Endocrine: Anatomy Physiology and Pharmacology

• Anatomy: How Hormones Work | Hypothalamus and Pituitary | Thyroid and Parathyroids | Adrenal Glands | Endocrine Pancreas
• Physiology: Hypothalamic–Pituitary Axes and Feedback | Growth Hormone and Prolactin | ADH, Water and Sodium | Thyroid Hormones | Cortisol | Aldosterone and the RAAS | Adrenaline and Noradrenaline | Insulin, Glucagon and Glucose Control | Calcium, PTH and Vitamin D | Sex Hormones | Appetite, Fat and Gut Hormones | Principles of Endocrine Testing | Normal Values
• Pharmacology: Insulin | Metformin | Sulfonylureas | SGLT2 Inhibitors | GLP-1 Agonists, Tirzepatide and DPP-4 Inhibitors | Pioglitazone | Levothyroxine | Antithyroid Drugs and Radioiodine | Corticosteroids | Drugs for Adrenal Disease | Pituitary and Water Balance Drugs | Bone and Calcium Drugs | Sex Hormone Drugs | Drugs That Cause Endocrine Problems
• Revision: Drug Reference Table | Spot the Answer | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧪 Endocrine anatomy, physiology and pharmacology — hormones are chemical messengers that control growth, metabolism, salt and water, blood sugar, calcium and reproduction. Almost every endocrine disease is either too much or too little of a hormone, and most are understood through feedback loops. Most endocrine drugs either replace a missing hormone, block an excess one, or mimic a hormone's action (as in diabetes and bone disease).
Your four questions for every drug: How does it work? What is it used for? What are the important side effects and safety issues? What does it interact with, and how is it monitored?

How Hormones Work

• Hormones are released into the blood and act on distant target cells that have the right receptor.
• Two main types:
  • Water-soluble (peptides and catecholamines — insulin, glucagon, PTH, ADH, ACTH, adrenaline) — act on cell-surface receptors and second messengers (cAMP, calcium); act in seconds to minutes; short half-lives.
  • Fat-soluble (steroids — cortisol, aldosterone, sex hormones, vitamin D; and thyroid hormones) — cross the cell membrane, bind nuclear receptors and change gene expression; act over hours to days; carried in blood on binding proteins.
• Binding proteins — most cortisol, thyroid hormone and testosterone is bound (to CBG, TBG and SHBG); only the free fraction is active. Oestrogen (pregnancy, the pill) raises binding proteins, so total levels rise but free levels may be normal — measure free hormone where possible.
• Receptor problems can mimic hormone deficiency — e.g. nephrogenic diabetes insipidus (ADH receptor), androgen insensitivity, type 2 diabetes (insulin resistance), pseudohypoparathyroidism (PTH resistance — high PTH, low calcium).
• Patterns of release — circadian (cortisol peaks on waking), pulsatile (GH, GnRH, LH), stimulus-driven (insulin after a meal, ADH with high osmolality). This is why timing matters for blood tests.

Hypothalamus and Pituitary

• Pituitary gland sits in the sella turcica of the sphenoid bone, attached to the hypothalamus by the pituitary stalk.
• Anterior pituitary (adenohypophysis) — develops from Rathke's pouch (an upgrowth from the roof of the mouth — origin of craniopharyngiomas). It is controlled by hypothalamic releasing hormones carried in the hypophyseal portal veins.
• Posterior pituitary (neurohypophysis) — an extension of the brain; stores and releases ADH (vasopressin) and oxytocin, made in the supraoptic and paraventricular nuclei of the hypothalamus.
• Anterior pituitary cells and hormones:
  • Somatotrophs — GH (the most numerous cells; GH-secreting adenoma → acromegaly).
  • Lactotrophs — prolactin (prolactinoma — the commonest functioning adenoma).
  • Corticotrophs — ACTH (Cushing's disease).
  • Thyrotrophs — TSH.
  • Gonadotrophs — LH and FSH (non-functioning adenomas often come from these cells).
• Important neighbours:
  • Optic chiasm lies just above — an expanding tumour presses on the crossing nasal fibres → bitemporal hemianopia (upper quadrants first with tumours from below).
  • Cavernous sinuses on each side contain the internal carotid artery and cranial nerves III, IV, V1, V2 and VI — lateral spread causes double vision and ptosis.
  • The sphenoid sinus lies below — the route for transsphenoidal surgery.
• Pituitary apoplexy — bleeding into or infarction of a tumour: sudden headache, visual loss, eye movement problems and acute ACTH deficiency — give hydrocortisone.
• Sheehan's syndrome — the pituitary enlarges in pregnancy and can infarct after major postpartum haemorrhage (failure to breastfeed, amenorrhoea, hypopituitarism).

Thyroid and Parathyroids

• Thyroid — two lobes joined by an isthmus over the 2nd–4th tracheal rings; enclosed in the pretracheal fascia, so it moves up on swallowing.
• Development — the thyroid starts at the foramen caecum at the back of the tongue and descends along the thyroglossal duct:
  • Thyroglossal cyst — a midline neck lump that moves up when the tongue is stuck out.
  • Lingual thyroid — failure of descent; may be the only thyroid tissue.
• Blood supply — superior thyroid artery (from the external carotid) and inferior thyroid artery (from the thyrocervical trunk of the subclavian).
• Nerves at risk in thyroid surgery:
  • Recurrent laryngeal nerve — runs near the inferior thyroid artery; damage → hoarse voice (one side) or stridor and airway obstruction (both sides).
  • External branch of the superior laryngeal nerve — runs with the superior thyroid artery; damage → loss of high-pitched voice and voice fatigue (singers).
• Parathyroid glands — usually four, behind the thyroid:
  • Superior glands come from the 4th pharyngeal pouch; inferior glands from the 3rd pouch with the thymus — so they can be found low, even in the mediastinum (ectopic adenomas).
  • Damage or removal in thyroid surgery → hypocalcaemia (check calcium after thyroidectomy — tingling, cramps, Chvostek's and Trousseau's signs).
• Cells of the thyroid:
  • Follicular cells — make T4 and T3 (origin of papillary and follicular cancers).
  • Parafollicular (C) cells — make calcitonin (origin of medullary thyroid cancer — calcitonin and CEA are tumour markers; associated with MEN 2 and RET mutations).

Adrenal Glands

• Two small glands on top of the kidneys, inside the renal fascia.
• Venous drainage — right adrenal vein → IVC (short — tricky in surgery and adrenal vein sampling); left adrenal vein → left renal vein.
• Arterial supply — three arteries (superior from the inferior phrenic, middle from the aorta, inferior from the renal artery). A rich blood supply makes the adrenals vulnerable to haemorrhage in sepsis (meningococcal — Waterhouse–Friderichsen syndrome) and anticoagulation.
• Adrenal cortex — three zones from outside in, "GFR" makes "salt, sugar, sex":
  • Zona glomerulosa — aldosterone (controlled mainly by renin–angiotensin and potassium, not ACTH).
  • Zona fasciculata — cortisol (controlled by ACTH).
  • Zona reticularis — adrenal androgens (DHEA) (controlled by ACTH).
• Adrenal medulla — chromaffin cells (modified sympathetic neurons) make adrenaline and noradrenaline; the enzyme that makes adrenaline needs high local cortisol from the cortex (origin of phaeochromocytoma).
• Why it matters clinically:
  • Pituitary (secondary) adrenal failure — ACTH lost, cortisol low, but aldosterone is preserved (no hyperkalaemia, no need for fludrocortisone).
  • Primary adrenal failure (Addison's) — the whole cortex fails: low cortisol and low aldosterone (hyperkalaemia, salt craving, postural hypotension), high ACTH (pigmentation).
  • Incidentalomas — adrenal lumps found on scans in about 1 in 20 older adults; check whether they make hormones and whether they look benign.

Endocrine Pancreas

• The endocrine pancreas is the islets of Langerhans — about 1–2% of the pancreas, scattered through the exocrine tissue.
• Islet cells:
  • Beta cells (most) — insulin and C-peptide (released in equal amounts), and amylin.
  • Alpha cells — glucagon.
  • Delta cells — somatostatin (inhibits both insulin and glucagon).
  • PP cells — pancreatic polypeptide.
• Insulin goes first to the liver via the portal vein — the liver removes about half on first pass. Injected insulin goes into the general circulation instead, so the liver sees relatively less.
• Type 3c (pancreatogenic) diabetes — from chronic pancreatitis, pancreatic cancer, surgery, cystic fibrosis or haemochromatosis; loss of both insulin and glucagon, so hypoglycaemia can be severe and brittle.
• Islet tumours — insulinoma (fasting hypoglycaemia with high insulin and C-peptide), glucagonoma (diabetes, weight loss, necrolytic migratory erythema), gastrinoma (Zollinger–Ellison) — linked to MEN 1 ("3 Ps": pituitary, parathyroid, pancreas).

Hypothalamic–Pituitary Axes and Feedback

• Using feedback to find the problem:
  • Primary gland failure — target hormone low, pituitary hormone high (e.g. low T4, high TSH in primary hypothyroidism).
  • Secondary (pituitary) failure — target hormone low, pituitary hormone low or "inappropriately normal" (e.g. low T4 with normal TSH — don't be reassured by a normal TSH).
  • Primary excess — target hormone high, pituitary hormone suppressed (e.g. Graves': high T4, TSH under 0.01).
  • Pituitary-driven excess — target and pituitary hormones both high (e.g. Cushing's disease — high cortisol with normal or high ACTH).
• Prolactin is the exception — it is held down by dopamine, so pituitary stalk compression (any large tumour) raises prolactin modestly ("stalk effect"), as do dopamine-blocking drugs.
• Order of hormone loss in progressive pituitary failure — usually GH first, then LH/FSH, then TSH, then ACTH (the most dangerous to miss).
• Exogenous hormones suppress the axis — e.g. long-term steroids suppress ACTH (adrenal atrophy), testosterone suppresses LH/FSH (infertility), too much levothyroxine suppresses TSH.
• Continuous GnRH (goserelin, leuprorelin) — paradoxically switches off LH and FSH after an initial surge (used in prostate and breast cancer, endometriosis, precocious puberty).

Growth Hormone and Prolactin

• Growth hormone:
  • Released in pulses, mostly during deep sleep; stimulated by GHRH, ghrelin, exercise, stress, hypoglycaemia and fasting; inhibited by somatostatin, IGF-1 and glucose.
  • Acts mostly through IGF-1 made in the liver — growth of bone, cartilage and muscle; also raises blood glucose (anti-insulin) and breaks down fat.
  • Random GH is unhelpful because it fluctuates — measure IGF-1 as a screen. In acromegaly, GH fails to suppress with an oral glucose load (OGTT); in deficiency, GH fails to rise with stimulation (e.g. glucagon or insulin tolerance test).
  • Excess before the growth plates fuse → gigantism; after → acromegaly (big hands and feet, coarse face, sweating, diabetes, hypertension, sleep apnoea, cardiomyopathy, bowel polyps).
• Prolactin:
  • Stimulates milk production; high levels suppress GnRH → low LH/FSH → amenorrhoea, infertility, low libido, erectile dysfunction, osteoporosis; galactorrhoea.
  • Causes of high prolactin — pregnancy and breastfeeding, drugs (antipsychotics, metoclopramide, domperidone, some antidepressants), prolactinoma, stalk compression, primary hypothyroidism (high TRH stimulates prolactin), kidney failure, stress (including a difficult blood test), seizures, chest wall injury, macroprolactin (inactive large form — ask the lab to check).
  • Very high prolactin (several thousand mU/L) suggests a prolactinoma; a modest rise with a large tumour suggests stalk compression.

ADH, Water and Sodium

• ADH (vasopressin) — released when plasma osmolality rises (osmoreceptors in the hypothalamus, very sensitive — a 1–2% rise) or when blood volume or pressure falls (a stronger stimulus that overrides osmolality).
• Actions:
  • V2 receptors in the kidney collecting ducts → aquaporin-2 water channels inserted → water reabsorbed → concentrated urine.
  • V1 receptors on blood vessels → vasoconstriction (vasopressin and terlipressin in shock and variceal bleeding).
• Thirst — also triggered by high osmolality; the main protection against hypernatraemia (so hypernatraemia mostly occurs in people who can't drink — frail, confused, infants, intubated).
• Normal plasma osmolality — about 275–295 mOsm/kg; estimated as 2 × (Na + K) + urea + glucose.
• Too little ADH or ADH action — diabetes insipidus (now often called arginine vasopressin deficiency or resistance): large volumes of dilute urine, thirst, high-normal or high sodium.
  • Cranial — pituitary surgery, trauma, tumours, infiltration (sarcoid, histiocytosis) — responds to desmopressin.
  • Nephrogenic — lithium, hypercalcaemia, hypokalaemia, genetic — doesn't respond to desmopressin.
• Too much ADH — SIADH: low sodium with low plasma osmolality, inappropriately concentrated urine (over 100 mOsm/kg), urine sodium over 30 mmol/L, in a patient who is euvolaemic — after excluding hypothyroidism, adrenal insufficiency and diuretics. Causes include lung disease, CNS disease, cancers (small cell), drugs (SSRIs, carbamazepine, PPIs, opioids), pain, nausea and surgery.
• Oxytocin — uterine contraction in labour and milk let-down; synthetic oxytocin is used to induce labour and prevent postpartum haemorrhage (has ADH-like effects — hyponatraemia with large volumes).
• Assessment of hyponatraemia is covered in the Endocrine Emergencies chapter.

Thyroid Hormones

• Making thyroid hormone:
  • Iodide is pumped into follicular cells by the sodium–iodide symporter (the target of radioiodine and of technetium uptake scans).
  • Thyroid peroxidase (TPO) attaches iodine to tyrosines on thyroglobulin and couples them into T4 and T3 (the step blocked by carbimazole and propylthiouracil; TPO antibodies mark autoimmune thyroid disease).
  • Stored in the colloid, released when stimulated by TSH (or, in Graves', by TSH receptor antibodies).
• T4 and T3:
  • The thyroid releases mostly T4 (a prohormone); T3 is the active hormone, mostly made in tissues by deiodinase enzymes.
  • T4 half-life is about 7 days — so after a dose change, wait 6–8 weeks before rechecking TFTs. T3 half-life is about 1 day.
  • Over 99% is bound to proteins (TBG, albumin); free T4 is measured.
• Actions — raise metabolic rate, heat production, heart rate and contractility (more beta-receptors), gut motility, bone turnover; needed for brain development (congenital hypothyroidism — heel-prick screening) and growth.
• Iodine effects:
  • Wolff–Chaikoff effect — a large iodine load briefly switches off hormone production (used before thyroid surgery and in thyroid storm with Lugol's iodine).
  • Jod–Basedow effect — iodine (e.g. contrast, amiodarone) can trigger hyperthyroidism in people with nodular goitre.
  • Amiodarone contains about 37% iodine by weight — causes both hypo- and hyperthyroidism.
• Sick euthyroid (non-thyroidal illness) — in acute illness, T3 falls and TSH can be low or high temporarily; avoid testing TFTs in acutely ill patients unless thyroid disease is suspected.
• Pregnancy — hCG stimulates the TSH receptor (TSH can be low in the first trimester; hyperemesis can cause transient hyperthyroidism); TBG rises; needs for levothyroxine increase.

Cortisol

• Release — controlled by CRH and ACTH; highest on waking (around 7–9 am), lowest around midnight; rises sharply with stress, illness, surgery and hypoglycaemia.
• Actions:
  • Raises blood glucose (gluconeogenesis, insulin resistance) — steroid-induced hyperglycaemia.
  • Breaks down protein (muscle wasting, thin skin, bruising, poor wound healing) and redistributes fat (central obesity, moon face).
  • Suppresses inflammation and immunity (the basis of steroid treatment).
  • Maintains blood pressure — needed for vessels to respond to catecholamines (cortisol deficiency → shock that doesn't respond to fluids or pressors).
  • Reduces bone formation and calcium absorption (osteoporosis); affects mood and sleep.
  • At high levels, acts on the mineralocorticoid receptor (normally protected in the kidney by an enzyme that inactivates cortisol — overwhelmed in Cushing's and blocked by liquorice) → hypertension, low potassium.
• Too little (adrenal insufficiency) — tiredness, weight loss, nausea, abdominal pain, low blood pressure, hyponatraemia, hypoglycaemia; adrenal crisis if stressed — an emergency needing IV or IM hydrocortisone.
• Too much (Cushing's syndrome) — most often from steroid medication; otherwise pituitary (Cushing's disease), adrenal tumours or ectopic ACTH (small cell lung cancer — often rapid with low potassium).

Aldosterone and the RAAS

• Renin — released by the kidney (juxtaglomerular cells) when renal perfusion falls, sodium delivery falls, or sympathetic activity rises.
• Cascade — renin converts angiotensinogen → angiotensin I → (ACE in the lungs) → angiotensin II → vasoconstriction, thirst, ADH release, and aldosterone release.
• Aldosterone acts on the distal tubule and collecting duct (ENaC sodium channels):
  • Retains sodium (and so water).
  • Excretes potassium and hydrogen ions.
  • Also stimulated directly by high potassium.
• Primary aldosteronism (Conn's adenoma or bilateral adrenal hyperplasia) — the commonest secondary cause of hypertension (about 5–10% of hypertensives); high aldosterone, suppressed renin; potassium is often normal. Screen with the aldosterone-to-renin ratio.
• Secondary aldosteronism — renin high too (heart failure, cirrhosis, renal artery stenosis, diuretics).
• Drugs acting on the system — ACE inhibitors, ARBs, spironolactone, eplerenone (all can raise potassium); heparin suppresses aldosterone (hyperkalaemia); NSAIDs reduce renin.
• Natriuretic peptides (ANP, BNP) — released by stretched heart chambers; promote sodium loss — the opposite of aldosterone.

Adrenaline and Noradrenaline

• Made from tyrosine → DOPA → dopamine → noradrenaline → adrenaline (the last step mostly in the adrenal medulla).
• Actions — "fight or flight": raised heart rate and blood pressure, bronchodilatation, raised glucose (glycogen breakdown, less insulin), sweating, dilated pupils.
• Receptors: alpha-1 (vasoconstriction), alpha-2 (less noradrenaline release), beta-1 (heart rate and force), beta-2 (bronchodilatation, vasodilatation in muscle, potassium into cells, tremor), beta-3 (fat breakdown, bladder relaxation).
• Breakdown — to metanephrines (by COMT) and vanillylmandelic acid; plasma free metanephrines (or 24-hour urine metanephrines) are the best test for phaeochromocytoma.
• Phaeochromocytoma and paraganglioma — episodic headache, sweating, palpitations, pallor, high (or swinging) blood pressure; about a third are inherited (MEN 2, von Hippel–Lindau, NF1, SDH genes) — offer genetic testing.
• Hypoglycaemia awareness — adrenaline produces the warning symptoms (shaking, sweating, palpitations); these are lost with repeated hypos and long diabetes, and blunted by non-selective beta-blockers.

Insulin, Glucagon and Glucose Control

• How beta cells release insulin:
  • Glucose enters via GLUT2 → is metabolised → ATP rises → ATP-sensitive potassium channels close → the cell depolarises → calcium enters → insulin is released.
  • Sulfonylureas close the same potassium channels (so they release insulin whatever the glucose — hypoglycaemia risk).
  • Incretins (GLP-1 and GIP from the gut) amplify insulin release after a meal — the reason oral glucose gives more insulin than IV glucose. GLP-1 drugs and DPP-4 inhibitors use this pathway.
• Insulin's actions (the "fed" hormone):
  • Moves glucose into muscle and fat via GLUT4.
  • Stops the liver making glucose; builds glycogen, fat and protein.
  • Stops fat breakdown and ketone production — so absolute insulin deficiency causes DKA; even small amounts of insulin prevent ketosis (why HHS has little ketosis).
  • Drives potassium into cells — insulin with glucose treats hyperkalaemia; potassium falls during DKA treatment.
• Counter-regulatory hormones (raise glucose) — glucagon (first), adrenaline (fast), cortisol and GH (slower). Deficiency of cortisol or GH causes hypoglycaemia; excess causes diabetes.
• Fasting — glycogen supplies glucose for about 12–24 hours, then gluconeogenesis and fat breakdown (ketones fuel the brain in prolonged fasting).
• Type 1 diabetes — autoimmune beta-cell destruction (GAD, IA-2, ZnT8 antibodies); low C-peptide; needs insulin.
• Type 2 diabetes — insulin resistance (fat, especially around the liver and abdomen) plus progressive beta-cell failure; weight loss can put it into remission.
• C-peptide — a marker of the body's own insulin: high in insulinoma and sulfonylurea misuse, low with injected insulin (suspect factitious hypoglycaemia if insulin is high but C-peptide low).
• HbA1c — reflects glucose over about 2–3 months (red cell lifespan); falsely low with shortened red cell life (haemolysis, blood loss, transfusion, some haemoglobin variants, pregnancy) and falsely high with iron or B12 deficiency, splenectomy and CKD in some cases.

Calcium, PTH and Vitamin D

• Calcium — 99% is in bone. In blood, about 45% is ionised (active), about 40% bound to albumin, the rest bound to anions. Use adjusted calcium (corrected for albumin) or ionised calcium on a blood gas. Alkalosis increases binding and lowers ionised calcium (tingling with hyperventilation).
• PTH (released when calcium falls; needs magnesium to be secreted):
  • Bone — increases resorption (via osteoblasts signalling to osteoclasts through RANKL).
  • Kidney — increases calcium reabsorption, increases phosphate excretion, and activates vitamin D (1-alpha-hydroxylase).
  • Net effect — calcium up, phosphate down.
• Vitamin D:
  • Made in the skin with UVB (or eaten) → liver makes 25-hydroxyvitamin D (the measured storage form) → kidney makes 1,25-dihydroxyvitamin D (calcitriol — active).
  • Increases gut absorption of calcium and phosphate.
  • CKD — the kidney can't activate vitamin D → low calcium, high phosphate → secondary hyperparathyroidism (use alfacalcidol or calcitriol, which don't need kidney activation).
  • Granulomas (sarcoidosis, TB, lymphoma) make active vitamin D themselves → hypercalcaemia.
• Calcitonin — lowers calcium a little; of minor importance in humans (but a tumour marker for medullary thyroid cancer).
• FGF-23 — from bone; makes the kidney lose phosphate; high in CKD.
• Interpreting calcium and PTH:
  • High calcium with high or normal PTH — primary hyperparathyroidism (commonest outpatient cause); rule out familial hypocalciuric hypercalcaemia (low urine calcium).
  • High calcium with suppressed PTH — malignancy (commonest inpatient cause — PTHrP, bone metastases, myeloma), vitamin D excess, sarcoidosis, thiazides, milk-alkali syndrome, immobility, thyrotoxicosis.
  • Low calcium with high PTH — vitamin D deficiency, CKD (secondary hyperparathyroidism), pseudohypoparathyroidism.
  • Low calcium with low PTH — after neck surgery, autoimmune, low magnesium (PPIs, alcohol, diuretics).
  • Tertiary hyperparathyroidism — long-standing secondary hyperparathyroidism (CKD) becomes autonomous → high calcium with very high PTH.

Sex Hormones

• Men — LH stimulates Leydig cells to make testosterone; FSH plus local testosterone stimulates Sertoli cells to support sperm production (and release inhibin, which suppresses FSH).
  • Measure testosterone on a morning (fasting) sample, and repeat before diagnosing deficiency.
  • Primary hypogonadism (testis failure — Klinefelter's, mumps, chemotherapy) — low testosterone, high LH/FSH.
  • Secondary — low testosterone with low or normal LH/FSH (pituitary disease, high prolactin, obesity, opioids, anabolic steroids, illness, Kallmann syndrome — with loss of smell).
  • Testosterone is converted to DHT (5-alpha-reductase — blocked by finasteride) and to oestrogen (aromatase — gynaecomastia).
• Women — the menstrual cycle:
  • Follicular phase — FSH grows follicles; rising oestrogen thickens the endometrium.
  • Ovulation — high oestrogen switches to positive feedback → LH surge → ovulation about 36 hours later.
  • Luteal phase — the corpus luteum makes progesterone (day-21 progesterone confirms ovulation in a 28-day cycle — measure 7 days before the expected period); without pregnancy it fails after about 14 days → period.
  • Menopause — the ovaries stop responding: low oestrogen, high FSH. Premature ovarian insufficiency if under 40.
  • PCOS — raised LH-to-FSH ratio and androgens, insulin resistance, irregular periods.
• Pregnancy — hCG (from the placenta) keeps the corpus luteum going; the placenta then makes progesterone and oestrogen; human placental lactogen causes insulin resistance (gestational diabetes).
• Reproductive disorders are covered in the Reproductive Endocrinology chapter.

Appetite, Fat and Gut Hormones

• Leptin — made by fat cells in proportion to fat mass; signals "enough stores" to the hypothalamus. Obesity is usually leptin resistance, not deficiency (rare genetic deficiency responds to leptin).
• Ghrelin — from the stomach; rises before meals and stimulates hunger (and GH release).
• GLP-1 — from the small bowel after eating; boosts insulin, reduces glucagon, slows stomach emptying and reduces appetite — the basis of semaglutide and tirzepatide for weight loss.
• Peptide YY and cholecystokinin — satiety signals from the gut.
• Bariatric surgery works partly through gut hormones (higher GLP-1 and PYY) — often improves or reverses type 2 diabetes quickly.
• Fat as an endocrine organ — abdominal and liver fat drive insulin resistance, inflammation and MASLD (fatty liver); fat makes oestrogen in men and postmenopausal women.

Principles of Endocrine Testing

• Suspect too little? Stimulate it. Suspect too much? Suppress it.
• Deficiency tests (stimulation):
  • Short Synacthen test — 250 micrograms tetracosactide IV or IM, cortisol at 0 and 30 minutes (sometimes 60) — a low peak (cut-off is assay-specific) suggests adrenal insufficiency. Recent pituitary failure may give a normal result (the adrenals haven't wasted yet).
  • 9 am cortisol as a screen — very low suggests adrenal insufficiency; high makes it unlikely (thresholds are assay-specific). Not valid on oral oestrogen (raised CBG) or recent steroids (including inhaled, injected and topical).
  • Insulin tolerance test or glucagon stimulation — for GH and ACTH reserve (specialist; ITT contraindicated in IHD and epilepsy).
• Excess tests (suppression):
  • Overnight dexamethasone suppression — 1 mg at 11 pm–midnight, cortisol at 9 am; failure to suppress (cortisol over 50 nmol/L) suggests Cushing's syndrome. Also late-night salivary cortisol and 24-hour urinary free cortisol.
  • OGTT with GH — GH fails to suppress in acromegaly.
  • Saline suppression — aldosterone fails to suppress in primary aldosteronism.
• Water deprivation test — for diabetes insipidus: urine fails to concentrate with dehydration; then desmopressin concentrates it in cranial but not nephrogenic DI. Increasingly replaced by copeptin (a stable marker of ADH release).
• Practical pitfalls:
  • Timing — cortisol at 9 am; testosterone in the morning; progesterone in the luteal phase; TFTs 6–8 weeks after a dose change.
  • Interfering drugs — steroids, oestrogen, biotin supplements (interfere with many immunoassays — falsely high or low TFTs; stop for a few days before testing), heterophile antibodies.
  • Acute illness distorts TFTs, cortisol, testosterone and sodium.
  • Imaging comes after biochemistry — incidental pituitary and adrenal lumps are common; scan only once a hormone problem is proven (except mass effects).

Normal Values

Insulin

• Regimens — type 1: basal–bolus (long-acting plus mealtime rapid-acting, with carbohydrate counting) or insulin pump, increasingly with continuous glucose monitoring and hybrid closed-loop systems; type 2: usually once-daily basal insulin added to tablets.
• Side effects — hypoglycaemia, weight gain, lipohypertrophy (lumpy injection sites — erratic absorption; rotate sites), low potassium with IV insulin.
• Safety rules:
  • Write "units" in full — never "U" or "IU" (10U misread as 100).
  • Never draw insulin from a pen or cartridge with a syringe — especially high-strength insulins (U200, U300, U500) — risk of large overdose.
  • Never stop insulin in type 1 diabetes — even if not eating (risk of DKA); continue long-acting basal insulin during DKA treatment.
  • Check brand, strength and device on admission; let patients self-manage where safe.
  • Insulin is a top high-risk drug in hospital errors.
• IV insulin — fixed-rate (0.1 units/kg/hour) in DKA and HHS (when ketotic); variable-rate (VRIII) for people who can't eat or are peri-operative — always with glucose-containing fluid and potassium monitoring (JBDS).
• Driving — check glucose before driving and every 2 hours on long journeys; "five to drive" (over 5 mmol/L); tell the DVLA if on insulin (group 2 has stricter rules).

Metformin

• Mechanism — mainly reduces glucose production by the liver and improves insulin sensitivity; doesn't stimulate insulin, so no hypoglycaemia on its own; weight neutral or slight loss.
• Use — first-line drug for type 2 diabetes (NICE NG28); also prediabetes, PCOS, gestational diabetes.
• Side effects — diarrhoea, nausea, abdominal pain, metallic taste (start low, increase slowly, take with food; modified-release is better tolerated); vitamin B12 deficiency (MHRA — check B12 if there are symptoms such as neuropathy or anaemia, and periodically in those at risk); lactic acidosis (rare — mainly with acute kidney injury, sepsis, shock or hypoxia).
• Kidney function — review the dose if eGFR is under 45; stop if eGFR is under 30.
• Sick day rules — stop temporarily with vomiting, diarrhoea, fever or dehydration; restart 24–48 hours after eating and drinking normally.
• Iodinated contrast and surgery — withhold in AKI or with eGFR under 30 (and around major surgery per local guidance); restart when kidney function is stable.

Sulfonylureas

• Examples — gliclazide (the commonest in the UK), glimepiride, glipizide.
• Mechanism — close ATP-sensitive potassium channels on beta cells → insulin release regardless of glucose. Need working beta cells.
• Side effects — hypoglycaemia (can be prolonged, especially in older people, CKD and with long-acting drugs — may need admission and IV glucose for 24 hours or more; octreotide in refractory cases), weight gain.
• Cautions — frailty, kidney and liver impairment, irregular eating, drivers (DVLA — group 2 drivers must monitor glucose).
• Interactions — hypoglycaemia increased by other glucose-lowering drugs, alcohol, some antibiotics (clarithromycin, co-trimoxazole, fluconazole).
• Special uses — MODY due to HNF1A or HNF4A mutations is very sensitive to low-dose sulfonylureas; some neonatal diabetes (KATP channel mutations) switches from insulin to sulfonylureas.
• Meglitinides (repaglinide) — same mechanism, short-acting, taken with meals.