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Hormones act on membrane receptors (peptides, catecholamines) or nuclear receptors (steroids, thyroid hormones, vitamin D). Axes: hypothalamus (CRH, TRH, GnRH, GHRH, somatostatin, dopamine) -> anterior pituitary (ACTH, TSH, LH/FSH, GH, prolactin) -> target gland -> hormone with negative feedback. Diagnostic principles: low target hormone with high trophic hormone indicates primary failure; low with low or inappropriately normal trophic hormone indicates pituitary or hypothalamic disease. Use stimulation tests to confirm deficiency (for example ACTH stimulation, insulin tolerance test) and suppression tests to confirm excess (dexamethasone suppression, oral glucose tolerance for growth hormone).

Diabetes insipidus: polyuria and polydipsia with dilute urine. Central (lack of ADH; pituitary surgery, trauma, tumours) and nephrogenic (kidney resistance; lithium, hypercalcaemia). Diagnosis: water deprivation test or copeptin (a stable surrogate for ADH), response to desmopressin. Treatment: desmopressin for central; thiazides and treatment of the cause for nephrogenic. Syndrome of inappropriate antidiuresis (SIAD): excess ADH causing euvolaemic hyponatraemia with concentrated urine (urine osmolality above 100 mOsm/kg, urinary sodium above 30 mmol/L); causes: lung cancer, CNS disease, drugs (SSRIs, carbamazepine). Treatment: fluid restriction, salt tablets, urea, vaptans; correct sodium slowly (not more than 8-10 mmol/L per 24 hours) to avoid osmotic demyelination.

Mass effects: headache, bitemporal hemianopia, hypopituitarism. Prolactinoma: galactorrhoea, amenorrhoea and infertility in women, hypogonadism in men; treated with dopamine agonists (cabergoline). Acromegaly: growth hormone excess with coarse features, enlarged hands and feet, sweating, diabetes and cardiomyopathy; diagnosis by IGF-1 and failure of GH suppression during an OGTT; treatment: transsphenoidal surgery, somatostatin analogues, pegvisomant. Cushing disease: ACTH-secreting adenoma (see adrenal chapter). Non-functioning adenomas need surgery if compressing. Replace deficient hormones after treatment.

1. What are the features of central versus nephrogenic diabetes insipidus? 2. Describe the biochemical picture of SIAD. 3. How is acromegaly diagnosed? 4. What is the first-line treatment of prolactinoma?

1. Central: lack of ADH, responds to desmopressin. Nephrogenic: kidney resistance to ADH, does not respond. 2. Euvolaemic hyponatraemia with inappropriately concentrated urine (osmolality above 100, urine sodium above 30). 3. Raised IGF-1 and failure of GH to suppress after an oral glucose load. 4. A dopamine agonist such as cabergoline.

Tests: TSH first (suppressed in hyperthyroidism), then free T4 and T3. Causes: Graves disease (TSH-receptor stimulating antibodies; diffuse goitre, orbitopathy, pretibial myxoedema), toxic multinodular goitre, toxic adenoma, thyroiditis (transient; low radioiodine uptake), and drugs (amiodarone). Symptoms: weight loss, heat intolerance, palpitations, tremor, atrial fibrillation. Treatment: beta-blockers for symptoms; antithyroid drugs (carbimazole or methimazole, propylthiouracil in first trimester of pregnancy) for 12-18 months in Graves; radioiodine or thyroidectomy for relapse or nodular disease. Graves orbitopathy: smoking cessation, selenium, steroids, teprotumumab. Thyroid storm is an emergency.

Causes: Hashimoto thyroiditis (anti-TPO antibodies), iodine deficiency, thyroidectomy or radioiodine, drugs (amiodarone, lithium), central hypothyroidism. Symptoms: fatigue, weight gain, cold intolerance, constipation, dry skin, bradycardia, goitre. Diagnosis: raised TSH with low free T4 (subclinical: raised TSH with normal T4). Treatment: levothyroxine, taken fasting; adjust by TSH. Pregnancy: needs increased levothyroxine dose (about 25-30 percent) and TSH targets in the lower range; uncontrolled thyroid disease harms mother and fetus; antibodies cross the placenta in Graves (fetal or neonatal thyrotoxicosis).

Nodules: most are benign. Assess with TSH, ultrasound (suspicious features: hypoechoic, irregular margins, microcalcifications, taller than wide) and fine needle aspiration cytology (Bethesda categories). Cancers: papillary (commonest, excellent prognosis), follicular, medullary (calcitonin; RET mutations) and anaplastic. Treatment: thyroidectomy, radioactive iodine for differentiated cancer with high risk, TSH suppression, follow-up with thyroglobulin and ultrasound.

MEN 1 (menin): parathyroid hyperplasia, pituitary adenomas, pancreatic neuroendocrine tumours. MEN 2A (RET): medullary thyroid cancer, phaeochromocytoma, parathyroid hyperplasia; MEN 2B: medullary cancer, phaeochromocytoma, mucosal neuromas. Prophylactic thyroidectomy in RET carriers. Autoimmune polyendocrine syndrome type 1 (AIRE mutation): chronic mucocutaneous candidiasis, hypoparathyroidism, Addison disease; type 2: Addison disease with autoimmune thyroid disease and type 1 diabetes.

1. How do you interpret a suppressed TSH with high free T4? 2. Which antithyroid drug is preferred in early pregnancy? 3. List the ultrasound features that suggest a malignant nodule. 4. Which conditions form MEN 2A?

1. Primary hyperthyroidism. 2. Propylthiouracil in the first trimester. 3. Hypoechoic, irregular margins, microcalcifications and taller-than-wide shape. 4. Medullary thyroid carcinoma, phaeochromocytoma and parathyroid hyperplasia.

Hypercalcaemia: primary hyperparathyroidism (raised calcium with inappropriately normal or high PTH; commonest cause of outpatient hypercalcaemia; stones, bones, groans, moans; parathyroidectomy) and malignancy (PTHrP or bone metastasis; low PTH; commonest cause in hospital). Treatment of severe hypercalcaemia: fluids, bisphosphonates. Hypocalcaemia: hypoparathyroidism (after neck surgery), vitamin D deficiency, chronic kidney disease; symptoms: paraesthesia, tetany, Chvostek and Trousseau signs, QT prolongation; treatment with calcium and active vitamin D.

Risk factors: age, female sex, menopause, previous fracture, glucocorticoids, low BMI, smoking, alcohol, hypogonadism, hyperthyroidism, malabsorption. Diagnosis: DXA T-score of minus 2.5 or lower or a fragility fracture; fracture risk with FRAX. Investigations for secondary causes. Treatment: calcium and vitamin D, bisphosphonates (alendronate, zoledronate), denosumab, teriparatide or romosozumab for very high risk, hormone therapy in selected women.

Cushing syndrome: exogenous steroids (commonest), ACTH-dependent (pituitary or ectopic) and adrenal tumour. Screening: overnight dexamethasone suppression test, late-night salivary cortisol, 24-hour urinary free cortisol; then ACTH, imaging. Primary aldosteronism: hypertension with hypokalaemia; screening with aldosterone-renin ratio; treatment spironolactone or adrenalectomy. Phaeochromocytoma: episodic headache, sweating and palpitations; plasma or urinary metanephrines; alpha-blockade before surgery. Adrenal insufficiency: fatigue, hypotension, hyponatraemia, hyperkalaemia; morning cortisol and short synacthen test; hydrocortisone and fludrocortisone replacement; stress dosing and adrenal crisis management.

Hypokalaemia: gastrointestinal loss, diuretics, hyperaldosteronism, magnesium depletion, insulin and beta-agonists (shift). Effects: weakness, ileus, ECG U waves and arrhythmias. Evaluate with urinary potassium and blood pressure, acid-base state and renin/aldosterone. Treatment: oral or intravenous potassium, correct magnesium, treat the cause. Hyperkalaemia is treated with calcium, insulin-glucose, salbutamol and potassium removal.

1. How do you distinguish primary hyperparathyroidism from malignant hypercalcaemia? 2. Give the diagnostic threshold for osteoporosis. 3. Which tests screen for Cushing syndrome? 4. What are the features of primary aldosteronism?

1. Primary hyperparathyroidism: PTH normal or high; malignancy: PTH suppressed (PTHrP or bone metastases). 2. DXA T-score of minus 2.5 or lower (or a fragility fracture). 3. Overnight dexamethasone suppression, late-night salivary cortisol, 24-hour urinary free cortisol. 4. Hypertension with hypokalaemia and a raised aldosterone-renin ratio.

Causes: primary (testicular failure: Klinefelter syndrome, orchitis, chemotherapy; high LH and FSH) and secondary (hypothalamic-pituitary disease, obesity, drugs, hyperprolactinaemia; low or normal LH and FSH). Symptoms: low libido, erectile dysfunction, fatigue, reduced muscle mass, osteoporosis, infertility. Diagnosis: morning total testosterone measured twice, LH, FSH, prolactin, semen analysis. Treatment: testosterone replacement (gels, injections) monitoring haematocrit and PSA; gonadotropins to restore fertility. Testosterone is contraindicated in prostate cancer.

Diagnosis (Rotterdam criteria; two of three after exclusion of other causes): oligo- or anovulation, clinical or biochemical hyperandrogenism (hirsutism, acne, raised free testosterone), polycystic ovarian morphology. Associated: insulin resistance, obesity, type 2 diabetes, dyslipidaemia, endometrial hyperplasia, infertility. Management: lifestyle and weight loss; combined oral contraceptive for cycle control and hirsutism; metformin; letrozole or clomiphene for ovulation induction; anti-androgens.

Definition: BMI 30 or more (with waist circumference and body composition considered). Causes: energy imbalance with genetic, hormonal (hypothyroidism, Cushing), drug (antipsychotics, steroids), psychological and environmental factors. Complications: type 2 diabetes, hypertension, dyslipidaemia, sleep apnoea, fatty liver, cancers, osteoarthritis. Management: diet, physical activity and behavioural therapy; drugs (GLP-1 receptor agonists such as semaglutide and liraglutide, tirzepatide, orlistat); bariatric surgery for severe obesity.

1. How are primary and secondary hypogonadism distinguished? 2. State the Rotterdam criteria for PCOS. 3. Which drug classes are used for obesity?

1. Primary: low testosterone with high LH and FSH. Secondary: low testosterone with low or normal LH and FSH. 2. Two of: oligo/anovulation, hyperandrogenism (clinical or biochemical), polycystic ovarian morphology, after excluding other causes. 3. GLP-1 receptor agonists (semaglutide, liraglutide), tirzepatide and orlistat, plus bariatric surgery.