Physiology: Endocrine control, metabolism and thermoregulation

⚗️ Endocrine control, metabolism and thermoregulation. The body keeps its internal environment stable through hormones and the autonomic nervous system, using feedback loops that explain both disease and its investigation. Suppression and stimulation tests, the effects of steroids, the metabolic response to starvation, surgery and trauma, and the management of hypothermia and fever all rest on this physiology. Detailed endocrine disease is covered in the Endocrinology chapters.
Your four questions for an endocrine problem: Which axis is involved, and where in the axis is the fault (primary, secondary or tertiary)? Is the hormone too high or too low for the feedback signal? Which test suppresses an excess or stimulates a deficiency? What metabolic state is the patient in (fed, fasting, stressed)?

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Hormones, Receptors and Feedback

• Hormone types:
  • Peptides and proteins (insulin, GH, PTH, ACTH, ADH) - water-soluble, stored in vesicles, act on cell-surface receptors (G-protein-coupled or tyrosine kinase), rapid effects via second messengers (cAMP, IP₃/Ca²⁺).
  • Steroids (cortisol, aldosterone, sex steroids, vitamin D) - lipid-soluble, synthesised on demand from cholesterol, carried by binding proteins, act on intracellular (nuclear) receptors to alter gene transcription (slower onset, longer effect).
  • Amines - catecholamines (water-soluble, surface receptors) and thyroid hormones (lipid-soluble behaviour, nuclear receptors).
• Negative feedback - the main control mechanism (e.g. cortisol inhibits CRH and ACTH). Positive feedback - rare (LH surge before ovulation, oxytocin in labour).
• Binding proteins (TBG, SHBG, cortisol-binding globulin) - only the free hormone is active; oestrogen (pregnancy, the pill) raises binding proteins and total hormone levels without changing free levels.
• Receptor changes - down-regulation (tachyphylaxis, e.g. continuous GnRH agonists suppress the axis - used in prostate cancer) and resistance (type 2 diabetes, pseudohypoparathyroidism, androgen insensitivity).

The Hypothalamic–Pituitary Axes

Hypothalamus	Anterior pituitary	Target	Feedback hormone
CRH	ACTH	Adrenal cortex	Cortisol
TRH	TSH	Thyroid	T4, T3
GnRH (pulsatile)	LH, FSH	Gonads	Testosterone, oestradiol, inhibin
GHRH (+), somatostatin (−)	GH	Liver (IGF-1)	IGF-1
Dopamine (inhibits)	Prolactin	Breast	-

• Posterior pituitary - stores and releases ADH and oxytocin, made in the supraoptic and paraventricular nuclei and carried down axons.
• Prolactin is unique - under tonic inhibition by dopamine; pituitary stalk compression ("stalk effect") or dopamine antagonists (antipsychotics, metoclopramide) raise prolactin.
• Localising the fault:
  • Primary (gland) failure - low target hormone, high trophic hormone (e.g. primary hypothyroidism: low T4, high TSH; Addison's: low cortisol, high ACTH).
  • Secondary (pituitary) failure - low target hormone, low or inappropriately normal trophic hormone.
  • Hormone excess: primary (adrenal adenoma - high cortisol, suppressed ACTH) versus pituitary or ectopic (high cortisol, high ACTH).
• Pituitary tumours may cause hormone excess, hypopituitarism (GH and gonadotrophins fail first; ACTH and TSH later), and mass effects (bitemporal hemianopia from optic chiasm compression).

Dynamic Tests - Suppression and Stimulation

• Principle: suspect excess → try to suppress it; suspect deficiency → try to stimulate it.

Question	Test	Normal response
Cortisol excess (Cushing's)	Overnight 1 mg dexamethasone suppression test; 24-hour urinary free cortisol; late-night salivary cortisol	Cortisol suppresses (<50 nmol/L)
Cortisol deficiency (Addison's)	Short Synacthen test (250 micrograms ACTH)	Cortisol rises above the assay-specific cut-off (about 430–450 nmol/L)
GH excess (acromegaly)	Oral glucose tolerance test with GH	GH suppresses; IGF-1 normal
GH deficiency	Insulin tolerance test (gold standard), glucagon or arginine stimulation	GH rises
Primary hyperaldosteronism	Aldosterone/renin ratio, then saline suppression test	Aldosterone suppresses with saline
Diabetes insipidus	Water deprivation test, then desmopressin; copeptin-based tests	Urine concentrates with deprivation
Phaeochromocytoma	Plasma or urine metanephrines	-

• Rule: stop interfering drugs where possible (e.g. oral oestrogen raises cortisol-binding globulin and total cortisol; some antihypertensives interfere with the aldosterone/renin ratio).

Adrenal Physiology

• Cortex - "GFR" layers ("salt, sugar, sex"):
  • Zona glomerulosa - aldosterone (controlled by angiotensin II and K⁺, not ACTH).
  • Zona fasciculata - cortisol (ACTH).
  • Zona reticularis - adrenal androgens (DHEA - ACTH).
• Medulla (neural crest) - adrenaline and noradrenaline, under sympathetic preganglionic control.
• Cortisol actions: raises glucose (gluconeogenesis, insulin resistance), protein catabolism, lipolysis (with central fat redistribution), anti-inflammatory and immunosuppressive effects, permissive effect on catecholamines (vascular tone), bone resorption, mood effects. Diurnal rhythm - highest on waking, lowest at midnight.
• Aldosterone - Na⁺ reabsorption and K⁺ and H⁺ excretion in the collecting duct.
• Congenital adrenal hyperplasia (21-hydroxylase deficiency in about 95%) - impaired cortisol and aldosterone synthesis, excess androgens: virilised female infants, salt-wasting crisis in the first weeks of life.
• Adrenal insufficiency - primary (Addison's - low cortisol and aldosterone; hyperpigmentation from high ACTH/POMC; hyperkalaemia) versus secondary (ACTH deficiency, including steroid withdrawal - aldosterone preserved, no pigmentation).
• Adrenal crisis - hypotension, vomiting, abdominal pain, hyponatraemia, hyperkalaemia, hypoglycaemia → IV/IM hydrocortisone 100 mg immediately, IV fluids.

Thyroid Physiology

• Synthesis: iodide uptake (sodium–iodide symporter) → oxidation and organification by thyroid peroxidase (TPO - target of antibodies and of carbimazole/PTU) → coupling on thyroglobulin → stored in colloid → released mainly as T4 (about 90%).
• T4 is a prohormone - converted peripherally to active T3 by deiodinases (and to inactive reverse T3 in illness). Propylthiouracil (and amiodarone, steroids, propranolol in high doses) inhibit peripheral conversion.
• Transport - 99% bound (TBG, transthyretin, albumin); free T4 and free T3 are measured.
• Actions - raise basal metabolic rate, heat production, heart rate and contractility (increase β-receptor sensitivity), bone turnover; essential for brain development (congenital hypothyroidism - newborn screening).
• Wolff–Chaikoff effect - large iodide loads acutely inhibit hormone synthesis and release (used in thyroid storm); Jod–Basedow phenomenon - iodine-induced hyperthyroidism in iodine-deficient or nodular glands (amiodarone, contrast).
• Sick euthyroid syndrome (non-thyroidal illness) - low T3 (and sometimes T4 and TSH) during acute illness; do not treat; repeat tests after recovery.

Insulin, Glucagon and Glucose Homeostasis

• Insulin (β cells) - released by glucose entering β cells via GLUT2 → ATP rises → K-ATP channels close (target of sulfonylureas) → depolarisation → Ca²⁺ influx → insulin exocytosis. Incretins (GLP-1, GIP) amplify glucose-stimulated release (the "incretin effect" - why oral glucose produces more insulin than IV glucose).
• Insulin actions: glucose uptake into muscle and fat (GLUT4), glycogen synthesis, lipogenesis, protein synthesis; inhibits gluconeogenesis, glycogenolysis, lipolysis and ketogenesis; drives K⁺ into cells.
• Counter-regulatory hormones (raise glucose): glucagon (α cells - glycogenolysis, gluconeogenesis, ketogenesis), adrenaline, cortisol, growth hormone.
• C-peptide - released in equal amounts to endogenous insulin; low C-peptide with high insulin = exogenous insulin (factitious hypoglycaemia); high both = insulinoma or sulfonylurea (check a drug screen).
• DKA physiology - absolute insulin deficiency → unrestrained lipolysis and ketogenesis + hyperglycaemia → osmotic diuresis, dehydration, ketoacidosis; total body potassium depleted despite normal or high plasma K⁺.
• HHS - relative insulin deficiency sufficient to prevent ketosis; extreme hyperglycaemia and hyperosmolality (>320 mOsm/kg), severe dehydration.

Growth Hormone, Prolactin and Reproductive Hormones

• Growth hormone - pulsatile, mainly during sleep; acts directly (lipolysis, insulin antagonism) and via IGF-1 from the liver (growth of bone and soft tissue). Excess → gigantism (before epiphyseal fusion) or acromegaly; deficiency → short stature in children, reduced muscle mass and wellbeing in adults.
• Prolactin - lactation; inhibits GnRH → hypogonadism (amenorrhoea, galactorrhoea, low libido, erectile dysfunction). Causes of raised prolactin: pregnancy, prolactinoma, drugs (antipsychotics, metoclopramide, domperidone), stalk compression, hypothyroidism (TRH stimulates prolactin), CKD, macroprolactin.
• Menstrual cycle: follicular phase (FSH → follicle growth, rising oestradiol), LH surge (positive feedback from high oestradiol) → ovulation at about day 14, luteal phase (corpus luteum → progesterone; day 21 progesterone confirms ovulation in a 28-day cycle - test 7 days before the next expected period).
• Testis: LH → Leydig cells → testosterone; FSH + testosterone → Sertoli cells → spermatogenesis (about 74 days); inhibin B feedback to FSH.
• Menopause - ovarian follicle depletion → low oestradiol, high FSH and LH.

The Fed State, Fasting and Starvation

• Fed state (0–4 hours): high insulin → glucose used by all tissues; glycogen, fat and protein synthesis.
• Post-absorptive and early fasting (4–24 hours): insulin falls, glucagon rises → hepatic glycogenolysis (liver glycogen lasts about 24 hours) and gluconeogenesis; fatty acids become the main fuel for muscle.
• Prolonged starvation (days): gluconeogenesis from amino acids (muscle protein), lactate and glycerol; ketogenesis from fatty acids in the liver; after several days the brain adapts to use ketones, reducing protein breakdown. Red cells and the renal medulla always need glucose.
• Starvation ketoacidosis - usually mild (bicarbonate rarely <18); can be significant in pregnancy, alcohol excess or children.
• Energy requirements - about 25–30 kcal/kg/day; protein 0.8–1.5 g/kg/day (more in critical illness and older people).

The Metabolic Response to Injury and Surgery

• Ebb phase (first 24–48 hours) - reduced metabolic rate, hypothermia, hypovolaemia, shock.
• Flow phase - catabolism driven by cortisol, catecholamines, glucagon and cytokines (IL-6, TNF-α): hyperglycaemia with insulin resistance, protein breakdown (negative nitrogen balance, muscle wasting), lipolysis, increased metabolic rate.
• Fluid and electrolyte effects - ADH and aldosterone rise → water and sodium retention, oliguria, risk of hyponatraemia if hypotonic fluids are given; potassium release from damaged cells.
• Acute phase response - raised CRP, fibrinogen, ferritin, complement; reduced albumin and transferrin (negative acute phase reactants) - albumin falls in illness regardless of nutrition.
• Modifying the response - ERAS (enhanced recovery after surgery): avoid prolonged fasting (carbohydrate loading), minimally invasive surgery, regional anaesthesia, early feeding and mobilisation, glycaemic control.

Refeeding Syndrome

• Mechanism: after starvation, feeding (especially carbohydrate) triggers insulin release → phosphate, potassium and magnesium move into cells and thiamine is consumed → dangerous falls in plasma levels.
• Consequences: hypophosphataemia (the hallmark - muscle weakness, respiratory failure, cardiac failure, arrhythmias, rhabdomyolysis, confusion), hypokalaemia, hypomagnesaemia, fluid retention, Wernicke's encephalopathy.
• High risk (NICE CG32): BMI <16, unintentional weight loss >15% in 3–6 months, little or no intake for >10 days, or low K⁺/PO₄/Mg before feeding; or two of: BMI <18.5, weight loss >10%, little intake for >5 days, history of alcohol misuse or drugs such as insulin, chemotherapy, antacids or diuretics.
• Prevention: start feeding at no more than 10 kcal/kg/day (5 kcal/kg/day if extreme risk), increase slowly over 4–7 days; give thiamine and vitamin B before and during feeding; monitor and replace phosphate, potassium and magnesium daily.

Thermoregulation

• Core temperature about 36.5–37.5°C; lowest in the early morning, highest in the late afternoon; rises about 0.5°C after ovulation.
• Control centre - the hypothalamus (preoptic area) compares core and skin temperature with a set point.
• Heat production: basal metabolism, muscle activity, shivering, non-shivering thermogenesis (brown fat in neonates - uncoupling protein-1), thyroid hormones.
• Heat loss: radiation (about 60% at rest), conduction, convection, evaporation (sweating - the only mechanism when ambient temperature exceeds skin temperature), respiration.
• Responses to heat: cutaneous vasodilation, sweating (sympathetic cholinergic fibres), behaviour. Responses to cold: vasoconstriction, shivering, piloerection, behaviour.
• Vulnerable groups: neonates (large surface area, little insulation), older people (impaired sensation, shivering and vasoconstriction; drugs), people with autonomic neuropathy, hypothyroidism, alcohol and sedative use.

Fever, Hyperthermia and Hypothermia

• Fever - the hypothalamic set point is raised by pyrogens (IL-1, IL-6, TNF-α → prostaglandin E₂); the body actively warms itself (rigors, shivering). Antipyretics (paracetamol, NSAIDs) inhibit prostaglandin synthesis.
• Hyperthermia - core temperature rises with a normal set point because heat production or gain exceeds loss: heatstroke (core >40°C with CNS dysfunction - classic in older people during heatwaves; exertional in young people), neuroleptic malignant syndrome (antipsychotics - rigidity, high CK), serotonin syndrome (clonus, hyperreflexia), malignant hyperthermia (volatile anaesthetics or suxamethonium - RYR1 mutation; treat with dantrolene), thyroid storm, sympathomimetic drugs (MDMA, cocaine). Antipyretics do not work - use active cooling.
• Hypothermia - core <35°C: mild 32–35°C (shivering, confusion), moderate 28–32°C (shivering stops, arrhythmias, J (Osborn) waves on ECG), severe <28°C (coma, VF risk, apparent death).
• Management of hypothermia: handle gently (VF risk), remove wet clothing, passive then active rewarming (warm fluids, forced-air warming; ECMO in arrest); during cardiac arrest withhold adrenaline below 30°C and give at double intervals between 30–35°C; limit shocks to 3 below 30°C; "not dead until warm and dead".

At a Glance

Concept	Remember
Primary failure	Low target hormone, high trophic hormone
Excess → suppress	Dexamethasone (Cushing's), OGTT (acromegaly), saline (Conn's)
Deficiency → stimulate	Synacthen (Addison's), ITT/glucagon (GH)
Adrenal cortex	Glomerulosa - aldosterone; fasciculata - cortisol; reticularis - androgens
Insulin vs C-peptide	High insulin + low C-peptide = exogenous insulin
Refeeding	Hypophosphataemia; start ≤10 kcal/kg/day; thiamine
Fever vs hyperthermia	Raised set point vs failed heat loss
Hypothermia arrest	No adrenaline below 30°C

Spot the Diagnosis

• Hypoglycaemic nurse with high insulin and undetectable C-peptide. → Exogenous insulin administration.
• Low cortisol, high ACTH, hyperkalaemia and pigmented palmar creases. → Primary adrenal insufficiency (Addison's disease).
• Phosphate 0.3 mmol/L and breathlessness 3 days after starting NG feeding in an alcohol-dependent man. → Refeeding syndrome.
• Temperature 41°C, rigidity and CK 25,000 in a patient started on haloperidol. → Neuroleptic malignant syndrome.
• Galactorrhoea and amenorrhoea in a woman on risperidone. → Drug-induced hyperprolactinaemia (dopamine D2 antagonism).

Exam-style Scenarios

• Scenario. A 45-year-old has central obesity, purple striae and hypertension. Midnight salivary cortisol is raised and cortisol fails to suppress after 1 mg dexamethasone. ACTH is undetectable. Where is the lesion?
  Answer: ACTH-independent Cushing's syndrome - an adrenal adenoma or carcinoma (cortisol suppresses ACTH). Next step is adrenal CT.
• Scenario. A patient on long-term prednisolone 20 mg daily is admitted with vomiting and hypotension after stopping it abruptly. What is the physiology and treatment?
  Answer: Secondary adrenal insufficiency from HPA axis suppression - the adrenals cannot produce enough cortisol. Give IV/IM hydrocortisone 100 mg immediately and IV fluids, then a maintenance regimen; aldosterone production is preserved (no hyperkalaemia).
• Scenario. An 85-year-old is found at home with a core temperature of 29°C and is in VF. How does management differ from normothermic arrest?
  Answer: Handle gently, start CPR and active rewarming (ideally ECMO/ECLS if available); give up to 3 shocks, withhold adrenaline until the temperature is above 30°C, then double the interval between doses until 35°C; continue resuscitation until rewarmed.

Key Points

• Primary gland failure gives high trophic hormone; secondary failure gives low or normal trophic hormone.
• Suppress suspected excess; stimulate suspected deficiency.
• Only free hormone is active - binding proteins change with oestrogen and illness.
• C-peptide distinguishes endogenous from exogenous insulin.
• Refeeding syndrome is prevented by slow feeding, thiamine and phosphate monitoring.
• Fever raises the set point; hyperthermia overwhelms a normal set point - antipyretics will not help.

Guidelines and Further Reading

• Society for Endocrinology: Endocrine emergency guidance (adrenal crisis); NHS Steroid Emergency Card
• NICE CG32: Nutrition support for adults (refeeding syndrome)
• Resuscitation Council UK: Special circumstances - hypothermia (2025 guidelines)
• Joint British Diabetes Societies: Management of DKA and HHS in adults
• Greenspan's Basic and Clinical Endocrinology