Growth and growth hormone
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 normally 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.
a single random GH level tells you nothing — it can be high in a healthy person mid-pulse and undetectable in a person with a GH-secreting tumour between pulses. So you measure IGF-1, which is stable through the day and reflects integrated GH exposure over roughly the preceding day (and shifts over days to weeks, not minute to minute), and when you need certainty you use a dynamic test: suppress with glucose if you suspect excess, stimulate if you suspect deficiency. IGF-1 must always be read against an age- and sex-matched reference range, because it falls with age.
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.
anything that stops the liver responding uncouples the axis: in malnutrition, untreated coeliac disease, inflammatory bowel disease, chronic kidney disease and liver disease, GH is normal or high but IGF-1 is low and the child does not grow. That is GH resistance, not GH deficiency, and injecting more GH does not fix it — the same uncoupling in its inherited form is Laron syndrome (GH receptor defect). It also means IGF-1 is the single number that best summarises whether the whole axis is working.
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.
a glucose load normally shuts GH off — the basis of the oral glucose tolerance suppression test. It also means that too much GH causes impaired glucose tolerance and diabetes, that too little GH in a newborn contributes to hypoglycaemia, and that giving GH as a drug can unmask diabetes.
Length comes from the growth plate (physis), a disc of cartilage near each end of a long bone where chondrocytes stack in columns, swell, die, and are replaced by bone (endochondral ossification). Oestrogen matures and then closes that plate — in girls directly, in boys after testosterone is aromatised to oestradiol. Once the plate is fused, the bone cannot get any longer; it can only get thicker by laying down new bone under the periosteum.
the state of the growth plate decides what excess GH looks like. Before fusion you get height (gigantism); after fusion you get width — jaw, hands, feet, skull, soft tissue (acromegaly). It also explains why an x-ray of the left hand and wrist for bone age is the most informative film in a short child, and why untreated precocious puberty ends in a short adult.
What goes wrong
A benign somatotroph tumour of the anterior pituitary — a macroadenoma in most patients at diagnosis, because the disease is recognised late — secretes GH autonomously, escaping the normal feedback restraint of IGF-1 and hypothalamic somatostatin. (Autonomous does not mean unresponsive: most of these tumours still carry somatostatin receptors, which is exactly why somatostatin analogues work.) IGF-1 stays high for years. Because the growth plates fused at the end of puberty, none of that drive can add height. Instead bone thickens by periosteal apposition — brow, jaw, hands, feet — and every soft tissue enlarges: skin, tongue, larynx, heart, colon, synovium. A macroadenoma can also grow upward into the optic chiasm and laterally into the cavernous sinus, and compress the rest of the pituitary.
Coarse features, big hands and feet, carpal tunnel, sweating, OSA and new diabetes. Screen with IGF-1 (age-matched); confirm with failure of GH to suppress after 75 g oral glucose — nadir below 1 microgram/L is the traditional cut-off, and guidelines now use below 0.4 microgram/L with modern ultrasensitive assays, so read the cut-off your laboratory quotes. Then MRI pituitary. Mortality is cardiovascular and respiratory, not from the tumour.
You would find: Rings that no longer fit, shoes gone up two sizes, a jaw that has moved forward so the lower teeth now sit in front of the upper ones (prognathism) with gaps opening between the teeth. Coarse features, greasy skin, drenching sweats, a deep voice, a big tongue. Carpal tunnel syndrome from swollen soft tissue in a fixed canal. Obstructive sleep apnoea, hypertension, type 2 diabetes, arthritis of big joints. Bitemporal hemianopia (upper quadrants first) if the chiasm is compressed. The most useful thing you can ask for in the room is a photograph from ten years ago to hold next to the patient's face — the change is far too slow for family to notice, which is why diagnosis is typically delayed several years (historically around seven to ten). It is uncommon but not vanishingly rare: reported prevalence is of the order of 60 per million.
The same GH excess, but the growth plates are still open. IGF-1 drives chondrocyte columns at every physis, so the child grows in length as well as width. These tumours are often large, and when they compress or disrupt the gonadotrophs (or raise prolactin) puberty is delayed, oestrogen does not rise to close the plates, and growth runs on for years longer than it should. Rare, and more often than in adults it is genetic — AIP mutations, X-linked acrogigantism (GPR101), McCune-Albright syndrome, Carney complex — so a young patient warrants a family history and genetic referral.
Same disease, different growth plate. Open plate equals gigantism; fused plate equals acromegaly. A very tall adolescent with coarse features and headache gets an IGF-1, not reassurance.
You would find: A child or adolescent crossing height centiles upward rather than tracking along them, with coarsening features, large hands and feet, sweating and headache. Height alone is not the alarm — the change in trajectory is. Untreated they end tall with all the adult acromegalic features layered on top, because the plates eventually do fuse.
- Growth hormone deficiency in childhood← from “Most of GH's growth effect is second-hand. GH …”
Either the pituitary cannot make GH, or the hypothalamus cannot drive it. Congenital causes include midline structural defects and pituitary transcription factor mutations; acquired causes are craniopharyngioma, cranial irradiation for childhood cancer, head injury and infiltrative disease. Without GH the liver makes little IGF-1, chondrocyte columns at the plate stall, and bone matures as slowly as it grows — so bone age lags behind chronological age, and the child keeps some growth potential in reserve.
A short child who is growing slowly is a problem; a short child growing along their centile usually is not. Delayed bone age plus low height velocity plus low IGF-1 points at the axis. Never diagnose on a random GH.
You would find: Height velocity falls before height does: the child crosses centiles downward on the growth chart. They look proportionate but young — chubby around the middle, an underdeveloped midface, frontal bossing, a high-pitched voice, delayed dentition. In a newborn the picture is congenital hypopituitarism rather than isolated GH lack: hypoglycaemia (GH and cortisol are the counter-regulatory hormones that are missing), prolonged cholestatic jaundice (ACTH and TSH deficiency), and micropenis (mainly gonadotrophin deficiency, with GH deficiency contributing). Investigate with IGF-1 and IGFBP-3, a bone age film, and a GH stimulation test; image the pituitary if it is confirmed. Look for the other axes at the same time — deficiency is rarely isolated.
- Short stature that has nothing to do with growth hormone← from “Most of GH's growth effect is second-hand. GH …”
Most short children have a normal GH axis. In familial short stature the plates are working exactly as their genes intend, and bone age matches chronological age. In constitutional delay of growth and puberty the whole timetable is shifted late, so bone age is delayed and final height is normal or near the target range. In secondary causes the plate is starved of drive despite adequate GH: hypothyroidism removes the permissive thyroid hormone effect on chondrocytes; coeliac disease, inflammatory bowel disease and chronic kidney disease produce inflammation and undernutrition that lower IGF-1; Turner syndrome loses one copy of the SHOX gene, which the plate needs directly.
Bone age equal to chronological age with short parents means familial short stature. Bone age delayed with a late-developing parent means constitutional delay. Bone age delayed with poor height velocity means find the disease — thyroid, coeliac, kidney, Turner, or nutrition.
You would find: The growth chart plus the mid-parental height plus a bone age answers most of this before any hormone is measured. Check coeliac serology, thyroid function, a full blood count and renal function, and a karyotype (or microarray) in any short girl — Turner syndrome is missed for years. In Australia, growth faltering in early childhood falls disproportionately on Aboriginal and Torres Strait Islander children in remote communities, driven by low birthweight, food insecurity, recurrent gastrointestinal and respiratory infection and chronic otitis media. That is an environmental and social problem presenting as a growth problem, and GH is not the answer to it.
- The metabolic and cardiac cost of GH excess← from “GH's direct metabolic actions oppose insulin. …”
GH's anti-insulin actions run unopposed for years. Muscle takes up less glucose, the liver makes more, and the pancreas compensates until it cannot — a substantial minority (roughly a quarter to a third) have diabetes at diagnosis, and with impaired glucose tolerance included the figure approaches half. In the heart, GH and IGF-1 drive myocyte hypertrophy and interstitial fibrosis, which combines with hypertension and sleep apnoea to give a thick, stiff, poorly relaxing ventricle (diastolic dysfunction first); only late, and now uncommonly with treatment, does it dilate and fail. IGF-1 is also a mitogen for colonic epithelium.
GH is a counter-regulatory hormone, so its excess is a metabolic disease as much as a pituitary one. Glucose, blood pressure, echo, sleep study and colonoscopy all belong in acromegaly follow-up.
You would find: New type 2 diabetes in a patient whose face has changed. Hypertension, left ventricular hypertrophy on echo, arrhythmia and heart failure. Loud snoring and daytime sleepiness. Colonoscopy at diagnosis, with surveillance thereafter, is part of standard acromegaly care. These complications, not the pituitary mass, are what kills people — and controlling GH improves them, with mortality approaching that of the general population when IGF-1 is normalised.
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
- Somatostatin receptors on the adenoma cell — mainly subtype 2 (SST2) for octreotide and lanreotide; pasireotide is multi-receptor (SST1, 2, 3 and 5) with its highest affinity at SST5
- Which does
- These are Gi-coupled receptors. Binding lowers cyclic AMP and reduces calcium entry, so the secretory pulse is blocked. The drugs are a stable, long-acting copy of the body's own brake, given as a depot injection every few weeks. Tumour volume also shrinks modestly in many patients.
- So you see
- GH falls within hours and IGF-1 over weeks. Sweating, headache and joint pain settle first, soft tissue swelling next — rings loosen and carpal tunnel symptoms ease. Roughly 40 to 50 per cent of unselected patients reach a normal IGF-1 on an SST2 agonist alone.
- And the same mechanism causes
- Somatostatin receptors are not confined to the pituitary. In the gallbladder and gut the same brake stops gallbladder contraction (partly by cutting cholecystokinin release) and slows motility, so patients get biliary sludge and gallstones, bloating, cramps, loose fatty stools and nausea. On the pancreatic islet the receptor inhibits insulin release, so glucose tolerance can worsen — although with octreotide and lanreotide the net effect is usually small, because removing the GH excess improves insulin sensitivity at the same time. Pasireotide is the exception and clearly raises glucose, because the human beta cell and the incretin-secreting gut cells carry SST5, which is exactly the receptor pasireotide adds.
- Handling
- Long-acting depot given by intramuscular (octreotide LAR, pasireotide LAR) or deep subcutaneous (lanreotide) injection every four weeks, sometimes after a short-acting subcutaneous trial; IGF-1 is the number followed, with glucose monitored alongside.
Catches people out: Pasireotide gives better biochemical control than octreotide but causes hyperglycaemia in the majority of patients — a predictable trade, not a surprise, and one that needs glucose monitored from the first dose. Surgery, not drugs, is first-line for acromegaly: an experienced pituitary surgeon cures the majority of microadenomas.
- Binds
- The GH receptor itself. Pegvisomant is a modified GH molecule, pegylated for a long half-life, that binds one face of the receptor with enhanced affinity but carries a mutation at the second binding site.
- Which does
- The receptor is occupied but cannot be brought into its working (functionally dimerised) configuration, so JAK2 and STAT5 never fire. The liver stops transcribing IGF-1 no matter how much GH is circulating.
- So you see
- IGF-1 normalises in most patients — over 90 per cent in the registration trials, and lower than that in routine practice — with symptoms and insulin sensitivity improving alongside — it has the most favourable glucose effect of the acromegaly drugs, because it blocks GH's anti-insulin action too.
- And the same mechanism causes
- Blocking the receptor removes IGF-1 feedback onto the pituitary, so GH secretion rises. Two consequences follow directly: GH levels become meaningless for monitoring (you must follow IGF-1, and the drug cross-reacts with some GH assays), and because the drug has no action on the tumour itself, the adenoma is left untreated — so periodic MRI is done to check it is not enlarging. Raised transaminases occur and liver function is monitored.
- Handling
- Daily subcutaneous injection.
Catches people out: If someone hands you a rising GH level in a patient on pegvisomant, that is the drug working, not failing. Judge control on IGF-1.
- Binds
- D2 dopamine receptor on the adenoma cell
- Which does
- Another Gi-coupled receptor: cyclic AMP falls, hormone secretion falls, and the tumour cell shrinks. Cheap, oral, once or twice weekly.
- So you see
- IGF-1 normalises in roughly a third of suitable patients — much less effective than the injectables, but easy to add and easy to stop.
- And the same mechanism causes
- D2 receptors sit in other places and each gives its own predictable problem. In the area postrema (chemoreceptor trigger zone) they trigger nausea and vomiting, so the drug is started low and taken with food. Through central and peripheral effects on sympathetic outflow they cause postural hypotension and dizziness. In the mesolimbic reward pathway D2/D3 agonism produces impulse control disorders — new gambling, compulsive shopping, hypersexuality — which patients will not volunteer and must be asked about directly at every review, including of the partner.
- Handling
- Oral, once or twice weekly.
Catches people out: Ergot-derived dopamine agonists cause cardiac valve fibrosis through 5-HT2B receptors, but this is a problem of the high daily doses used in Parkinson disease rather than the weekly pituitary doses; echocardiographic monitoring practice varies with dose and duration.
- Binds
- GH receptor, signalling through JAK2 and STAT5
- Which does
- Replaces the missing hormone. The liver resumes IGF-1 output, resting chondrocytes are recruited into the growth plate columns, and those columns start dividing and stacking again.
- So you see
- Height velocity accelerates sharply in the first year of treatment (catch-up growth) then settles to a normal rate, and the child climbs back toward their genetic centile. Lean mass rises and fat mass falls. It only works while the plates are open — after fusion it can change body composition but it cannot add a millimetre of height.
- And the same mechanism causes
- Every important adverse effect is the hormone doing its normal job. Its anti-insulin action raises blood glucose and can unmask diabetes. It makes the kidney retain sodium and water, so patients get oedema, arthralgia and carpal tunnel syndrome — adult acromegaly in miniature — and fluid shift is the usual explanation given for the rise in intracranial pressure that causes headache and papilloedema (benign intracranial hypertension). Because it is actively pushing the growth plate, the femoral head can slip through its own physis: a child on GH with a new limp, or knee or groin pain, needs hip imaging for slipped capital femoral epiphysis, and existing scoliosis can progress as the child grows.
- Handling
- Daily evening subcutaneous injection to mimic the sleep pulse; long-acting weekly analogues (for example somatrogon) are now registered. Response is judged on height velocity and IGF-1, and treatment for height stops when the plates fuse.
Catches people out: In Australia somatropin is subsidised through the PBS Growth Hormone Program against specific auxological and biochemical criteria, not on height alone. It is avoided in active malignancy and in acute critical illness, and in Prader-Willi syndrome it should not be started in a child with severe obesity or untreated severe obstructive sleep apnoea (deaths have been reported) — assess the airway first. Giving it to a short child with untreated coeliac disease or hypothyroidism treats the wrong problem: find and fix the cause before reaching for the hormone.
The growth plate is the hinge for the whole topic. Open plate plus too much GH equals gigantism; fused plate plus too much GH equals acromegaly; open plate plus too little GH equals a child falling off their centiles. Because GH is secreted in pulses, a random GH level is worthless in both directions — screen with IGF-1 against an age-matched range, and confirm with a dynamic test that pushes the axis the way it should not want to go: glucose fails to suppress GH in acromegaly (physiology fact 3, the counter-regulatory one, in reverse), and GH fails to rise on stimulation in deficiency. In a short child the growth chart outperforms every blood test, and the bone age film separates familial short stature (bone age normal) from constitutional delay and disease (bone age delayed). Then notice where the drugs actually act: somatostatin analogues and cabergoline act on the pituitary tumour, pegvisomant acts on the liver receptor and deliberately lets GH rise, and somatropin acts on the liver and the plate — none of them act on the bone that is the thing you can see changing.
Now test whether it stuck
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