dissolve mineral [indirect resorption]. Kidney, part one: it turns up calcium reabsorption in the distal convoluted tubule and at the same time pulls the sodium-phosphate cotransporters out of the proximal tubule membrane, dumping phosphate into the urine. Kidney, part two: it switches on 1-alpha-hydroxylase in the proximal tubule, the enzyme that makes the active form of vitamin D [calcitriol], and calcitriol is what actually absorbs calcium from the gut. Net result: calcium up, phosphate down.

There are usually four glands (about 10-15% of people have a fifth or a missing one), each about the size of a grain of rice, lying on the back of the thyroid and fed by tiny end branches of the inferior thyroid artery. Position is variable: the lower pair share a pharyngeal-pouch origin with the thymus and migrate with it, so they can end up anywhere from high in the neck near the carotid bifurcation to the mediastinum. PTH itself has a half-life in blood of only two to four minutes.

What goes wrong

Primary hyperparathyroidismFamilial hypocalciuric hypercalcaemia (FHH)Secondary and tertiary hyperparathyroidismHypocalcaemia after thyroid surgery (surgical hypoparathyroidism)Hungry bone syndrome after parathyroidectomy

What we give

Calcium salts plus activated vitamin DCalcimimeticPlain vitamin D (colecalciferol)Bisphosphonate

A thin golden rind sitting on top of each kidney, built in three layers that make three different steroids from the same cholesterol — salt (aldosterone), sugar (cortisol) and sex steroids (adrenal androgens) — and almost every adrenal disease you will meet is one of those three being made in too small or too large an amount, most often because of a drug someone prescribed.

What it does

Three layers, three products, made from cholesterol down a largely shared assembly line. Outer layer (zona glomerulosa) makes aldosterone; middle layer (zona fasciculata) makes cortisol; inner layer (zona reticularis) makes weak androgens, mostly DHEA, DHEA-sulfate and androstenedione. Salt, sugar, sex — outside in. The early steps are common to all three (cholesterol side-chain cleavage, 3-beta-HSD), and 21-hydroxylase (CYP21A2) is needed for BOTH cortisol and aldosterone but not for androgens. The final 11-beta-hydroxylation step is done by two different isoenzymes: 11-beta-hydroxylase (CYP11B1) finishes cortisol in the fasciculata, while aldosterone synthase (CYP11B2) finishes aldosterone in the glomerulosa — so a block in one does not automatically block the other. Block a shared enzyme and everything upstream backs up and spills into whichever branch is still open. The medulla in the middle is a different organ entirely (neural crest tissue making adrenaline) and fails independently.

Cortisol is on a chain of command with a feedback loop: hypothalamus releases CRH, the anterior pituitary corticotrophs release ACTH, the zona fasciculata releases cortisol, and cortisol switches off both the hypothalamus and the pituitary [hypothalamic-pituitary-adrenal, HPA, axis]. Two features matter clinically. First, ACTH is cut out of a bigger precursor molecule (pro-opiomelanocortin, POMC) that also yields melanocyte-stimulating hormone, and ACTH itself stimulates melanocortin-1 receptors in skin (weakly per molecule, but enough when ACTH is grossly elevated). Second, cortisol runs on a daily rhythm — peaking around waking, lowest around midnight — with stress, illness and surgery overriding the rhythm and driving output up several-fold. Aldosterone is essentially NOT on this axis: the zona glomerulosa answers to angiotensin II and to plasma potassium, and ACTH has only a small, short-lived effect on it.

What cortisol actually does, in a sentence each. It raises blood glucose (drives gluconeogenesis in the liver, breaks down muscle protein for the raw material, opposes insulin in fat and muscle). It lets catecholamines work — without cortisol, alpha-1 receptors on vessels are under-expressed and noradrenaline barely holds blood pressure up [permissive effect]. It suppresses inflammation and immunity (fewer cytokines, fewer circulating eosinophils and lymphocytes, more neutrophils released from the marrow). It inhibits bone formation and collagen synthesis and reduces intestinal calcium absorption. And at high enough concentration it will bind the mineralocorticoid receptor and act like aldosterone.

What goes wrong

Addison disease (primary adrenal insufficiency)Secondary adrenal insufficiency and steroid withdrawalCushing syndromeCongenital adrenal hyperplasia (21-hydroxylase deficiency)Primary hyperaldosteronism (Conn syndrome)

What we give

Hydrocortisone (glucocorticoid replacement)Fludrocortisone (mineralocorticoid replacement)Synthetic glucocorticoids used as anti-inflammatoriesMineralocorticoid receptor antagonists

A sympathetic ganglion that never grew axons: its cells dump adrenaline straight into the blood instead of onto a synapse, so when a tumour forms here the problem is never local — it is a whole-body adrenergic storm, and almost every drug you give aims at receptors somewhere else.

What it does

The medulla is the core of the adrenal gland and is not really a gland at all — it is a sympathetic ganglion whose cells never grew axons. Preganglionic sympathetic fibres from the lower thoracic cord (greater splanchnic nerve, T5-T9, with a contribution from the lesser splanchnic, T10-T11) run through the cortex and synapse directly on chromaffin cells. Acetylcholine on nicotinic receptors depolarises the cell, calcium enters, and the granules empty into the venous blood [neuroendocrine transducer]. About 80% of what comes out is adrenaline, the rest noradrenaline.

The assembly line: tyrosine to DOPA by tyrosine hydroxylase (the rate-limiting step), then dopamine, then noradrenaline inside the granule (dopamine beta-hydroxylase), then adrenaline in the cytosol by PNMT before being repackaged. PNMT is switched on by the very high cortisol arriving from the cortex in the blood that drains inward, so only chromaffin cells sitting inside an adrenal gland make much adrenaline. Breakdown has two arms: COMT is the one that makes the metanephrines — adrenaline to metanephrine, noradrenaline to normetanephrine — while MAO takes those on to VMA. The critical point is that chromaffin cells carry their own membrane-bound COMT, so a tumour metabolises its stored catecholamines to metanephrines continuously inside itself, whether or not it is having a surge.

Where the hormones land: alpha-1 on vascular smooth muscle (Gq, calcium up, vessels constrict); alpha-2 presynaptically on nerve terminals and on pancreatic beta cells (brakes noradrenaline release and insulin release); beta-1 on the heart (Gs, cAMP up, faster and harder); beta-2 on bronchi and on skeletal muscle arterioles (Gs — airways open, those vessels dilate, muscle tremors, potassium moves into cells). Adrenaline hits alpha and beta. Noradrenaline hits alpha and beta-1 with almost no beta-2 effect.

What goes wrong

Phaeochromocytoma (and paraganglioma)Hypertensive crisis from unopposed alpha stimulationCatecholamine cardiomyopathyCirculatory collapse and hypoglycaemia after resectionLoss of the adrenaline warning system in diabetes

What we give

Alpha blockade, given before anything else — phenoxybenzamine (non-selective, irreversible)Beta blocker, added only after alpha blockade is establishedShort-acting intravenous vasodilators for the crisis — phentolamine, magnesium sulfate, nitrovasodilatorsVolume replacement and vasopressors after resection — sodium chloride 0.9%, noradrenaline, vasopressin

One to two per cent of the pancreas runs the whole of glucose control: beta cells push glucose into storage, alpha cells pull it back out, and nearly every diabetes drug either flips one of those two switches or bypasses them entirely.

What it does

Beta cells (roughly half to two-thirds of each islet) are a glucose meter wired to a secretory machine. Glucose enters on a glucose transporter (GLUT2 in the classic rodent account; human beta cells rely mainly on GLUT1/GLUT3 — the principle is the same, uptake is not rate-limiting), is burnt to ATP, and ATP shuts a potassium channel in the membrane (the ATP-sensitive potassium channel, K_ATP). With that exit for positive charge closed, the cell depolarises, voltage-gated calcium channels open, and calcium makes insulin granules fuse with the membrane. More glucose in, more insulin out. Insulin and C-peptide are released in equal amounts, one for one.

Insulin is the storage signal. It opens the door for glucose into muscle and fat (moves GLUT4 transporters to the cell surface), tells the liver to stop making new glucose (gluconeogenesis) and stop breaking down glycogen, and switches off fat breakdown (lipolysis) — the supply of free fatty acids that is the main substrate for ketone production. It also drives potassium into cells by stimulating the Na+/K+-ATPase.

Alpha cells do the opposite job. (In rodent islets they form a neat rim around the beta cell core; in human islets they are scattered through it, which is why human islets are drawn both ways.) When glucose falls they release glucagon, which tells the liver to break down glycogen and make new glucose. Insulin normally holds glucagon back, so the two hormones move in opposite directions. Behind glucagon sits the sympathoadrenal response — adrenaline and sympathetic nerve traffic — which is also what produces the warning symptoms of a low: sweating, shaking, pounding heart.

What goes wrong

Type 1 diabetesDiabetic ketoacidosisType 2 diabetesInsulinomaTreatment-related hypoglycaemia and hypoglycaemia unawareness

What we give

Insulin (hormone replacement)Biguanide — metforminSulfonylureasGlucagon (as a rescue drug)

Insulin is the only hormone that directly lowers blood glucose and the main hormone that switches off ketone production; four counter-regulatory hormones defend the brain's supply. Lose either side of that balance and you get hypoglycaemia, ketoacidosis, or hyperosmolar collapse.

What it does

After a meal, beta cells in the pancreatic islets release insulin. It pushes glucose into muscle and fat by moving GLUT4 transporters to the cell surface, tells the liver to store glucose as glycogen, and — the part students forget — switches OFF fat breakdown in adipose tissue (it inhibits hormone-sensitive lipase). Little free fatty acid reaching the liver means little substrate for ketones.

Between meals insulin falls and glucagon rises. Glucagon tells the liver to break down its glycogen store (glycogenolysis), which is the dominant source for the first several hours and is largely exhausted by about 24 hours; gluconeogenesis from lactate, amino acids and glycerol contributes from early in the fast and takes over as glycogen runs down. The brain uses roughly 120 g of glucose a day, cannot make its own, and stores almost none.

The defence against falling glucose happens in a fixed order, at roughly fixed thresholds: insulin secretion switches off first (around 4.5 mmol/L), then glucagon and adrenaline fire (around 3.8), then you feel it — sweating, tremor, hunger, palpitations, largely adrenergic (around 3.0), and only then does the brain run out — confusion, seizure, coma (below about 2.8). Cortisol and growth hormone add a slower second line.

What goes wrong

HypoglycaemiaDiabetic ketoacidosis (DKA)Hyperosmolar hyperglycaemic state (HHS)Euglycaemic ketoacidosis on an SGLT2 inhibitor

What we give

Insulin (replacement therapy)GlucagonSulfonylureasSGLT2 inhibitors (gliflozins)

Bone is not scaffolding you build once — it is torn down and rebuilt for life, and the same tissue doubles as the body's calcium bank, so every disease here is either a remodelling balance that has tipped, a mineral supply that has run short, or a hormone that will rob the skeleton to keep the blood calcium right.

What it does

Bone is rebuilt continuously in small packets. A cell that digs (osteoclast, a fused multinucleated cell of the monocyte-macrophage line) resorbs a pit over two to three weeks; cells that fill (osteoblasts) then lay down new matrix over three to four months. About 10% of the skeleton is replaced each year, trabecular bone faster than cortical. Crucially, the digger takes its orders from the builder: osteoblasts and osteocytes display RANK ligand (RANKL), which binds RANK on osteoclast precursors and drives them to mature and survive, and they also secrete osteoprotegerin (OPG), a decoy that mops RANKL up. The RANKL:OPG ratio is the dial. Oestrogen turns it down; parathyroid hormone (when the level is continuously high), glucocorticoids and inflammatory cytokines turn it up.

Bone is two things at once: a protein scaffold of type I collagen (osteoid), and mineral crystallised onto it (hydroxyapatite, essentially calcium phosphate). Osteoblasts pump out alkaline phosphatase (ALP) to strip the local inhibitor pyrophosphate so mineral can crystallise — which is why serum ALP is a marker of osteoblast activity, not of bone loss. So bone can fail two entirely different ways: too little of a normal, properly mineralised matrix, or a normal or increased amount of matrix that never got mineralised.

Serum calcium is defended, and the skeleton is what pays. Of the total calcium (normal 2.10-2.60 mmol/L), roughly 40% is protein-bound — mostly to albumin — about 10% is complexed to anions, and the remaining half circulates free as ionised calcium (1.15-1.30 mmol/L), which is what the body actually senses. So a low albumin gives a falsely low total: correct it, or measure ionised calcium. Parathyroid chief cells read ionised calcium through a calcium-sensing receptor; a fall of a few hundredths releases stored parathyroid hormone (PTH) within seconds to minutes. PTH then does three things: pulls calcium out of bone (indirectly — osteoclasts carry no PTH receptor, so PTH acts by raising osteoblast and osteocyte RANKL), makes the kidney reabsorb more calcium in the distal tubule, and switches on renal 1-alpha-hydroxylase to make active vitamin D so the gut absorbs more. It also dumps phosphate in the urine.

What goes wrong

Osteoporosis (postmenopausal and age-related)Osteomalacia and rickets (vitamin D deficiency)Paget disease of bonePrimary hyperparathyroidismGlucocorticoid-induced osteoporosis

What we give

BisphosphonatesRANKL inhibitor (monoclonal antibody)Colecalciferol (vitamin D3), with dietary or supplemental calciumPTH analogue (anabolic)

The ovary is a gland with a countdown on it: it makes one egg and two hormones a month from a pool that only ever shrinks, and it does it by talking to the brain in pulses. Almost every disease here is that conversation breaking — too much drive, too little drive, or nothing left to answer — and almost every drug on this page acts on the brain, the liver or the fat, not on the ovary itself.

What it does

The hypothalamus does not release gonadotrophin-releasing hormone (GnRH) in a steady stream. It fires it in pulses, roughly one every 60-90 minutes in the follicular phase, slowing to every 3-4 hours in the luteal phase under progesterone. The pituitary reads the rhythm, not just the amount: fast pulses favour luteinising hormone (LH); slow pulses favour follicle-stimulating hormone (FSH). Give GnRH continuously instead of in pulses and the pituitary GnRH receptors downregulate and the whole axis switches off [pulsatile GnRH, hypothalamic-pituitary-ovarian axis].

Making oestrogen takes two cells and two hormones. LH tells the theca cell to turn cholesterol into androgens (androstenedione and testosterone) — the theca has no aromatase, so that is as far as it can go. FSH tells the neighbouring granulosa cell to switch on aromatase, which converts those androgens into oestradiol — the granulosa has essentially no 17-hydroxylase/17,20-lyase (CYP17A1), so it cannot make its own substrate. Androgen is not a contaminant of the process; it is the raw material [two-cell, two-gonadotrophin model].

Oestradiol normally feeds back negatively. But once a dominant follicle pushes oestradiol high and holds it there — in the order of 700 pmol/L (about 200 pg/mL) for roughly two days — the feedback flips positive and the pituitary dumps LH. Ovulation follows roughly 36 hours after the surge begins (about 10-12 hours after the LH peak). The emptied follicle becomes the corpus luteum and makes progesterone, which slows GnRH pulses back down and turns proliferative endometrium into secretory endometrium. With no hCG from an implanting embryo the corpus luteum involutes on schedule at about 14 days, oestradiol and progesterone fall off a cliff, and the endometrium is shed [oestradiol positive feedback, luteal phase, hormone withdrawal bleed].

What goes wrong

Polycystic ovary syndrome (PCOS)Unopposed oestrogen: anovulatory bleeding and endometrial hyperplasiaFunctional hypothalamic amenorrhoeaPremature ovarian insufficiency (POI)Menopause

What we give

Combined oral contraceptive pill (oestrogen plus progestogen)Metformin (biguanide, insulin sensitiser)Aromatase inhibitor for ovulation inductionMenopausal hormone therapy (oestradiol, plus a progestogen if she has a uterus)

One organ doing two jobs with two different cells — Leydig cells make the hormone, Sertoli cells make the sperm — both driven by a feedback loop with the brain, and almost every disease and every drug on this page either breaks that loop or hijacks it.

What it does

Leydig cells sit in the spaces between the tubules and make testosterone when luteinising hormone (LH) from the pituitary tells them to. Testosterone, and the oestradiol made from it, then travel back and turn the signal down at both the hypothalamus and the pituitary (the hypothalamic-pituitary-gonadal axis, a classic negative feedback loop). Testosterone is released in pulses and is highest in the early morning, which is why a level taken at 4 pm can be low in a perfectly normal man and cannot be used to diagnose anything.

Sertoli cells line the seminiferous tubules and nurse the developing sperm from spermatogonium to spermatozoon, a process that takes about 70 days. They need two things: FSH from the pituitary, and testosterone at roughly 50 to 100 times the blood concentration right there inside the tubule, supplied locally by the neighbouring Leydig cells. Sertoli cells and the peritubular myoid cells around the tubule carry androgen receptors, and it is their response to that huge local testosterone concentration that drives spermatogenesis. Sertoli cells send back inhibin B, which brakes FSH specifically, and their tight junctions wall the developing sperm off from the bloodstream (blood-testis barrier).

The testis hangs outside the abdomen on the spermatic cord, held about 2 to 3 °C below core temperature by the scrotal skin and by a countercurrent heat exchange between the testicular artery and the surrounding venous plexus (pampiniform plexus). Spermatogenesis fails at body temperature. The price of that arrangement is that everything the testis depends on — testicular artery, pampiniform veins and the vas deferens — runs through one narrow, mobile stalk.

What goes wrong

Primary hypogonadism — the testis itself has failedSecondary (hypogonadotrophic) hypogonadism — nobody is telling the testis to workAnabolic-androgenic steroid use — axis shutdown, small testes, no spermVaricoceleTesticular torsion

What we give

Testosterone replacement (androgen)hCG (human chorionic gonadotrophin) — an LH analogueClomifene (selective oestrogen receptor modulator)Aromatase inhibitor

A hypothalamic pulse generator driving somatotrophs in the anterior pituitary, which tell the liver to make IGF-1, which drives cartilage at the growth plate to lengthen bone — and which, once those plates have fused, can only make bone and soft tissue thicker.

What it does

Growth hormone (GH) is released in bursts from somatotrophs in the anterior pituitary, but the rhythm is set above them: growth hormone releasing hormone (GHRH) from the hypothalamus turns the pulses on, hypothalamic somatostatin turns them off, and ghrelin from the stomach adds to them. The biggest pulse of the day comes in slow-wave (deep) sleep. Between pulses the level sits near zero, and IGF-1 feeds back to raise somatostatin and damp the next pulse. Output peaks in puberty and falls steadily through adult life.

Most of GH's growth effect is second-hand. GH binds the GH receptor on liver cells — a preformed receptor pair that GH re-orientates into the active configuration — and signals through JAK2 and STAT5, and the liver secretes insulin-like growth factor 1 (IGF-1). IGF-1 travels bound to IGFBP-3 and an acid-labile subunit, which is why it has a long half-life, and acts on chondrocytes at the growth plate. GH also acts directly on the plate — it recruits resting chondrocytes into the growing column, then locally produced IGF-1 drives them to divide.

GH's direct metabolic actions oppose insulin. It breaks down fat (lipolysis), reduces glucose uptake into muscle, and pushes the liver to make glucose. It is one of the counter-regulatory hormones, released in fasting and hypoglycaemia to keep blood glucose up and spare protein.

What goes wrong

AcromegalyGigantismGrowth hormone deficiency in childhoodShort stature that has nothing to do with growth hormoneThe metabolic and cardiac cost of GH excess

What we give

Somatostatin analoguesGrowth hormone receptor antagonistDopamine agonistsRecombinant human growth hormone

Two hormones on two clocks: adrenaline in seconds, cortisol over an hour - and cortisol is what lets adrenaline work. Take cortisol away and the blood pressure stops answering to catecholamines, which is exactly what an adrenal crisis is. Give cortisol from a bottle for a month and the axis switches itself off, which is now the commonest cause of adrenal insufficiency in Australia.

What it does

Stress - infection, surgery, trauma, a low blood sugar - makes the hypothalamus release CRH, which makes the pituitary release ACTH, which makes the middle layer of the adrenal cortex (zona fasciculata) make cortisol [hypothalamic-pituitary-adrenal axis]. Cortisol then switches the hypothalamus and pituitary back off [negative feedback]. Normally the axis fires in pulses, peaking around waking and bottoming near midnight; in serious illness the pulses merge, the rhythm disappears, and circulating cortisol climbs broadly with severity - driven partly by ACTH and partly by slowed cortisol breakdown, so in prolonged critical illness ACTH is often low while cortisol stays high. The axis cannot tell where a steroid came from - a tablet occupies the same receptors and closes the same feedback loop as the hormone.

Cortisol holds up the blood pressure mainly by letting other things work rather than by constricting vessels itself [permissive action]. It keeps alpha-1 adrenoceptors expressed on blood vessels and keeps their signalling coupled, so adrenaline and noradrenaline can constrict. It keeps the liver making glucose (gluconeogenesis) and blunts insulin action in muscle and fat. It lets the kidney get rid of free water, partly by restraining vasopressin. It holds inflammation in check. In pharmacological excess it does raise blood pressure in its own right, largely by spilling onto the mineralocorticoid receptor. In illness the carrier protein (cortisol-binding globulin) falls, so the free, active fraction rises more than a total cortisol measurement suggests.

The adrenal medulla is a sympathetic ganglion that lost its axons [chromaffin cells]. Preganglionic sympathetic fibres release acetylcholine onto nicotinic receptors and the cells squirt adrenaline (about 80%) and noradrenaline straight into the blood. Effects are on in seconds and gone in minutes: alpha-1 constricts vessels, beta-1 drives heart rate and force, beta-2 opens bronchi, dilates muscle vessels and pushes potassium into cells. Cortisol takes an hour because it works through gene transcription. The medulla also depends on the cortex - the very high cortisol in blood draining past it induces the enzyme (PNMT) that converts noradrenaline to adrenaline.

What goes wrong

Adrenal crisisPrimary adrenal insufficiency (Addison disease)Secondary adrenal insufficiency from glucocorticoid withdrawalCatecholamine-resistant shock in critical illness

What we give

Hydrocortisone (glucocorticoid replacement)Synthetic glucocorticoids used for anti-inflammatory effectFludrocortisone (mineralocorticoid replacement)Catecholamines (vasopressors and adrenaline)