The endocrine system consists of ductless glands (hypothalamus, pituitary, pineal, thyroid, parathyroids, adrenals, pancreatic islets, gonads) and diffuse endocrine cells in organs whose main job is something else: atrial myocytes (atrial natriuretic peptide), renal interstitial fibroblasts and juxtaglomerular cells (erythropoietin, renin, calcitriol), enteroendocrine cells of the gut (gastrin, secretin, cholecystokinin, ghrelin, GLP-1), adipocytes (leptin), thymic epithelium (thymosins) and the placenta (hCG, progesterone, estrogens). Hormones are secreted into interstitial fluid, diffuse into fenestrated capillaries and reach almost every cell, but only cells that express the matching receptor respond. Local variants of the same idea are paracrine (acting on neighbouring cells, e.g. somatostatin within an islet), autocrine (acting on the secreting cell itself) and neuroendocrine signalling (neurons releasing hormones into blood, e.g. ADH and oxytocin).
Compared with the nervous system, endocrine control is slower in onset (seconds to days), longer lasting and broadcast rather than point-to-point. The two systems are tightly fused at the hypothalamus, which integrates limbic, circadian, osmotic, thermal and metabolic information and converts it into hormonal output. Parvocellular hypothalamic neurons release releasing and inhibiting hormones (TRH, CRH, GnRH, GHRH, somatostatin, dopamine) into the hypophyseal portal system, which delivers them in high concentration to the anterior pituitary; this responds with six tropic hormones (TSH, ACTH, FSH, LH, GH, prolactin) that drive peripheral glands. Magnocellular neurons instead send their axons down the pituitary stalk and release ADH and oxytocin directly from the posterior pituitary.
Most hierarchical axes (hypothalamic–pituitary–thyroid, –adrenal, –gonadal and the GH–IGF-1 axis) are stabilised by negative feedback: the final hormone inhibits secretion at both the pituitary and hypothalamus (long-loop feedback), and pituitary hormones may inhibit the hypothalamus (short-loop feedback). Many glands sit outside this hierarchy and respond directly to the variable they control: parathyroid chief cells to ionised calcium, β cells to glucose, zona glomerulosa cells to potassium and angiotensin II, atrial myocytes to stretch. The adrenal medulla and, partly, the islets are driven by autonomic nerves. Rare positive-feedback loops produce explosive, self-terminating events: the mid-cycle LH surge, oxytocin release during labour (Ferguson reflex) and the milk-ejection reflex.
Hormone chemistry predicts behaviour. Peptide and protein hormones (the majority, plus the catecholamines) are water-soluble, stored in secretory granules, travel free in plasma, have half-lives of minutes and bind cell-surface receptors that signal through second messengers (cAMP, IP₃/DAG–Ca²⁺, cGMP) or kinase cascades — effects are fast. Steroid hormones (cortisol, aldosterone, sex steroids, calcitriol) are synthesised from cholesterol on demand rather than stored, circulate bound to carrier proteins, cross membranes and act on intracellular nuclear receptors that alter gene transcription — effects take hours but persist. Thyroid hormones, though amines, behave like steroids (protein-bound, long half-life, nuclear receptors). Only the free fraction of a hormone is biologically active.
The effective strength of a hormonal signal depends on its secretion rate (often pulsatile or circadian: GnRH pulses every 60–120 min, cortisol peaking on waking, GH surging in slow-wave sleep), binding-protein levels, metabolic clearance by liver and kidney, peripheral activation (T4 → T3, testosterone → DHT, 25-hydroxyvitamin D → calcitriol) and receptor number (up- and down-regulation). Hormones also interact: permissive (cortisol and thyroid hormone allow catecholamines to act fully), synergistic (FSH plus testosterone for spermatogenesis) and antagonistic (insulin versus glucagon, PTH versus calcitonin).
Endocrine disease is therefore usually a problem of excess (adenoma, hyperplasia, stimulating antibodies, ectopic secretion), deficiency (autoimmune destruction, infarction, surgery, enzyme defects) or resistance (receptor or post-receptor defects, as in type 2 diabetes). Diagnosis pairs each hormone with its controller to locate the lesion — a high TSH with low T4 points to a primary thyroid failure, low TSH with low T4 to the pituitary — and uses dynamic tests: stimulate when you suspect deficiency (short Synacthen test) and suppress when you suspect excess (dexamethasone suppression, oral glucose suppression of GH).
Development
Endocrine glands arise from all three germ layers. The anterior pituitary develops from Rathke's pouch, an upgrowth of oral (stomodeal) ectoderm in week 3–4 that loses its connection with the mouth; remnants can form craniopharyngiomas (calcified suprasellar tumours of children). The posterior pituitary grows down from the floor of the diencephalon (neuroectoderm) as the infundibulum. The thyroid begins as an endodermal diverticulum at the foramen caecum of the tongue (week 3–4) and descends in front of the pharyngeal gut, remaining attached by the thyroglossal duct — persistent remnants give midline thyroglossal cysts that move upward on tongue protrusion, and failed descent gives a lingual thyroid. Parafollicular C cells are neural-crest cells delivered by the ultimobranchial body (4th/5th pouch). The inferior parathyroids arise from the 3rd pharyngeal pouch together with the thymus and migrate further (so they are more variable and may lie in the mediastinum); the superior parathyroids arise from the 4th pouch. The adrenal cortex forms from intermediate mesoderm (coelomic epithelium near the gonadal ridge); the large fetal zone produces DHEA-S that the placenta converts to estriol and involutes after birth. The adrenal medulla is neural crest (modified sympathetic neurons). Islet cells differentiate from pancreatic endoderm and secrete insulin from ≈10 weeks; maternal hyperglycaemia causes fetal hyperinsulinaemia, macrosomia and neonatal hypoglycaemia. The pineal gland is an outgrowth of the diencephalic roof (epithalamus).