Endocrine: Anatomy Physiology and Pharmacology

🧪 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?

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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

Hypothalamus	Pituitary	Target and hormone	Feedback
CRH	ACTH	Adrenal cortex → cortisol	Cortisol suppresses CRH and ACTH
TRH	TSH	Thyroid → T4 and T3	T4/T3 suppress TRH and TSH
GnRH (pulsatile)	LH and FSH	Gonads → testosterone, oestrogen, progesterone, inhibin	Sex steroids and inhibin suppress (oestrogen can also trigger the mid-cycle LH surge)
GHRH (stimulates); somatostatin (inhibits)	GH	Liver → IGF-1	IGF-1 suppresses GH
Dopamine (inhibits)	Prolactin	Breast → milk	Prolactin increases dopamine
Supraoptic and paraventricular nuclei	Posterior -ADH, oxytocin	Kidney (water) / uterus and breast	Osmolality and blood volume control ADH

• 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

Measure	Typical adult value (check your lab)
TSH	About 0.4–4.0 mU/L
Free T4	About 10–22 pmol/L
Fasting plasma glucose	Under 6.1 mmol/L (diabetes 7.0 or more; impaired fasting glucose 6.1–6.9)
Random plasma glucose	Diabetes if 11.1 mmol/L or more with symptoms
HbA1c	Under 42 mmol/mol (prediabetes 42–47; diabetes 48 or more)
Adjusted calcium	About 2.2–2.6 mmol/L
Phosphate	About 0.8–1.5 mmol/L
Magnesium	About 0.7–1.0 mmol/L
PTH	About 1.5–7 pmol/L (interpret with calcium)
25-hydroxyvitamin D	Deficient under 25 nmol/L; insufficient 25–50 nmol/L; adequate over 50 nmol/L
Sodium	135–145 mmol/L
Plasma osmolality	About 275–295 mOsm/kg
9 am cortisol	Assay-specific; very low suggests insufficiency, high makes it unlikely
Prolactin	Roughly under 500 mU/L (varies by lab and sex)
Testosterone (men, morning)	About 8–30 nmol/L

Insulin

Type	Examples	Action
Rapid-acting analogue	Aspart (NovoRapid, Fiasp), lispro (Humalog), glulisine	Onset 5–15 min, lasts 3–5 hours; with meals
Short-acting (soluble)	Actrapid, Humulin S	Onset 30 min, lasts 6–8 hours; used IV in infusions
Intermediate (isophane/NPH)	Humulin I, Insulatard	Lasts about 12–16 hours; once or twice daily
Long-acting analogue	Glargine (Lantus, Toujeo U300), detemir (Levemir), degludec (Tresiba)	Basal insulin, about 24 hours (degludec over 40 hours)
Premixed	NovoMix 30, Humalog Mix 25, Humulin M3	Twice daily with meals

• 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.

SGLT2 Inhibitors

• Examples -dapagliflozin, empagliflozin, canagliflozin, ertugliflozin.
• Mechanism -block sodium–glucose co-transporter 2 in the proximal tubule → glucose and sodium lost in the urine → lower glucose, weight loss (about 2–3 kg), lower blood pressure; little hypoglycaemia alone. The glucose-lowering effect falls as eGFR falls, but heart and kidney benefits continue.
• Benefits beyond glucose -fewer heart failure admissions and slower CKD progression -now used in heart failure and CKD with or without diabetes.
• NICE NG28 -offer an SGLT2 inhibitor with metformin in type 2 diabetes if there is heart failure, established cardiovascular disease or high cardiovascular risk (check the current version -recent updates widen early use).
• Side effects and risks:
  • Genital fungal infections (thrush) -common; advise good hygiene.
  • Diabetic ketoacidosis -can occur with near-normal glucose (euglycaemic DKA) -check ketones if unwell, even if glucose isn't high.
  • Fournier's gangrene (necrotising fasciitis of the perineum) -rare but serious.
  • Volume depletion and dizziness (especially with diuretics, in older people); a small initial fall in eGFR is expected.
  • Canagliflozin -possible increased risk of lower limb amputation (check feet).
• Sick day rules -stop during acute illness, vomiting or dehydration; stop before major surgery (usually the day before and the day of surgery) and during fasting; restart once eating and drinking normally.
• Avoid in type 1 diabetes (except specialist use) and in those prone to ketosis (low-carbohydrate diets, heavy alcohol use).

GLP-1 Agonists, Tirzepatide and DPP-4 Inhibitors

• GLP-1 receptor agonists -semaglutide (weekly injection, or daily tablet), dulaglutide (weekly), liraglutide (daily), exenatide.
  • Mechanism -glucose-dependent insulin release, less glucagon, slower stomach emptying, reduced appetite -large weight loss; low hypoglycaemia risk alone.
  • Uses -type 2 diabetes (especially with obesity or cardiovascular disease -reduce cardiovascular events); weight management (semaglutide, liraglutide -NICE TAs, specialist weight services).
  • Side effects -nausea, vomiting, diarrhoea, constipation (increase dose slowly); dehydration and AKI; gallstones; pancreatitis (stop and don't restart); worsening diabetic retinopathy with rapid glucose falls; loss of muscle with rapid weight loss.
• Tirzepatide -dual GIP and GLP-1 agonist, weekly injection; greater weight and glucose reduction; similar side effects.
• Safety points (MHRA):
  • Aspiration under anaesthesia or sedation -slowed stomach emptying; tell the anaesthetist.
  • Pregnancy -avoid and use effective contraception; stop before trying to conceive. Tirzepatide may reduce the effectiveness of oral contraceptives -use a non-oral method or add a barrier method for 4 weeks after starting and after each dose increase.
  • Hypoglycaemia when combined with insulin or sulfonylureas -reduce those doses.
  • Fake or unlicensed pens bought online -serious harm reported.
• DPP-4 inhibitors ("gliptins") -sitagliptin, linagliptin, alogliptin, saxagliptin, vildagliptin.
  • Block the enzyme that breaks down GLP-1 → modest glucose lowering; weight neutral; low hypoglycaemia risk; well tolerated -useful in frail older people.
  • Linagliptin needs no dose change in kidney disease.
  • Risks -pancreatitis, bullous pemphigoid; saxagliptin and alogliptin -caution in heart failure.
  • Don't combine with a GLP-1 agonist (no added benefit).

Pioglitazone

• Mechanism -a thiazolidinedione; activates PPAR-gamma → improves insulin sensitivity in fat, muscle and liver; no hypoglycaemia alone; may help fatty liver disease.
• Side effects:
  • Fluid retention and oedema -contraindicated in heart failure (any history).
  • Weight gain.
  • Fractures (especially in women).
  • Bladder cancer -avoid with current or past bladder cancer or unexplained visible haematuria.
  • Liver problems -check LFTs.
• Other oral options (rarely used) -acarbose (slows carbohydrate absorption -flatulence).

Levothyroxine

• Use -replacement in hypothyroidism; TSH suppression after thyroid cancer (specialist).
• Starting dose:
  • Young and healthy -full replacement, about 1.6 micrograms/kg/day.
  • Older people or heart disease -start low (25 micrograms, or 25–50 micrograms) and increase slowly (risk of angina or arrhythmia).
• Monitoring -aim for TSH in the reference range; check 6–8 weeks after each change, then yearly once stable. In secondary hypothyroidism, TSH is useless -titrate to free T4.
• How to take it -on an empty stomach, 30–60 minutes before breakfast (or at bedtime), with water; keep the same brand if possible.
• Absorption interactions -separate by about 4 hours from iron, calcium, antacids, PPIs reduce absorption; coffee and soya; coeliac disease and atrophic gastritis can cause malabsorption.
• Increased dose needs -pregnancy (increase as soon as pregnancy is confirmed -often by 25–50 micrograms -and check TFTs each trimester), oral oestrogen, enzyme inducers (rifampicin, carbamazepine, phenytoin), weight gain.
• Over-replacement (suppressed TSH) -atrial fibrillation and osteoporosis, especially in older people.
• Liothyronine (T3) -faster acting; specialist use only (e.g. myxoedema coma with caution, some patients not improving on T4).
• Adrenal insufficiency first -if both are present (e.g. hypopituitarism), start hydrocortisone before levothyroxine, because thyroxine increases cortisol breakdown and can trigger an adrenal crisis.

Antithyroid Drugs and Radioiodine

• Carbimazole (converted to methimazole) and propylthiouracil (PTU) -block thyroid peroxidase; PTU also reduces T4-to-T3 conversion.
  • Regimens -titration (adjust dose to TFTs) or block and replace (high dose plus levothyroxine) -usually for 12–18 months in Graves'; about half relapse.
  • Agranulocytosis (about 1 in 300–500, usually in the first 3 months) -warn all patients: sore throat, mouth ulcers, fever → stop the drug and get an urgent FBC.
  • Rash and itch (common), joint pains, liver problems (cholestatic with carbimazole; severe hepatitis with PTU), vasculitis (PTU -ANCA).
  • Pregnancy -carbimazole in the first trimester can cause birth defects (e.g. aplasia cutis) -use PTU in the first trimester, then switch to carbimazole. Women of childbearing age on carbimazole should use effective contraception (MHRA).
• Beta-blockers (propranolol) -control tremor, palpitations and anxiety quickly while waiting for antithyroid drugs to work; useful in thyroiditis (where antithyroid drugs don't help).
• Radioiodine (I-131) -destroys thyroid tissue over weeks to months:
  • Contraindicated in pregnancy and breastfeeding; avoid pregnancy for at least 6 months afterwards (men should avoid fathering a child for at least 4 months).
  • Can worsen thyroid eye disease -avoid in active eye disease or give steroid cover; smokers are at higher risk.
  • Radiation safety -avoid close prolonged contact, especially with children and pregnant women, for a period after treatment.
  • Hypothyroidism is common afterwards -lifelong TFT monitoring.
• Lugol's iodine -briefly reduces hormone release (Wolff–Chaikoff); before thyroidectomy and in thyroid storm (given after an antithyroid drug).
• Thyroid eye disease -stop smoking (most important), keep thyroid levels normal, selenium in mild disease, IV methylprednisolone in active moderate–severe disease; urgent referral if vision is affected.

Corticosteroids

Steroid	Approximate equivalent dose	Salt-retaining (mineralocorticoid) effect
Hydrocortisone	20 mg	High
Prednisolone	5 mg	Moderate
Methylprednisolone	4 mg	Low
Dexamethasone	750 micrograms	Almost none
Fludrocortisone	Not used for anti-inflammatory effect	Very high

• Replacement in adrenal insufficiency -hydrocortisone about 15–25 mg a day in 2–3 doses (largest on waking -e.g. 10 mg, 5 mg, 5 mg), plus fludrocortisone 50–100 micrograms daily in primary adrenal insufficiency.
• Sick day rules (NICE NG243, Society for Endocrinology):
  • Double the daily dose during illness with fever or when needing antibiotics or bed rest.
  • Vomiting or unable to take tablets -hydrocortisone 100 mg IM (emergency injection kit) and go to hospital.
  • Carry an NHS Steroid Emergency Card; wear medical alert identification.
• Adrenal crisis -hydrocortisone 100 mg IV or IM immediately, then 200 mg over 24 hours (infusion or 50 mg every 6 hours), plus IV fluids; don't wait for test results.
• Surgery and procedures -extra hydrocortisone cover (e.g. 100 mg IV at induction for major surgery, then 200 mg over 24 hours) for anyone with adrenal insufficiency or on long-term steroids.
• Who is at risk of adrenal suppression -anyone taking the equivalent of prednisolone 5 mg or more a day for 4 weeks or more (by any route -oral, high-dose inhaled, injected, topical); give a steroid card.
• Stopping steroids -taper gradually after more than 3 weeks of treatment (or high doses, or repeated courses) to allow the axis to recover.
• Side effects of long-term steroids -hyperglycaemia, hypertension, weight gain, osteoporosis (bone protection if 3 months or more), infections, peptic ulcer (with NSAIDs), mood changes and psychosis, cataracts and glaucoma, skin thinning, myopathy, adrenal suppression, growth suppression in children.
• Interactions -CYP3A4 inhibitors (ritonavir and cobicistat, itraconazole, clarithromycin) block breakdown of inhaled or nasal fluticasone and budesonide → Cushing's syndrome and adrenal suppression; enzyme inducers (rifampicin, carbamazepine, phenytoin) reduce steroid effect -double replacement doses may be needed.
• Steroid-induced hyperglycaemia -once-daily morning prednisolone raises glucose in the afternoon and evening; a morning sulfonylurea or NPH insulin is often used (JBDS).

⚠️ Safety Pearl: Never stop or omit steroids in someone with adrenal insufficiency or on long-term steroids -especially when they are vomiting, nil by mouth or going for surgery. If in doubt, give hydrocortisone 100 mg IM or IV; it is safe, while adrenal crisis can kill.

Drugs for Adrenal Disease

• Cushing's syndrome (before surgery or if surgery isn't possible) -metyrapone and osilodrostat (block cortisol synthesis -risk of adrenal insufficiency and low potassium/high blood pressure from precursor build-up), ketoconazole (liver toxicity -specialist), etomidate IV in severe cases.
• Primary aldosteronism -surgery for a one-sided adenoma; otherwise spironolactone (gynaecomastia, breast pain, menstrual changes, erectile dysfunction, hyperkalaemia) or eplerenone (more selective -fewer hormonal effects).
• Phaeochromocytoma before surgery:
  • Alpha-blockade first -phenoxybenzamine or doxazosin -for at least 1–2 weeks, with a high salt and fluid intake.
  • Beta-blockade only after alpha-blockade -giving a beta-blocker first leaves alpha effects unopposed → hypertensive crisis.
• Congenital adrenal hyperplasia (21-hydroxylase deficiency) -glucocorticoids (to suppress ACTH and androgens) plus fludrocortisone if salt-wasting.
• Fludrocortisone -also used for postural hypotension; side effects include hypertension, oedema, low potassium; monitor blood pressure and potassium.

Pituitary and Water Balance Drugs

• Dopamine agonists -cabergoline (first-line for prolactinoma, weekly or twice weekly; shrinks most tumours), bromocriptine, quinagolide.
  • Side effects -nausea, dizziness, postural hypotension, headache, depression, impulse control disorders (gambling, hypersexuality, compulsive shopping -warn patients).
  • Fibrosis (heart valves, pleura, retroperitoneum) -mainly at the high doses used in Parkinson's; echocardiography if on long-term higher doses.
  • Also used to stop lactation.
• Somatostatin analogues -octreotide, lanreotide, pasireotide:
  • Uses -acromegaly, TSH-secreting adenomas, neuroendocrine tumours (carcinoid syndrome), refractory sulfonylurea hypoglycaemia (octreotide).
  • Side effects -gallstones, diarrhoea and abdominal cramps, injection site pain, glucose changes (pasireotide causes hyperglycaemia).
• Pegvisomant -GH receptor blocker for acromegaly; monitor IGF-1 (not GH) and LFTs.
• Growth hormone (somatropin) -children with GH deficiency, Turner, Prader–Willi, CKD; adults with severe deficiency affecting quality of life (NICE). Side effects -fluid retention, joint pain, carpal tunnel, raised glucose; slipped upper femoral epiphysis and raised intracranial pressure in children.
• Desmopressin (DDAVP) -synthetic ADH acting on V2 receptors:
  • Uses -cranial diabetes insipidus, nocturnal enuresis, nocturia, mild haemophilia A and von Willebrand disease (releases factor VIII and vWF).
  • Hyponatraemia is the major risk -limit fluid intake around doses, monitor sodium (especially in older people); nasal sprays should not be used for enuresis.
  • Never omit desmopressin in cranial DI patients in hospital (rapid hypernatraemia) -flag on admission (NatPSA 2016).
• Tolvaptan -ADH (V2) antagonist:
  • Uses -SIADH hyponatraemia (start in hospital, check sodium closely -too rapid a rise risks osmotic demyelination; don't fluid-restrict in the first 24 hours); ADPKD (slows kidney enlargement -liver toxicity, monthly LFTs).
  • Side effects -thirst, polyuria.
• Demeclocycline -a tetracycline that causes nephrogenic DI; used occasionally for SIADH (photosensitivity, kidney toxicity).
• GnRH agonists (goserelin, leuprorelin, triptorelin) -prostate and breast cancer, endometriosis, fibroids, precocious puberty; initial testosterone flare (cover with an anti-androgen such as bicalutamide in prostate cancer -can cause cord compression or urinary obstruction otherwise); then hot flushes, osteoporosis, loss of libido. Degarelix (GnRH antagonist) -no flare.

Bone and Calcium Drugs

• Vitamin D (colecalciferol) and calcium:
  • Deficiency -loading dose (e.g. about 300,000 units in total over 6–10 weeks), then maintenance (about 800–2,000 units daily).
  • Check adjusted calcium about 1 month after loading -vitamin D can unmask primary hyperparathyroidism (hypercalcaemia).
  • Correct vitamin D before starting bisphosphonates or denosumab (risk of hypocalcaemia).
• Alfacalcidol and calcitriol (active vitamin D) -CKD, hypoparathyroidism, vitamin D-resistant rickets; potent -hypercalcaemia risk; monitor calcium.
• Oral bisphosphonates -alendronic acid 70 mg weekly (first-line), risedronate:
  • Mechanism -bind to bone and stop osteoclasts resorbing it.
  • How to take -on waking, with a full glass of water, swallow whole, stay upright for 30 minutes, no food or other drugs for 30 minutes.
  • Side effects -oesophagitis and ulcers, osteonecrosis of the jaw (dental check before starting if at risk; good oral hygiene), atypical femoral fractures (thigh or groin pain), osteonecrosis of the ear canal.
  • Avoid if eGFR is under 35 (alendronate). Review the need after 5 years (consider a drug holiday).
• Zoledronic acid (IV, once a year for osteoporosis) -after hip fracture or if oral drugs aren't tolerated; acute-phase reaction (flu-like symptoms for 1–3 days), hypocalcaemia, kidney toxicity (check eGFR, hydrate). Also used IV for hypercalcaemia of malignancy and bone metastases.
• Denosumab -antibody against RANKL (blocks osteoclast formation); 60 mg subcutaneously every 6 months:
  • Hypocalcaemia -especially in CKD; check calcium before each dose (MHRA).
  • Don't stop or delay doses -rebound bone loss and multiple vertebral fractures; if stopping, switch to a bisphosphonate.
  • Osteonecrosis of the jaw, atypical femoral fractures, skin infections.
• Anabolic drugs (specialist, very high fracture risk -e.g. multiple vertebral fractures):
  • Teriparatide (PTH analogue, daily injection, for up to 24 months) -builds bone; hypercalcaemia, dizziness; avoid in Paget's, previous skeletal radiotherapy, bone cancer.
  • Romosozumab (anti-sclerostin, monthly for 12 months) -avoid with a history of MI or stroke.
  • Follow with an antiresorptive drug to keep the gain.
• Raloxifene (SERM) -postmenopausal spinal osteoporosis; VTE risk, hot flushes; reduces breast cancer risk.
• Cinacalcet -calcimimetic (makes the parathyroid more sensitive to calcium → less PTH); secondary hyperparathyroidism on dialysis, parathyroid cancer, primary hyperparathyroidism when surgery isn't possible; hypocalcaemia, nausea.
• Hypercalcaemia treatment -IV fluids (0.9% saline) first, then IV bisphosphonate; steroids if vitamin D-driven (sarcoidosis, lymphoma); denosumab or calcitonin in some cases.
• Hypocalcaemia treatment -severe or symptomatic: IV calcium gluconate (10 mL of 10% over 10 minutes, with ECG monitoring), then infusion; correct magnesium; oral calcium and active vitamin D after neck surgery.

Sex Hormone Drugs

• HRT (NICE NG23):
  • Oestrogen treats hot flushes, night sweats, mood and genital symptoms and prevents bone loss.
  • Women with a uterus need a progestogen too (to prevent endometrial cancer) -cyclical or continuous; the Mirena coil can provide it.
  • Transdermal oestrogen (patch, gel) -no increase in VTE or stroke risk compared with tablets -prefer if raised VTE risk, migraine or obesity.
  • Breast cancer risk -small increase with combined HRT, rising with duration; little or none with oestrogen alone.
  • Vaginal oestrogen -for genitourinary symptoms; minimal absorption; can be used long term.
  • Premature ovarian insufficiency -HRT or the combined pill until at least the average age of menopause (about 51).
• Testosterone (gel or injection) -for confirmed male hypogonadism:
  • Monitor haematocrit (polycythaemia -stop if over about 0.54), PSA and prostate symptoms, lipids, liver.
  • Suppresses sperm production -not for men wanting fertility (hCG or FSH are used instead).
  • Avoid in prostate or male breast cancer; can worsen sleep apnoea; children and partners should avoid skin contact with gel.
• Anti-androgens -cyproterone acetate (liver toxicity, meningioma risk with high doses -MHRA), spironolactone (hirsutism), finasteride (5-alpha-reductase inhibitor -BPH; MHRA warning on depression and suicidal thoughts and sexual side effects).
• Combined pill (oestrogen raises binding proteins) -falsely raises total T4 and cortisol; interacts with enzyme inducers (rifampicin, carbamazepine, St John's wort) and lamotrigine.
• Clomifene and letrozole -induce ovulation (PCOS -letrozole now often preferred); risk of multiple pregnancy and ovarian hyperstimulation.

Drugs That Cause Endocrine Problems

Drug	Endocrine effect
Amiodarone	Hypothyroidism (common) or thyrotoxicosis (type 1 -iodine-induced; type 2 -destructive thyroiditis) -TFTs before and every 6 months
Lithium	Hypothyroidism and goitre; nephrogenic diabetes insipidus; hyperparathyroidism and hypercalcaemia
Immune checkpoint inhibitors (pembrolizumab, nivolumab, ipilimumab)	Thyroiditis, hypophysitis (ACTH deficiency -headache, fatigue), adrenalitis, sudden type 1 diabetes and DKA
Corticosteroids	Hyperglycaemia, Cushing's syndrome, adrenal suppression, osteoporosis
Antipsychotics, metoclopramide, domperidone	Hyperprolactinaemia; olanzapine and clozapine -weight gain and diabetes
Thiazides	Hyponatraemia, hypokalaemia, hypercalcaemia, hyperglycaemia
SSRIs, carbamazepine, PPIs, opioids, cyclophosphamide, vincristine, MDMA	SIADH and hyponatraemia
PPIs (long-term)	Hypomagnesaemia → hypocalcaemia (low PTH)
Heparin, ACE inhibitors, ARBs, spironolactone, trimethoprim	Hyperkalaemia
Opioids (long-term)	Hypogonadism, adrenal insufficiency
Anabolic steroids	Hypogonadism, infertility, testicular atrophy, gynaecomastia, polycythaemia
Alemtuzumab, interferon alpha	Autoimmune thyroid disease (Graves')
Tyrosine kinase inhibitors (sunitinib)	Hypothyroidism
Etomidate, ketoconazole, metyrapone	Adrenal suppression
Beta-blockers (non-selective)	Mask hypoglycaemia warning symptoms
Fluoroquinolones	Hypo- and hyperglycaemia (MHRA)
Biotin supplements	Interfere with lab tests -falsely abnormal TFTs and other hormone results

Drug Reference Table

Drug	Key points
Insulin	Write "units" in full; hypoglycaemia, weight gain, lipohypertrophy; never stop in type 1; fixed-rate 0.1 units/kg/hour in DKA.
Metformin	First-line type 2; GI upset, B12 deficiency; stop if eGFR under 30 and during dehydrating illness.
Gliclazide	Closes KATP channels; prolonged hypoglycaemia in older people and CKD; weight gain.
Dapagliflozin / empagliflozin	SGLT2; heart and kidney benefit; thrush, euglycaemic DKA, Fournier's; stop on sick days and before surgery.
Semaglutide / tirzepatide	Weight loss; nausea, pancreatitis, gallstones; aspiration risk with anaesthesia; avoid in pregnancy.
Sitagliptin / linagliptin	DPP-4; weight neutral, few hypos; pancreatitis, bullous pemphigoid.
Pioglitazone	Insulin sensitiser; avoid in heart failure and bladder cancer; fractures, weight gain.
Levothyroxine	Empty stomach; separate from iron and calcium; recheck after 6–8 weeks; increase in pregnancy; start low in elderly.
Carbimazole / PTU	Agranulocytosis -sore throat means stop and FBC; PTU in first trimester; PTU liver toxicity.
Radioiodine	Not in pregnancy; avoid pregnancy 6 months; can worsen eye disease; hypothyroidism afterwards.
Hydrocortisone	Replacement 15–25 mg/day; double on sick days; 100 mg IM/IV for crisis; steroid card.
Fludrocortisone	Mineralocorticoid in primary adrenal failure; hypertension, low potassium.
Prednisolone / dexamethasone	5 mg pred = 20 mg hydrocortisone = 0.75 mg dex; taper after 3 weeks; bone protection if 3 months or more.
Phenoxybenzamine	Alpha-blockade first in phaeochromocytoma, then beta-blocker.
Cabergoline	Prolactinoma first-line; impulse control disorders; valve fibrosis at high doses.
Octreotide / lanreotide	Acromegaly, NETs; gallstones.
Desmopressin	Cranial DI, enuresis, bleeding disorders; hyponatraemia; never omit in cranial DI.
Tolvaptan	V2 antagonist for SIADH; start in hospital; avoid rapid sodium rise; liver toxicity.
Alendronic acid	Upright 30 min with water; oesophagitis, jaw osteonecrosis, atypical femoral fractures.
Zoledronic acid	IV yearly; acute-phase reaction; hypercalcaemia of malignancy.
Denosumab	RANKL antibody every 6 months; hypocalcaemia; rebound fractures if stopped.
Teriparatide / romosozumab	Bone-building; romosozumab -avoid after MI or stroke.
Colecalciferol / alfacalcidol	Check calcium 1 month after loading; active forms risk hypercalcaemia.
Cinacalcet	Calcimimetic; secondary hyperparathyroidism in dialysis; hypocalcaemia.
Calcium gluconate (IV)	Severe hypocalcaemia -10 mL of 10% over 10 minutes with ECG monitoring.
HRT	Progestogen if uterus; transdermal oestrogen lower VTE risk.
Testosterone	Monitor haematocrit and PSA; suppresses fertility.
Goserelin / leuprorelin	GnRH agonists; tumour flare -anti-androgen cover in prostate cancer.

Spot the Answer

Clue	Answer
Bitemporal hemianopia and headache	Pituitary tumour pressing on the optic chiasm
Sudden headache, double vision and collapse with a known pituitary adenoma	Pituitary apoplexy -give hydrocortisone
Midline neck lump that rises when the tongue is protruded	Thyroglossal cyst
Hoarse voice after thyroidectomy	Recurrent laryngeal nerve injury
Tingling lips and carpopedal spasm the day after thyroidectomy	Hypocalcaemia from parathyroid damage
Low free T4 with a normal TSH	Secondary (pituitary) hypothyroidism -check other axes
Hyperkalaemia, pigmentation and postural hypotension	Primary adrenal failure (Addison's) -aldosterone lost too
Hypertension with low potassium and suppressed renin	Primary aldosteronism
Mild raised prolactin with a large non-functioning pituitary tumour	Stalk compression (loss of dopamine inhibition)
Polyuria and thirst on long-term lithium	Nephrogenic diabetes insipidus
High calcium with a high-normal PTH	Primary hyperparathyroidism
High calcium with suppressed PTH and weight loss	Malignancy (PTHrP, metastases, myeloma)
Hypoglycaemia with high insulin and low C-peptide	Injected insulin (factitious or accidental)
Unwell with ketones of 4.5 and glucose of 11 on dapagliflozin	Euglycaemic DKA -stop the SGLT2 inhibitor
Older man on gliclazide with recurrent hypos after an AKI	Sulfonylurea accumulation -prolonged hypoglycaemia
Numb feet and macrocytic anaemia on long-term diabetes tablets	Metformin-related B12 deficiency
Severe abdominal pain after starting weekly semaglutide	Consider pancreatitis or gallstones
Sore throat and fever 6 weeks after starting carbimazole	Possible agranulocytosis -stop and urgent FBC
TSH still high despite rising levothyroxine doses; takes it with ferrous sulfate	Absorption interaction -separate by 4 hours
Cushingoid features in a patient on ritonavir and inhaled fluticasone	CYP3A4 inhibition -iatrogenic Cushing's and adrenal suppression
Compulsive gambling after starting a prolactinoma drug	Cabergoline impulse control disorder
Multiple vertebral fractures a year after stopping an osteoporosis injection	Denosumab rebound
Thigh pain after 7 years of a weekly osteoporosis tablet	Atypical femoral fracture (bisphosphonate)
Headache and fatigue with low sodium on pembrolizumab	Hypophysitis (ACTH deficiency)

Exam-style Scenarios

1. A 68-year-old man on prednisolone 10 mg daily for polymyalgia for 6 months is admitted with vomiting and diarrhoea. BP 82/50, sodium 129, glucose 3.6.
Answer: Adrenal crisis due to steroid-induced adrenal suppression and an intercurrent illness.

• Hydrocortisone 100 mg IV or IM immediately, then 200 mg over 24 hours; IV 0.9% saline; treat hypoglycaemia.
• Don't wait for a cortisol result (it will be uninterpretable on prednisolone anyway).
• Before discharge -sick day rules, steroid emergency card, emergency injection kit if appropriate.

2. A 55-year-old woman with type 2 diabetes on metformin and empagliflozin presents with vomiting and breathlessness after 3 days of gastroenteritis. Glucose 12.1, pH 7.18, bicarbonate 9, ketones 5.2.
Answer: Euglycaemic DKA associated with an SGLT2 inhibitor.

• Treat as DKA (JBDS) -fluids, fixed-rate insulin 0.1 units/kg/hour, potassium; add 10% glucose early because glucose is not very high.
• Stop empagliflozin and metformin.
• Teach sick day rules -stop SGLT2 inhibitors and metformin when unable to eat and drink; check ketones when unwell.

3. A 32-year-old woman with Graves' disease on carbimazole finds out she is 6 weeks pregnant.
Answer: Switch from carbimazole to propylthiouracil for the first trimester.

• Carbimazole in early pregnancy is associated with birth defects; switch to carbimazole again from the second trimester (PTU liver risk).
• Aim for free T4 at the upper end of normal on the lowest dose; joint endocrine–obstetric care.
• Check TSH receptor antibodies (fetal and neonatal thyrotoxicosis risk); radioiodine is contraindicated.

4. An 80-year-old woman on gliclazide 160 mg twice daily is found drowsy with glucose 1.9 mmol/L. eGFR has fallen from 55 to 24 with a UTI.
Answer: Sulfonylurea-induced hypoglycaemia worsened by AKI.

• IV glucose (e.g. 10% glucose 150–200 mL over 15 minutes), then a glucose infusion; consider octreotide if hypos keep recurring.
• Admit and monitor glucose hourly for at least 24 hours -hypos can recur.
• Stop gliclazide; review targets (relaxed HbA1c in frailty); consider a DPP-4 inhibitor such as linagliptin.

5. A 72-year-old woman has a hip fracture. Adjusted calcium 2.18, eGFR 28, vitamin D 18 nmol/L. The team want to start denosumab.
Answer: Correct vitamin D and calcium first.

• Vitamin D loading and calcium; recheck calcium before the first dose -denosumab can cause severe hypocalcaemia, especially in CKD.
• Oral alendronate is unsuitable (eGFR under 35); zoledronic acid also needs adequate kidney function.
• Explain that denosumab must not be stopped or delayed without a plan (rebound vertebral fractures); falls assessment and dental check.

Key Points

• Peptide hormones act on surface receptors (fast); steroids and thyroid hormones act on nuclear receptors (slow).
• Primary failure -target hormone low, pituitary hormone high; secondary -both low or "inappropriately normal".
• Pituitary tumours press on the optic chiasm (bitemporal hemianopia) and cavernous sinus nerves (III, IV, V1, V2, VI).
• Prolactin is held down by dopamine -stalk compression and dopamine blockers raise it.
• Recurrent laryngeal nerve and parathyroids are at risk in thyroid surgery.
• Adrenal cortex GFR -aldosterone, cortisol, androgens; pituitary failure spares aldosterone.
• T4 half-life about 7 days -recheck TFTs 6–8 weeks after a dose change.
• ADH acts on V2 receptors and aquaporin-2; lithium, hypercalcaemia and hypokalaemia cause nephrogenic DI.
• Insulin release -glucose → ATP → KATP channels close (sulfonylurea site) → calcium → insulin.
• Insulin deficiency causes ketosis; C-peptide is low with injected insulin.
• PTH raises calcium and lowers phosphate; magnesium is needed to secrete it.
• Suspect deficiency -stimulate; suspect excess -suppress.
• Insulin: write "units", never stop basal insulin in type 1; fixed-rate 0.1 units/kg/hour in DKA.
• Metformin: stop if eGFR under 30 or dehydrated; watch B12.
• SGLT2 inhibitors: heart and kidney benefit; euglycaemic DKA; stop on sick days and before surgery.
• GLP-1 agonists and tirzepatide: GI effects, pancreatitis, gallstones, aspiration with anaesthesia; avoid in pregnancy.
• Pioglitazone -avoid in heart failure and bladder cancer.
• Carbimazole -sore throat means stop and check FBC; PTU in the first trimester.
• Steroid sick day rules -double dose; 100 mg hydrocortisone IM if vomiting; steroid card.
• Start hydrocortisone before levothyroxine if both are needed.
• Phaeochromocytoma -alpha-blocker before beta-blocker.
• Denosumab -check calcium; never stop without a plan.

Guidelines and Further Reading

• NICE NG28: Type 2 diabetes in adults -management
• NICE NG17: Type 1 diabetes in adults -diagnosis and management
• JBDS-IP guidelines: DKA, HHS, hypoglycaemia, VRIII, perioperative care, steroid-induced hyperglycaemia
• NICE NG145: Thyroid disease -assessment and management
• NICE NG243: Adrenal insufficiency -identification and management
• Society for Endocrinology: Emergency endocrine guidance and adrenal crisis; NHS Steroid Emergency Card
• NOGG: Clinical guideline for the prevention and treatment of osteoporosis
• NICE NG23: Menopause -identification and management
• MHRA Drug Safety Updates: carbimazole, SGLT2 inhibitors, GLP-1 agonists and tirzepatide, denosumab, metformin and B12
• BNF -for current doses