Endocrine System
The endocrine system is the body's distributed long-range chemical signalling network — specialised secretory cells, tissues, and glands releasing hormones into blood to regulate distant target organs. It encompasses peptide hormones (insulin, GH, PTH, ADH, glucagon), steroid hormones (cortisol, aldosterone, sex steroids, calcitriol), and tyrosine-derived hormones (thyroid hormones, catecholamines). Three master neuroendocrine axes — HPA (cortisol/stress), HPT (thyroid/metabolism), and HPG (sex steroids/reproduction) — are governed by the hypothalamus via portal blood to the anterior pituitary. The endocrine system is deeply integrated with the nervous system, immune system, and cardiovascular/renal systems.
Overview
Endocrine signalling differs from nervous system signalling in three key ways: blood-borne (systemic reach vs. point-to-point), slow onset and prolonged duration (minutes to hours vs. milliseconds), and diverse targets (every cell type with the relevant receptor, not a single post-synaptic cell). This makes hormones ideal regulators of long-term adaptive processes — growth, reproduction, metabolic set point, and stress responsiveness — rather than moment-to-moment reflexes.
The endocrine system does not operate in isolation. The hypothalamus is simultaneously a brain region and the neuroendocrine master controller — receiving cortical, limbic, brainstem, retinal, and peripheral sensor inputs and translating them into trophic hormone pulses to the anterior pituitary. The immune system is regulated by cortisol (HPA axis) and sex steroids, while cytokines (IL-1β, IL-6) activate the HPA axis. The cardiovascular and renal systems are governed by aldosterone (RAAS), ANP/BNP (heart), ADH (posterior pituitary), and EPO (kidney).
Key Endocrine Components
| Gland / Tissue | Key hormones | Primary regulated process |
|---|---|---|
| Hypothalamus | CRH, TRH, GnRH, GHRH, somatostatin, dopamine, ADH/AVP, oxytocin | Neuroendocrine master controller; parvocellular → portal blood; magnocellular → posterior pituitary |
| Anterior pituitary | GH (50%), ACTH (20%), prolactin (15%), LH/FSH (10%), TSH (5%) | Drives all four peripheral endocrine axes (adrenal, thyroid, gonadal, growth); IGF-1 via GH/liver |
| Posterior pituitary | ADH/AVP, oxytocin | Water reabsorption (V2R → AQP2), vasoconstriction (V1aR), uterine contraction, milk ejection, bonding |
| Thyroid gland | T3, T4, calcitonin | Basal metabolic rate, cardiac output, CNS myelination, thermogenesis, bone turnover |
| Parathyroid glands (×4) | PTH | Serum Ca²⁺ (↑bone resorption, ↑renal Ca²⁺, ↑calcitriol synthesis) |
| Adrenal cortex | Aldosterone (ZG), cortisol (ZF), DHEA/DHEAS (ZR) | Na⁺/K⁺ balance, gluconeogenesis/stress/immunity, adrenarche/sex steroids |
| Adrenal medulla | Epinephrine (~80%), norepinephrine (~20%) | Acute stress (fight-or-flight): ↑HR, ↑CO, ↑glycogenolysis, ↑lipolysis, ↑alertness |
| Pancreatic islets | Insulin (β), glucagon (α), somatostatin (δ), PP (γ), ghrelin (ε) | Glucose homeostasis (insulin ↓ glucose; glucagon ↑ glucose; GLP-1 incretin) |
| Gonads | Testosterone (Leydig cells), oestradiol + progesterone (granulosa/CL) | Reproduction, secondary sexual characteristics, bone density, anabolism, CVD risk |
| Other sources | Leptin (adipose), ANP/BNP (heart), EPO + calcitriol + renin (kidney), GLP-1/GIP (GI), IGF-1 (liver), melatonin (pineal) | Distributed endocrine — energy balance, volume regulation, erythropoiesis, Ca²⁺, circadian timing |
Hormone Chemistry and Receptor Mechanisms
Peptide / protein hormones
Water-soluble; membrane receptors (GPCRs → cAMP or IP₃/Ca²⁺; RTKs → PI3K/Akt; cytokine receptors → JAK/STAT). Rapid onset (seconds–minutes). Examples: insulin, GH, PTH, LH, FSH, glucagon, prolactin, ACTH, ADH, oxytocin, GLP-1, leptin.
Steroid hormones
Lipophilic; freely cross membranes; nuclear/cytoplasmic receptors (NR superfamily: GR, MR, AR, ERα/β, PR, VDR). Slow onset (hours–days), genomic + rapid non-genomic signalling. Examples: cortisol, aldosterone, testosterone, oestradiol, progesterone, calcitriol.
Tyrosine-derived hormones
Two subtypes: (1) Catecholamines (dopamine, NE, Epi) — water-soluble, membrane α/β-adrenergic GPCRs; (2) Thyroid hormones (T3/T4 — lipophilic, nuclear TRα/TRβ receptors → major genomic effects on BMR, cardiac function, myelination).
Feedback regulation
Most axes operate under negative feedback (HPA: cortisol → ↓CRH/ACTH; HPT: T3 → ↓TSH/TRH; RAAS: ↑BP → ↓renin; Ca²⁺: ↑Ca²⁺ → ↓PTH). Exception: positive feedback — mid-cycle oestradiol surge → LH surge (ovulation); Ferguson reflex (oxytocin + cervical stretch → labour).
Metabolic Coordination — Fed and Fasted States
FED STATE (post-prandial)
↑blood glucose → ↑insulin (β-cells) + GLP-1 (L-cells, ileum)
Insulin effects:
↑GLUT4 in muscle + adipose (glucose uptake)
↑glycogen synthesis (muscle + liver)
↓hepatic gluconeogenesis
↑lipogenesis (adipose), ↓lipolysis
↑protein synthesis
→ blood glucose normalised
FASTED STATE (>4h post-meal)
↓blood glucose → ↓insulin, ↑glucagon (α-cells)
Glucagon effects:
↑hepatic glycogenolysis (PKA → phosphorylase kinase)
↑gluconeogenesis (↑PEPCK, ↑FBPase)
↑lipolysis (PKA → HSL) → ↑FFA → β-oxidation → ketones
After 12–16 h: GH + cortisol amplify lipolysis +
gluconeogenesis
STRESS RESPONSE
CRH → ACTH → cortisol + sympathetic → epinephrine
→ ↑blood glucose + ↑CO + ↑bronchodilation +
↑alertness + ↑pain threshold (fight-or-flight +
HPA co-activation)
Regulatory Mechanisms
The endocrine system uses multiple regulatory strategies beyond simple negative feedback:
| Mechanism | Example |
|---|---|
| Negative feedback | HPA axis: cortisol → ↓CRH (hypothalamus) + ↓ACTH (pituitary). HPT axis: T3 → ↓TSH + ↓TRH. RAAS: ↑BP → ↓renin. Ca²⁺: ↑Ca²⁺ → CaSR → ↓PTH. |
| Positive feedback | Mid-cycle LH surge: oestradiol >200 pg/mL for >36 h → AVPV kisspeptin → positive feedback → 10-fold LH surge → ovulation. Ferguson reflex: oxytocin + cervical stretch → more oxytocin → more contractions (until delivery). |
| Circadian rhythms | Cortisol peak 06:00–08:00 (CRH/ACTH pulses), nadir ~00:00. GH: pulsatile during first hour of slow-wave sleep. LH/FSH: pulsatile (GnRH every 60–90 min follicular, 3–4 h luteal). Melatonin: dusk → peak 02:00–03:00 → suppressed by light. |
| Permissive effects | Cortisol is permissive for catecholamine responsiveness (↑β-AR expression + vascular sensitivity) — explains poor pressor response in Addisonian patients. T3 permissive for GH action on growth. |
| Ultradian pulsatility | GnRH and LH/FSH are secreted in pulses — continuous GnRH downregulates pituitary GnRH-R (basis of GnRH agonist therapy: leuprolide → initial flare → medical castration). |
Pathology
Diabetes Mellitus (T1DM and T2DM)
Most prevalent endocrine disorder (~500 million adults globally). T1DM: autoimmune β-cell destruction (CD8+ CTL; HLA-DR4/DQ8) → absolute insulin deficiency → hyperglycaemia + DKA. T2DM: insulin resistance (↓IRS-1/PI3K/Akt; ↑FFA → DAG → PKC-ε inhibits IR kinase) → compensatory hyperinsulinaemia → progressive β-cell failure (ER stress, IAPP amyloid, IL-1β apoptosis). Key treatments: metformin (AMPK), SGLT2 inhibitors (empagliflozin — ↑glucosuria + cardioprotection), GLP-1 agonists (semaglutide — ↓appetite + ↓weight + ↓glucose), sulfonylureas, insulin.
Cushing's Syndrome
Chronic cortisol excess. Causes: Cushing's disease (pituitary ACTH adenoma, ~70%), ectopic ACTH (SCLC, carcinoid, ~10%), adrenal adenoma/carcinoma (~20%), iatrogenic (most common globally). Features: central obesity (visceral fat ↑, buffalo hump), moon face, purple striae, skin thinning, hypertension, osteoporosis, insulin resistance, proximal myopathy, psychiatric disturbance (depression, psychosis). Diagnosis: 24h urine free cortisol + late-night salivary cortisol + low-dose dexamethasone suppression test.
Addison's Disease (Primary Adrenal Insufficiency)
Autoimmune adrenal cortical destruction (anti-21-hydroxylase antibodies) → ↓cortisol + ↓aldosterone → hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia, hyperpigmentation (↑ACTH → ↑α-MSH → MC1R). Adrenal crisis (severe hypotension, vomiting, collapse) precipitated by stress or illness. Treatment: hydrocortisone + fludrocortisone; double dose sick-day rules; parenteral hydrocortisone for crisis.
Phaeochromocytoma
Chromaffin cell tumour (adrenal medulla or extra-adrenal paraganglioma) secreting catecholamines → paroxysmal hypertensive crises, headache, diaphoresis, palpitations. "Rule of 10s": 10% malignant, 10% bilateral, 10% extra-adrenal, 10% children, 10% familial. Associated with MEN2A/2B (RET), VHL, NF1, SDH mutations. Diagnosis: plasma metanephrines + 24h urine catecholamines. Treatment: α-blockade (phenoxybenzamine) first, then β-blockade, then surgical resection.
Multiple Endocrine Neoplasia (MEN) Syndromes
MEN1 (MEN1/menin): parathyroid adenomas (>95%), pituitary adenomas (prolactinoma), pancreatic NETs (gastrinoma/ZE, insulinoma). MEN2A (RET codon 634): medullary thyroid carcinoma (95%), phaeochromocytoma (50%), primary hyperparathyroidism (25%). MEN2B (RET codon 918): MTC (aggressive/early), phaeochromocytoma, marfanoid habitus, mucosal neuromas, GI ganglioneuromatosis.
Pituitary Adenomas
~10% prevalence on MRI. Prolactinoma (40%): hyperprolactinaemia → amenorrhoea/galactorrhoea (F), hypogonadism/ED (M); treat with dopamine agonists (cabergoline). GH-secreting (15–20%): acromegaly (adults: enlarged hands/jaw, sleep apnoea, CVD) or gigantism (children). ACTH-secreting (10–15%): Cushing's disease. Non-functioning (30–40%): mass effects — bitemporal hemianopia (optic chiasm compression), hypopituitarism.
Cross-Atlas Connections
References
- Hall JE, Hall ME. Guyton and Hall Textbook of Medical Physiology. 14th ed. Elsevier; 2021. elsevier.com
- Berg JM, Tymoczko JL, Stryer L. Biochemistry. 9th ed. W.H. Freeman; 2019. macmillanlearning.com
- IDF Diabetes Atlas. 10th ed. International Diabetes Federation; 2021. diabetesatlas.org
- Nieman LK, et al. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. doi:10.1210/jc.2008-0125
- Thakker RV, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011. doi:10.1210/jc.2012-1230