Lecture 7.1 - The Adrenal Glands PDF

Adrenal glands (suprarenal glands): ◦Adrenals - pair of multifunctional endocrine glands ◦Located above the upper poles of the kidneys (suprarenal glands) - lie against the diaphragm in the retroperitoneal space ‣ Adjacent to kidneys, hence why they are called adrenal ◦Small...

Adrenal glands (suprarenal glands): ◦Adrenals - pair of multifunctional endocrine glands ◦Located above the upper poles of the kidneys (suprarenal glands) - lie against the diaphragm in the retroperitoneal space ‣ Adjacent to kidneys, hence why they are called adrenal ◦Small in size ~4g each (slightly less in women) ◦Extensively vascularised (receive blood supply also directly from the aorta - blood drains through the suprarenal vein to the left renal vein or directly to the inferior vena cava on the right) ◦The adrenal glands are necessary for life - damage of both adrenals is rapidly fatal (non-compatible with life) ‣ No other organ except the brain is as well protected from interruptions of the blood supply ‣ Associated with fight or flight ◦Cortex is the most important physiological aspect of adrenal gland ◦GFR acronym to remember structures of adrenal gland (Zona glomerulosa, Fasiculata and reticularis (mesh-like)) Adrenal cortex - steroid hormones: ◦Steroid hormones are synthesised from cholesterol in the adrenal glands and gonads ◦Lipid soluble hormones ◦Bind to INTRAcellular receptors of the nuclear receptor family to modulate gene transcription ‣ Mineralocorticoids (from zona glomerulosa) ‣ Glucocorticoids (from zona fasiculata) ‣ Androgens (from zona reticularis) ‣ Oestrogens ‣ Progestins ◦Steroid hormones are synthesised from cholesterol in the adrenal glands and gonads  ◦Steroid hormones act by regulating gene transcription: ‣ Steroid hormones diffuse across the plasma membrane ‣ Bind to intracellular receptors of the nuclear receptor family once inside the cell ‣ Binding causes dissociation of chaperone proteins (e.g. heat shock protein 90) ‣ Receptor-ligand complex translocates to nucleus ‣ Dimerisation with other receptors can occur ‣ Receptors bind to response elements (e.g. glucocorticoid response elements; GREs), or other transcription factors Glucocorticoids are tissue-specific Adrenal cortex - aldosterone: ◦Aldosterone: ‣ The most abundant mineralocorticoid ‣ Synthesised and released by zona glomerulosa of the adrenal cortex ‣ Lipophilic and so in blood binds mainly to serum albumin (binds to fatty complexes) and to a lesser extent corticosteroid-binding globulin (CBG) Dissolves in fat ‣ Has intracellular receptors (aldosterone receptors: nuclear mineralocorticoid receptors) ‣ Plays central role in the regulation of plasma Na+, K+ and arterial blood pressure and is a key component of the renin-angiotensin- aldosterone system (RAAS) ‣ Mainly acts in the distal tubules and collecting ducts of nephrons in the kidney where it promotes expression of Na+/K+ pump, causing reabsorption of Na+ and excretion of K+, thereby influencing water retention, blood volume and thus, blood pressure Renin-angiotensin-aldosterone system: ◦RAAS regulates plasma sodium concentration and arterial blood pressure ◦If plasma Na+ or the kidney blood flow falls, the juxtaglomerular cells (close to glomerulus in kidney) of the nephrons are activated and release the enzyme renin into the general circulation ◦Blood pressure drop or blood volume loss (e.g. haemorrhage or dehydration) can also simulate the release of renin via baroreceptors in the carotid sinus which detect these changes and increase the sympathetic tone to the kidney ◦Renin in the plasma can act on its target protein angiotensinogen (angiotensinogen is a globular protein released into the blood by the liver - by itself it doesn't do anything) ◦Renin cleaves angiotensin I from angiotensinogen (biologically inactive peptide of 10 amino acids at this point) ◦Angiotensin I is further cleaved to Angiotensin II (2 amino acids are removed) by the angiotensin-converting enzyme (ACE) primarily within the capillaries of the lungs - makes it biologically active ◦Angiotensin II is the biologically active product of the RAAS ‣ Condition known as sarcoidosis linked ◦Angiotensin II: ‣ A potent vasoconstrictor causing arterioles to constrict resulting in increased arterial blood pressure ‣ Stimulates the adrenal cortex to secrete aldosterone Aldosterone acts on the distal tubules and collecting ducts of nephrons in the kidney to cause increased reabsorption of Na+ and water back into the blood and increased secretion of K+ into urine resulting in increased blood volume and pressure ‣ Increases the release of antidiuretic hormone (ADH) from the posterior pituitary ADH complements the actions of aldosterone in the kidney by inducing translocation of aquaporin water channels in the plasma membrane of the collecting duct cells allowing more reabsorption of water back into the blood (retention of water in the body)  ◦All of these mechanisms lead to the final result of increasing blood pressure and blood volume ◦Overactive RAAS can result in high blood pressure (hypertension), so drugs blocking RAAS can be used to lower blood pressure ◦Drugs acting at the RAAS: ‣ Inhibitors of the angiotensin-converting enzyme (ACE inhibitors) reduce the formation of angiotensin II and are the most widely used ‣ Angiotensin II receptor blockers (ARBs) can be also used to block the actions of angiotensin II ‣ Inhibitors of renin (direct renin inhibitors) Adrenal cortex - cortisol: ◦Cortisol: ‣ The primary glucocorticoid hormone in humans (most abundant corticosteroid, accounting for ~95% of glucocorticoid activity) ‣ Synthesised and released by zona fasiculata in response to ACTH ‣ Inhibits CRH and ACTH release via negative feedback to hypothalamus and anterior pituitary (HPA axis - hypothalamic-pituitary-adrenal axis) Regulated through negative feedback system Cortisol is also under negative feedback system ‣ Lipophilic -> in blood is mainly (~90%) bound to corticosteroid-binding globulin (CBG; transcortin), and ~10% bound to serum albumin ‣ Acts via glucocorticoid receptors (intracellular receptors of the nuclear receptor family) which exert their actions by regulating gene transcription ◦HPA axis and control of cortisol secretion: ‣ Stress, such as: Physical (temperature, pain), chemical (hypoglycaemia), emotional, induce the release of CRH and activate the HPA axis ‣ In disease, these mechanisms are impaired ◦ACTH synthesis: ‣ ACTH (39 amino acids) derived from pro-opiomelanocortin (POMC ~250 amino acids) ‣ Alpha-melanocyte stimulating hormone (alpha-MSH; 13 amino acids) is contained within the ACTH sequence in POMC giving ACTH some MSH-like activity when present in excess  ‣ ACTH is responsible for secretion of cortisol from adrenal gland ◦ACTH actions: ‣ ACTH is hydrophilic and acts on high affinity G-protein coupled receptors (GPRCs) on the plasma membrane of target cells in the zona fasciculata and reticularis ‣ GPRCs for ACTH are a type of melanocortin receptor (melanocortin receptor type 2; MC2; also called the corticotropin receptor) which use cAMP as a second messenger (the mechanism of action of ACTH is different to that of steroid hormones, such as cortisol) ‣ ACTH binding to its receptors leads to activation of cholesterol esterase, increasing the conversion of cholesterol esters to free cholesterol, and also stimulates other steps in the synthesis of cortisol from cholesterol ‣ ACTH over-secretion has clinical consequences relating to: ACTH effects on the adrenal cortex which cause adrenal hyperplasia and over-production of cortisol Direct effects of ACTH on other tissues (increased pigmentation due to partial MSH activity) ‣ ACTH under-secretion causes symptoms related to the lack of glucocorticoids, but not those related to lack of minerocorticoids as aldosterone secretion is normal (not controlled by ACTH) ◦ACTH secretion: ‣ ACTH has a short half-life in the circulation (T 1/2 = 4-8 min) ‣ ACTH is released in pulses that follow a circadian rhythm ‣ ACTH peak plasma levels occur early in the morning and lowest levels (nadir) late in the evening ‣ Cortisol secretion follows the ACTH circadian rhythm, so cortisol plasma levels vary during the day and peak at about 7am to a nadir at about 7pm ‣ For this reason, the time should be noted when taking a sample of blood for cortisol measurement and repeated measurements should be taken at the same time of day ◦Cortisol actions on metabolism - different effects in different tissues: ‣ Increased proteolysis in most tissues (e.g. in muscles) but not liver ‣ Increased gluconeogenesis and glycogenolysis in the liver Glucose is also vital for the brain ‣ Increased lipolysis in adipose tissue (chronic high levels of cortisol can increase lipogenesis in adipose tissue and cause adipose tissue redistribution (in unusual situations), favouring abdominal obesity) Patients likely to have fat around the abdomen, puffy face etc ‣ Decreased amino acid uptake ‣ Decreased protein synthesis ‣ Decreased peripheral uptake of glucose (counter-regulatory hormone to insulin) ◦Cortisol additional actions: ‣ Primary stress hormone - resistance to stressors (e.g. increased supply of glucose, raised blood pressure by making vessels more sensitive to vasoconstriction) ‣ Anti-inflammatory effects - inhibits macrophage activity and mast cell degranulation (e.g. prescribed for allergic reactions) Explanation for why steroids are used to treat patients ‣ Immunosuppressive effects (prescribed to organ transplant patients) - do not want immune system to be overactive and reject organ  ‣ Decreases osteoblast function and decreases new bone formation (excess glucocorticoids can cause osteoporosis - bone mass is lost) ‣ CNS effects - excess cortisol can alter the excitability of neurones; induce neuronal death (particularly in the hippocampus), loss of neuron-neuron interactions; loss of memory and ability to learn new things; and affect mood and behaviour (e.g. cause depression) Adrenal cortex - androgens: ◦Dehydroepiandrosterone (DHEA) and androstenedione are weak androgens (in comparison to adrenaline or oestrogen) which are secreted by the innermost layer of adrenal cortex (zona reticularis) ◦Partially regulated by ACTH and CRH ◦In males - DHEA is converted to testosterone in the testes (after puberty this is insignificant, since the testes release far more testosterone themselves) ◦In females - adrenal androgens promote libido and are converted to oestrogens by other tissues - after menopause this is only source of oestrogens since the ovaries are no longer functional ◦Promote axillary and pubic hair growth in both sexes (secondary characteristics) Adrenal medulla: ◦Adrenal medulla is a modified sympathetic ganglion of the autonomic nervous system (ANS) ◦Chromaffin cells in the adrenal medulla lack axons, but act as postganglionic nerve fibres which release catecholamines into the circulation: ‣ Adrenaline (~80%) - used to treat anaphylaxis, since it causes vasoconstriction ‣ Noradrenaline (~20%) ◦Catecholamine actions: ‣ Adrenaline and noradrenaline stimulate G-protein coupled receptors (GPCRs) - the response of the target cell depends on the type of the expressed adrenergic receptor ‣ There are two main types of adrenergic receptors: Alpha type has two subtypes: ◦Alpha 1 receptors facilitate an increase in intracellular Ca2+ by coupling to Galpha q ◦Alpha 2 receptors facilitate a decrease in the intracellular second messenger cAMP by the inhibitory G protein G alpha i Beta type has three subtypes (Beta 1,2 and 3): all promote increase in cAMP by coupling to the stimulatory G protein G alpha s ‣ Adrenaline and noradrenaline are secreted in response to stressful situations and are released as part of the "fight or flight" response ‣ Adrenaline and noradrenaline have effects on the: Cardiovascular system (increased cardiac output, increased blood supply to skeletal muscles) Central nervous system (increased mental alertness) Carbohydrate metabolism (increased glycogenolysis in liver and skeletal muscles) Lipid metabolism (increased lipolysis in adipose tissue)