Cognitive Connie
The Endocrine System, Hormones & Stress Response
The endocrine system communicates through hormones — chemical messengers released by glands into the bloodstream that reach distant target organs and regulate physiology over seconds to hours. Working alongside the nervous system, it governs homeostasis, metabolism, growth, reproduction, and the body's response to stress.
Key figures
Walter Cannon
1871–1945American physiologist who coined "fight or flight" (1915; elaborated in The Wisdom of the Body, 1932) to describe the acute sympathetic response to threat. He also introduced the concept of homeostasis and described the sympatho-adrenal axis. His work established the physiological foundations of stress biology.
Hans Selye
1907–1982Canadian endocrinologist who developed the General Adaptation Syndrome (GAS, 1936): the body's stereotyped three-stage physiological response to prolonged stress (alarm, resistance, exhaustion). He showed that diverse stressors produce similar adrenocortical responses and popularised the concept of stress as a biological phenomenon. His work underpins the modern understanding of the HPA axis and stress-related illness.
Bruce McEwen
1938–2020American neuroendocrinologist who demonstrated that the hippocampus is a major target of glucocorticoids and a key regulator of the HPA axis. He showed that chronic stress causes hippocampal neuronal atrophy and introduced the concepts of allostasis and allostatic load — the cumulative physiological cost of chronic stress adaptation. His 2007 review in Physiological Reviews is a landmark in stress neurobiology.
Key concepts
Endocrine signalling
Communication via hormones released into the bloodstream that travel to distant target tissues. Key properties: slow onset (seconds to hours, limited by circulation time), long duration (minutes to days), wide distribution (all tissues exposed but only those with appropriate receptors respond), and concentration-dependent effects that can be amplified by receptor density and signalling cascades. Contrasts with neural signalling (milliseconds, highly targeted, brief).
Hormone types
Hormones are classified by chemical structure: (1) Peptide/protein hormones (e.g., insulin, ACTH, GH): water-soluble, act on surface receptors, rapid onset via second-messenger cascades; (2) Steroid hormones (e.g., cortisol, aldosterone, oestrogen, testosterone): lipid-soluble, synthesised from cholesterol, cross cell membranes and act on intracellular receptors that directly regulate gene transcription — slower but longer-lasting effects; (3) Amine hormones (e.g., adrenaline, thyroxine): derived from amino acids; adrenaline is water-soluble (surface receptors), thyroxine is lipid-soluble (nuclear receptors).
Hypothalamic-pituitary axis
The master regulatory axis of the endocrine system. Three-tier cascade: Hypothalamus (integrates neural and blood-borne signals) → releases short-range releasing/inhibiting hormones into the portal blood supply → Anterior pituitary releases tropic hormones (ACTH, TSH, GH, FSH, LH, prolactin) into systemic blood → Peripheral glands (adrenal cortex, thyroid, gonads) release effector hormones that act on target tissues and feed back to regulate the axis. The posterior pituitary (ADH, oxytocin) is regulated differently — by direct neural input from hypothalamic nuclei.
Adrenal cortex
The outer region (~80–90%) of the adrenal gland, embryologically derived from mesoderm. Three functional zones: zona glomerulosa → aldosterone (mineralocorticoid: stimulates renal Na+ reabsorption and K+ excretion, raises blood pressure; regulated by angiotensin II and plasma K+); zona fasciculata → cortisol (glucocorticoid: stress response, gluconeogenesis, immune modulation; regulated by ACTH); zona reticularis → DHEA and androstenedione (weak androgens). All cortical hormones are steroids synthesised from cholesterol.
Adrenal medulla
The inner region (~10–20%) of the adrenal gland, embryologically derived from neural crest (same lineage as sympathetic neurons) — effectively a modified sympathetic ganglion that secretes directly into blood. Chromaffin cells receive preganglionic sympathetic input (ACh on nicotinic receptors) and release catecholamines: ~80% adrenaline (epinephrine) and ~20% noradrenaline (norepinephrine) into the bloodstream. The key effector organ of the SAM axis.
Fight-or-flight response (SAM axis)
Walter Cannon's term (first used 1915; elaborated in The Wisdom of the Body, 1932) for the acute physiological response to perceived threat, mediated by the sympatho-adrenal medullary (SAM) axis. Stressor → hypothalamus/brainstem activate sympathetic preganglionic neurons → noradrenaline at target synapses (immediate, milliseconds) + adrenaline and noradrenaline from adrenal medulla into bloodstream (seconds). Effects: ↑ heart rate and cardiac output, vasoconstriction in skin and viscera, vasodilation in skeletal muscle, bronchodilation, ↑ blood glucose (glycogenolysis), pupil dilation, sweating. Peaks within 30 seconds; catecholamines cleared within minutes.
HPA axis
Hypothalamic-pituitary-adrenocortical axis: the slower, sustained arm of the stress response. Stressor → hypothalamic paraventricular nucleus releases CRH → anterior pituitary releases ACTH → adrenal cortex synthesises and releases cortisol. Cortisol peaks at 20–30 minutes; half-life ~90 minutes. Actions: gluconeogenesis and lipolysis (sustained energy), immunosuppression (reduces risk of excessive inflammation), potentiation of fear memory consolidation (amygdala), and negative feedback via glucocorticoid receptors in hypothalamus and pituitary. Chronic HPA hyperactivation causes hippocampal atrophy, immune dysregulation, and metabolic syndrome (McEwen, 2007).
Cortisol
The primary glucocorticoid produced by the adrenal cortex zona fasciculata under ACTH stimulation. Steroid hormone acting via intracellular glucocorticoid receptors (GR) that regulate gene transcription. Acute effects: mobilises energy via gluconeogenesis (new glucose from amino acids and glycerol), lipolysis, and glycogenolysis; immunosuppression (inhibits prostaglandin synthesis, reduces lymphocyte proliferation); potentiates catecholamine actions on blood vessels; enhances memory consolidation for emotional/stressful events. Chronic elevation: hippocampal neuronal atrophy, impaired memory, metabolic syndrome, depression.
Negative feedback in the HPA axis
The self-limiting mechanism that prevents sustained cortisol hypersecretion. Rising cortisol acts on glucocorticoid receptors (GR) in the hypothalamus (reduces CRH secretion) and anterior pituitary (reduces ACTH secretion), progressively turning off its own production. Fast feedback (minutes, membrane-mediated) and slow feedback (hours-days, genomic repression of CRH and POMC genes). Hippocampal GRs provide tonic inhibition of the HPA axis. Chronic stress downregulates hippocampal GRs, impairing feedback and perpetuating cortisol elevation.
Adrenaline and noradrenaline as hormones and NTs
Adrenaline (epinephrine) and noradrenaline (norepinephrine) are catecholamines (derived from tyrosine via dopamine) that function both as neurotransmitters (released at sympathetic synapses and CNS neurons, especially locus coeruleus) and as hormones (released from adrenal medulla). Same molecules, same adrenergic receptors (α1, α2, β1, β2, β3). As NTs: millisecond onset, highly localised, rapid reuptake via NET. As hormones: seconds onset, systemic, cleared by MAO/COMT/reuptake over minutes. Adrenaline has high β affinity (cardiac, bronchial); noradrenaline has high α affinity (vasoconstriction).
Test your knowledge
Frequently asked questions
How does the endocrine system differ from the nervous system in how it communicates?+
The nervous system uses electrical signals (action potentials) and neurotransmitters at synapses for fast (millisecond), highly targeted, and brief communication. The endocrine system releases hormones into the bloodstream for slow (seconds to hours), wide-distribution, long-duration communication that affects any tissue with appropriate receptors. The two systems are deeply intertwined — the hypothalamus translates neural signals into hormonal output — and together constitute the neuroendocrine system. Many molecules (e.g. noradrenaline, vasopressin) act as both neurotransmitters and hormones.
What is the difference between the SAM axis and the HPA axis in the stress response?+
The SAM (sympatho-adrenal medullary) axis is the rapid arm: stressors activate the sympathetic nervous system within seconds, releasing noradrenaline at target synapses and triggering the adrenal medulla to secrete adrenaline and noradrenaline into the bloodstream — producing the classic fight-or-flight state. The HPA axis is slower and sustained: CRH → ACTH → cortisol, with cortisol peaking at 20–30 minutes and a half-life of ~90 minutes. SAM prepares for immediate threat; HPA mobilises energy reserves, modulates immunity, and consolidates fear memories over a longer timescale.
How does negative feedback regulate the HPA axis?+
Rising cortisol acts on glucocorticoid receptors (GR) in the hypothalamus (reducing CRH) and anterior pituitary (reducing ACTH), progressively limiting its own production. The hippocampus, with its dense GR expression, provides additional tonic inhibition. Chronic stress downregulates hippocampal GRs, impairing this feedback and perpetuating elevated cortisol — contributing to hippocampal neuronal atrophy, immune dysregulation, and metabolic syndrome (McEwen, 2007). This mechanism explains why chronic stress produces lasting neurobiological changes even after the stressor resolves.
Why does the adrenal gland have two anatomically and functionally distinct regions?+
The adrenal cortex (outer ~80–90%) is derived from mesoderm and produces steroid hormones (aldosterone, cortisol, DHEA/androstenedione) organised in three functional zones (glomerulosa, fasciculata, reticularis) under hormonal control (angiotensin II, ACTH). The adrenal medulla (inner ~10–20%) is derived from neural crest — the same lineage as sympathetic neurons — and functions as a modified sympathetic ganglion, releasing catecholamines (adrenaline, noradrenaline) directly into the bloodstream in response to preganglionic sympathetic nerve signals. The dual embryological origin means the two regions respond to entirely different regulatory signals and operate on different timescales.
Sources
Last reviewed September 2026- 1.
Cannon, W. B. (1932). The Wisdom of the Body. W. W. Norton.
+About this source
Cannon's foundational work introducing homeostasis and the fight-or-flight response mediated by the sympatho-adrenal medullary axis.
- 2.
Selye, H. (1936). A syndrome produced by diverse nocuous agents. Nature, 138, 32. https://doi.org/10.1038/138032a0
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Selye's original one-page letter describing the general adaptation syndrome — the body's stereotyped three-stage response (alarm, resistance, exhaustion) to diverse stressors.
- 3.
McEwen, B. S. (1998). Stress, adaptation, and disease: Allostasis and allostatic load. Annals of the New York Academy of Sciences, 840, 33–44. https://doi.org/10.1111/j.1749-6632.1998.tb09546.x
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Landmark paper introducing allostasis and allostatic load, and describing cortisol effects on hippocampal structure via the HPA axis.
- 4.
McEwen, B. S. (2007). Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiological Reviews, 87(3), 873–904. https://doi.org/10.1152/physrev.00041.2006
+About this source
Comprehensive review of stress neurobiology including HPA axis regulation, glucocorticoid effects on hippocampus, negative feedback mechanisms, and allostatic load.
- 5.
Sapolsky, R. M. (2004). Why Zebras Don't Get Ulcers (3rd ed.). Henry Holt.
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Accessible but rigorous account of stress biology including the HPA axis, cortisol, adrenaline, and health consequences of chronic stress.
- 6.
Selye, H. (1956). The Stress of Life. McGraw-Hill.
+About this source
Selye's foundational description of the general adaptation syndrome and the adrenocortical stress response.