Cortisol and the HPA Axis - Podcast Version TeachMePhysiology 0:00 / 0:00 1x 0.25x 0.5x 0.75x 1x 1.25x 1.5x 1.75x 2x The hypothalamic-pituitary-adrenal (HPA) axis is a major neuroendocrine system that regulates responses to physical, emotional, and metabolic stress. It links the hypothalamus, anterior pituitary, and adrenal cortex through a coordinated series of hormonal signals. Within this axis, ACTH from the pituitary stimulates the adrenal cortex to produce cortisol – a hormone involved in metabolism, immune regulation, and stress responses. This article will outline the regulation, functions, and clinical relevance of the HPA axis, including the roles of ACTH and cortisol. Pro Feature - 3D Model You've Discovered a Pro Feature Access our 3D Model Library Explore, cut, dissect, annotate and manipulate our 3D models to visualise anatomy in a dynamic, interactive way. Learn More Regulation of the HPA Axis The HPA axis is regulated through coordinated control at two key levels: hormone release from the hypothalamus and subsequent signalling within the anterior pituitary. Hypothalamic Control The hypothalamus forms the first regulatory step in the HPA axis and initiates the processes that control cortisol secretion. Two key factors stimulate the release of corticotropin-releasing hormone (CRH): Diurnal rhythm – cortisol secretion follows a daily pattern, with levels highest in the early morning and lowest at night. Stressors – physical, emotional, and metabolic stressors such as fear, infection, hypoglycaemia, and blood loss increase the drive for cortisol release at any time. CRH travels through the hypophyseal portal system to the anterior pituitary, where it acts on corticotrope cells and triggers the release of ACTH. Pituitary Control ACTH is produced in pituitary cells via enzymatic processing of pro-opiomelanocortin (POMC) from pre-propiomelanocortin, a large precursor protein synthesised in the corticotrope cells of the anterior pituitary. Cleavage of POMC generates not just ACTH, but also melanocyte-stimulating hormone (MSH), endorphins (endogenous opioids) and enkephalins (peptides that regulate pain and mood). Adrenal Cortex Response ACTH travels in the blood and binds to the melanocortin-2 receptor (MC2r) located on cells in the adrenal cortex, the more superficial part of the adrenal gland. MC2r activation stimulates the synthesis and release of glucocorticoids (steroid hormones) such as cortisol and adrenal androgens from the zona fasciculata and zona reticularis of the adrenal cortex, respectively. The zona glomerulosa primarily produces aldosterone and is regulated mainly by the renin-angiotensin-aldosterone system, not ACTH. Negative Feedback of Cortisol Cortisol suppresses: CRH release from the hypothalamus ACTH release from the anterior pituitary (by reducing sensitivity to CRH) This allows cortisol to suppress its own release, allowing homeostasis to be maintained under normal physiological conditions. Created in BioRender Fig 1The HPA axis. Mechanism of Action of Cortisol Cortisol is lipophilic enough to cross phospholipid plasma membranes. In target cells, cortisol binds intracellularly to the glucocorticoid receptor (GR) in the cytoplasm. Without cortisol, the GR is bound to a chaperone and unable to translocate (enter) into the nucleus. When cortisol binds to the GR, the chaperone dissociates, allowing the cortisol-GR complex to move into the nucleus. Here, it associates with glucocorticoid-response elements (GREs) on DNA to up-regulate or down-regulate gene expression. Functions of Cortisol Cortisol acts on multiple tissues – including the liver, fat, muscle, bone and skin. Its key effects are listed below: Category Target sites Action Overall effect Metabolic Liver Anabolic gluconeogenesis effect Increase plasma glucose Muscle Catabolic proteolytic effect. Amino acids released act as substrates in glucose production Increase plasma glucose Adipose Tissue Catabolic lipolysis effect. Fatty acids released Energy production (beta oxidation) and increase plasma glucose Immune and inflammatory Lymphocytes Reduced activity Immunosuppression/anti-inflammatory effect Cytokines and prostaglandins Reduced production Immunosuppression/anti-inflammatory effect Bones and calcium Trabecular bone Reduced osteoblast (cells that synthesise bone) activity Decreased bone density (when cortisol chronically elevated) Gastrointestinal tract Reduced calcium absorption Reduced plasma calcium Central Nervous System CNS Modulates neural activity Regulation of behaviour, mood, stress responsiveness, and cognition Adobe Stock, Licensed to TeachMeSeries Ltd Fig 2The actions of cortisol within the body. Clinical Relevance Addison’s Disease Addison’s disease is defined as primary adrenal insufficiency. We can compare Addison’s disease with Cushing’s syndrome. Cushing’s syndrome is due to an excess of cortisol, whereas Addison’s disease is due to a lack of cortisol. Addison’s disease is most commonly caused by autoimmune destruction of the adrenal cortex, leading to insufficient cortisol production. Clinical Features: Fatigue Weight loss (due to reduced appetite) Hypotension (due to lack or cortisol and, often, aldosterone) Gastrointestinal changes (such as vomiting or diarrhea) Hyperpigmentation (particularly in palmar creases and oral mucosa). This is due to the HPA axis, whereby low cortisol levels increase ACTH production. ACTH and melanocyte stimulating hormone (MSH) share the same precursor (POMC). Therefore, increased ACTH also means increased MSH, which stimulates melanocytes, leading to hyperpigmentation. Addisonian Crisis Addisonian crisis is a life-threatening complication of Addison’s disease. Cortisol is linked to the “fight or flight” response and is released in times of stress to the body. Patients with Addison’s disease are unable to mount an adequate response to these stressors. This can result in numerous symptoms such as severe hypotension, shock and electrolyte imbalance. Do you think you’re ready? Take the quiz below Pro Feature - Quiz Cortisol and the HPA Axis Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePhysiology Pro Challenge yourself with over 2100 multiple-choice questions to reinforce learning Learn More Rate This Article