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Glucocorticoids The Adrenal Gland Produces corticosteroids and catecholamines Adrenal gland is divided into two regions: o Adrenal medulla synthesises and secretes catecholamines o Adrenal cortex synthesises and secretes steroid hormones, divided into three separate zones, each of which produces dif...

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Glucocorticoids The Adrenal Gland - Produces corticosteroids and catecholamines - Adrenal gland is divided into two regions: o Adrenal medulla = synthesises and secretes catecholamines o Adrenal cortex = synthesises and secretes steroid hormones, divided into three separate zones, each of which produces different steroids. Zona glomerulosa = mainly aldosterone, Zona fasciculate = mainly cortisol, Zona reticularis = mainly sex steroids Adrenal Gland Regulation Corticosteroids - Mineralocorticoid production is regulated by the renin-angiotensin-aldosterone (RAA) system - Glucocorticoid and adrenal sex steroid hormone production is under the control of the hypothalamic-pituitary-adrenal (HPA) axis o Hypothalamus releases corticotropin-releasing hormone (CRH) in response to stress. This stimulates the production of adenocrticotropic hormone (ACTH). ACTH is released by the corticotrope cells of the anterior pituitary then this promotes cortisol synthesis - CRH and ACTH are released in a pulsatile manner - Their release follows a circadian rhythm under the control of the hypothalamus - SO adrenal cortisol secretion also exhibits a distinct circadian rhythm o Peak levels in the morning o Low levels in the evening - This relationship is exploited for diagnostic and therapeutic purposes o Given in the MORNING and at latest, the EARLY AFTERNOON to avoid disturbances in sleep

Corticosteroids The Role in the Body - Regulate the 3 S’s o SALT = Mineralocorticoids o SUGAR = Glucocorticoids o SEX = Gonadocorticoids

Glucocorticoids Physiology - Exert effects on almost every organ system - Increase our ability to resist stressors o Respond to noxious stimuli and environmental changes - Involved with constitutive functions  homeostatic - Act co-operatively with other chemical mediators to produce responses  permissive effects - Normal cortisol secretion is ~10mg/mL - Diurnal pattern of release: o 8am: ~16mcg/100mL o 4pm: ~4mcg/100mL - Increased during pregnancy and severe stress o At least 10x higher - Thought to be a major signal in initiating labour Mechanism of Action - Act on target tissues through receptor interaction - Carried in the blood attached to plasma proteins  both albumin and corticosteroid binding globulin (CBG) - Generally act by direct gene activation - Glucocorticoids bind intracellular receptors that then dimerise and migrate to the nucleus - In the nucleus, interact with DNA to modify gene transcription  synthesis of some proteins is induced and synthesis of others is inhibited

Mineralocorticoids – Review - Production regulated by the pituitary and the renin-angiotensin-aldosterone (RAA) system o Renin released from the juxtaglomerular cells in the kidney o Renin promotes conversion of angiotensinogen to angiotensin I in the liver o AGI  AGII by ACE o AGII activates the angiotensin II receptor type 1 (AT1 receptor)  aldosterone production and vasoconstriction o Aldosterone  sodium retention and potassium excretion, increased arterial perfusion pressure  regulates renin release Glucocorticoids – Physiologic Effects Effects -

Carbohydrate metabolism Influence protein and fat utilisation Suppress immune and inflammatory responses Influence fluid and electrolyte balance

Effects on CHO Metabolism - Increase blood glucose levels by: o Decreasing glycolysis in muscle o Increasing liver glyconeogenesis (increased gluconeogenesis  AA and fat) - Protects glucose-dependent tissues from starvation o Protects the heart and brain o Promotes the glucose-sparing effect Other Metabolic Effects - Affects fat utilisation o Increase lipogenesis (fat production) and blood cholesterol o Alters total body fat levels  redistributes body fat from extremities to the trunk and head o Increases free fatty acid levels  NOTE this is a permissive effect that requires presence of lipolytic hormones: catecholamines require glucocorticoid Effects on Fluid and Electrolyte Balance - Promotes sodium retention - Promotes potassium loss - Decreases total body calcium  Osteoporosis o Reduce calcium reabsorption from kidneys o Reduce GI absorption of calcium Renal Effects - Permissive role on nephron

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Facilitates glomerular filtration and tubular functions  facilitates the filtration of free water

Endocrine Effects - Inhibit ADH release - Increase parathyroid hormone o Increases bone mineral loss (OP) - Decrease testosterone secretion - Decrease GH (growth hormone) secretion - Decrease LH (luteinising hormone) secretion - Decrease insulin secretion  Diabetes Cardiovascular Effects - Enhances response to noradrenaline and adrenaline (fight of flight) - Increases cardiac output - Increases vascular responses to pressor stimuli  vasoconstriction Nervous System Effects - Increases neuronal excitability o Irritability, mood changes - Can lead to hippocampal cell loss o ? negative effect on memory Effects on Musculoskeletal and GI Systems - Permits normal function of skeletal muscle  steroid myopathy - Breaks down muscle protein to increase blood amino acid levels - Decreases linear growth and skeletal maturation  especially kids  decrease in GH, bone is not resorbed - Increases gastric acid secretion  ulcers Effects on Immune System - Suppresses immune and inflammatory responses o Inhibits production and release of chemical mediators (PGs, cytokines – inhibits production of COX2) o Decreases chemotaxis o Inhibits T-helper cells  transplant patients o Decreases leukocyte migration to site of injury/inflammation o Inhibits fibroblast function  decreases HEALING - Immune effects have traditionally been seen as line between physiological and pharmacological role o Immune suppression has been seen as a pharmacological effect BUT this line is blurred - Immune system modulation is now recognised as a major physiological role of glucocorticoids o Protect against life-threatening consequences of full blown immune/inflammatory response o Vasoactive mediators can lead to cardiovascular collapse Glucocorticoids – Pharmacological Use Pharmacological Use

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Corticosteroids are grouped by: o Anti-inflammatory action o Effects on carbohydrate metabolism o Effects on sodium retention o Duration of action Hydrocortisone (cortisol) is the main natural glucocorticoid o Cortisone is a hydrocortisone prodrug All other CCS’s are synthetic agents modified for: o Increased potency AND/OR o Greater mineralocorticoid activity AND/OR o Longer duration of action

Pharmacology - Choice of agent is based on condition being treated - NOTE diseases are managed NOT cured - Dosage is often trial and error - Consider relative risk vs benefit o Single dose is unlikely to be harmful o Short course (ie. < 7 days) is unlikely to harm - Prolonged therapy may suppress the hypothalamic-pituitary axis (HPA) - Abrupt withdrawal after prolonged treatment can lead to potentially fatal adrenal insufficiency o Why – because nothing is regulating the HPA and the patient can go into acute adrenal insufficiency and all the organs the hormones regulate stop functioning - Common approaches to overcome this: o Short term, alternate day dosing o High-dose “pulse” therapy for three consecutive days Conditions Commonly Managed with Glucocorticoids - Rheumatic Diseases o Short term therapy or o When patient does not respond to first line drug - Allergic conditions o Useful in treating delayed and/or severe responses

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Asthma o IV, oral and inhaled preparations used Infectious disease o AIDS-related pneumonia o Bacterial meningitis in infants Eye conditions o Topical application in eye inflammation o ?? eye infections Skin conditions o Applied as ointment or under an occlusive dressing GI diseases o Inflammatory bowel diseases Malignancies o Particularly useful in leukaemia’s or lymphomas o Have been used in control of cancer related hypercalcaemia o Brain cancer-induced cerebral oedema Organ transplantation

Other Uses - Antepartum to prevent respiratory distress syndrome in premature neonates - To minimise chemotherapy-induced nausea and vomiting

Adrenal Dysfunction: Presentation and Clinical Management The Adrenal Gland – An Overview - CCS are secreted by the adrenal gland - What are the 3 regions of the adrenal cortex? o Zona Glomerulosa o Zona Fasiculata o Zona Reticularis - Which region produces what? o ZG  mineralocorticoids  aldosterone o ZF  glucocorticoids  cortisol AKA hydrocortisone o ZR  sex steroids - What are the hypothalamic signals for secretion? o CRH, ADH - What is the pituitary signal for secretion? o ACTH Corticosteroids – Physiologic Effects Review - Carbohydrate metabolism - Influence fat and protein utilisation - Supress immune and inflammatory responses - Influence fluid and electrolyte balance Adrenal Dysfunction Types - Hypocortical Functioning o Primary – occurring at the primary organ AKA the adrenal gland o Secondary – occurs at the pituitary gland (most common) or the hypothalamus (less common) - Hypercortical Functioning o Primary o Secondary - Congenital Adrenal Hyperplasia (CAH) - Hyperaldosteronism - Phaeochromocytoma Adrenal Dysfunction – Hypocortical Functioning - Also termed adrenal insufficiency - Can be further divided into primary or secondary dysfunction Primary Adrenal Insufficiency - Characterised by o Low cortisol and aldosterone (as is not being produced)

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o High ACTH (as is not being processed) Addison’s Disease o Most commonly autoimmune o Mainly in adults 30 to 60 years old  70% of adult sufferers are female o Rare, potentially fatal o Susceptible to infection and inflammation, can’t respond to stress

Secondary Hypocortisolism - Characterised by: o Low ACTH o Normal aldosterone levels  preserved because of RAA pathway - Pituitary cannot secrete ACTH OR - Chronic exogenous glucocorticoid administration suppresses HPA o Shuts pathway down as there are high levels of glucocorticoids in the blood and the HPA doesn’t know that they are exogenous Hypothalamus

Hypothalamus

Primary

Pituitary

Pituitary

Increased ACTH

Secondary 

Decreased ACTH

Adrenal Cortex

Adrenal Cortex

Glucocorticoid

Mineralocorticoid

Mineralocorticoid

Glucocorticoid

Decreased M&G

Diagnostic Testing - Consider clinical manifestations - Differentiate between problem at the adrenal gland and the pituitary level o Give ACTH  cortisol levels should go up and then down with normal peaks. If they stay high there is no negative feedback (problem with HPA) or could have a tumour Clinical Manifestations - Usually due to hypocortisolism and hypoaldosteronism: o Salt craving  decreased aldosterone  from losing salt o Muscle weakness  decreased BGLs and decreased cortisol o Low BP  decreased aldosterone o Hypoglycaemia  decreased cortisol - Poor responsiveness to stress  no adrenal gland - Anorexia / weight loss - Nausea / vomiting / diarrhoea / abdominal pain - Hyperpigmentation of the skin (sometimes)  due to increased ACTH as stimulates melanocytes - Moodiness / depression

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Altered sexual function (menstrual function and libido affected)  due to decreased androgens

Adrenal versus Pituitary Level Disease - Measure basal cortisol and ACTH levels o Levels expected of primary disease  decreased cortisol and increased ACTH o Levels expected of secondary disease  cortisol increased or decreased and decreased ACTH - Stimulate adrenal gland (with synthetic ACTH) o Normal response is increased ACTH levels o Primary disease = nothing or reduced response o Secondary disease = normal response - CT scan of adrenal glands o Atrophy  hypocortisolism o Hypertrophy  hypercortisolism Treatment - Glucocorticoid replacement therapy: o Hydrocortisone/cortisone/prednis(ol)one/dexamethasone o Possibly mineralocorticoid replacement therapy (in Addison’s)  good as significantly reduces the CCS dose – Fludrocortisone - Long term, daily replacement - Addition hydrocortisone for acute stressors Addison’s Disease - Primary adrenal insufficiency - Currently no cure and can be fatal - Rare - Primarily caused by auto-immune mediated destruction of the adrenal cortex - Signs and symptoms due to decreased production of glucocorticoids, mineralocorticoids and sex hormones (in women as men’s testicles make up for it) Clinical Manifestations - Symptoms are often vague and unspecific o Fatigue, malaise, weight loss, anorexia o Hypotension o Depression o Hyperpigmentation  somewhat reversible on treatment  gums, scar tissue o Amenorrhoea o Reduced libido o Dehydration and salt craving Biochemical Changes - Hypoglycaemia - Hyponatraemia - Hyperkalaemia (potential for DDIs) - Hypercalcaemia - Eosinophilia Management Goals - Restore HPA hormonal balance by replacing glucocorticoids and mineralocorticoids

Mineralocorticoid replacement allows good control at lower glucocorticoid dosage and minimises SE associated with chronic excess glucocorticoids Patients must understand the need for chronic hormonal replacement therapy o

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Management – Pharmacological - Replacement therapy for glucocorticoids and mineralocorticoids o Oral replacement with hydrocortisone tablets  Usually taken twice a day  2/3 in the morning, 1/3 at lunch o If aldosterone is also deficient, it is replaced with oral doses of fludrocortisone acetate (Florinef)  Taken once a day - Indefinite drug therapy is often required Management – Pharmacological – Dose Titration - Glucocorticoid dose is titrated to relieve clinical signs/symptoms and normalise plasma ACTH levels - Mineralocorticoid dose is titrated to relieve postural hypotension, normalise potassium levels and renin activity o Potential DDIs with drugs influencing either potassium retention or secretion - Therapeutic methods to minimise HPA axis suppression o Alternate day dosing o Pulse dosing - Dose increases usually required during periods of intercurrent illness, dental treatment etc where stress levels are higher  DOSE IS DOUBLED o Minimise risk of shock/adrenal crisis o Dose adjustment only required for glucocorticoids  as mineralocorticoids don’t help in stress - Dose will likely need to be increased ~50% in late pregnancy Patient Counselling and Monitoring - Emphasise importance of adhereance - Educate patient and carers about signs and symptoms of adrenal crisis  stress etc - Medic-alert bracelet o Information card with steroid dose and what to do in an emergency - Educate regarding IM hydrocortisone administration in emergencies o Patients in remote areas should carry a hydrocortisone self-injection emergency kit Patient Counselling and Monitoring – During Illness and Stress - Intercurrent illness/fever o Double the usual glucocorticoid dose o Bed rest - Prolonged illness/vomiting/surgery/trauma o Usually require 100mg IM hydrocortisone daily o Check with doctor/surgeon Acute Adrenal Insufficiency Adrenal Crisis - Usually occurs after a prolonged period of nonspecific complaints - Most common in patients with Addison’s disease

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Progressive worsening of symptoms o Postural hypotension  hypovolaemic shock o Abdominal tenderness, nausea, vomiting, fever o Decreased responsiveness  stupor and coma May be triggered by an intercurrent illness, surgical stress and other stress

Adrenal Crisis – Management - Same concepts as for chronic disease but in an emergency situation - Rehydration  hypovolaemic  saline (fluids and sodium) - Glucocorticoid replacement o IV/IM hydrocortisone 100mg stat, then 100-200mg hydrocortisone over the following 24 hours - Mineralocorticoid replacement o Initiate once daily once hydrocortisone dose has been reduced to 99% plasma protein bound  So if the protein levels in the body change there is less free thyroid hormone circulating o Mostly to thyroxine-binding globulin (TBG)  main protein, binds T4 more than T3 o Also to albumin  T3 binds more to this (~20%)  and transthyretin - Circulating thyroid hormone enter cells by passive diffusion (lipophilic) and specific transporters Action - Two thyroid hormone receptors, each with three subtypes o TR𝛼  TRα1 cardiac o TRβ  all subtypes bind T3 - After entering the cells, thyroid hormones act primarily at nuclear receptors o Act by directly activating genes  transcription etc o Induce conformational change  modifies its interactions with accessory transcription factors - Triiodothyronine binds more strongly to target receptors and is 10 times more efficacious o Which is why don’t need as much floating around Regulation – The Thyroid Axis - Involves the hypothalamus, anterior pituitary and thyroid

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Hypothalamus  Thyrotropin-releasing hormone (TRH) Anterior Pituitary  Thyroid Stimulating Hormone (TSH) Thyroid  TSH receptors on the thyroid stimulate hormone synthesis and secretion Negative feedback system

Hypothalamus

TRH

Pituitary

TSH

Thyroid

T4

T3

Regulation - Positive Stimuli (Increased Production) o Increased energy requirements o Pregnancy, cold weather - Negative Stimuli (Decreased Production) o Elevated blood iodide levels o Glucocorticoid, dopamine, sex hormones( at increased levels – therapeutic), somatostatin (inhibits sex hormones and other endocrine hormones) Calcitonin - Lowers blood calcium levels o Inhibits osteoclast activity o Stimulates calcium uptake into bone - Antagonist to parathyroid hormone - Stimulus for release is blood calcium level - Rapid (but short lived) action - Most important time of influence is in childhood when bones are developing Thyroid Hormone – Physiologic Effects Effects - Metabolic Effects o Regulates body temperature and basal metabolic rate (BMR) o CHO/lipid/protein metabolism - CNS effects - Cardiovascular effects - Other effects

Metabolic Effects – General - Thermogenesis/Calorigenesis (Production of heat with no other effect) o Stimulates mitochondria to consume oxygen and produce ATP o Maintains body temperature - Basal metabolic rate maintained/increased Effects on CHO/Protein/Fat Metabolism - Catabolic Actions o Stimulates  GIT absorption of glucose, hepatic glycogenolysis, insulin breakdown (increase BGLs) o Potentiates glycogenolytic actions of adrenaline - Lipolytic Actions o Mobilises fats o Increased oxidation of FFAs  bile salts - Required to protein synthesis - Promotes cholesterol uptake by the liver  maintains normal cholesterol o Increased expression of hepatic LDL receptors and the metabolism of cholesterol to bile acids o Hypothyroidism = increased cholesterol and triglycerides CNS Effects - Critical role in neurogenesis - Promotes myelinogenesis in the brain - Also required for normal protein synthesis; axonal and synaptic development - Important in the first 3 months of life Cardiovascular Effects - Regulates myocardial gene expression - Ionotropic and chronotropic effects: o Induces calcium channel formation of the sarcoplasmic reticulum  more calcium equals increased strength of contractions o Shortens diastolic relaxation time o Enhanced ATPase activity in the myosin  more fuel o Increased sinoatrial node firing  increases heart rate - Direct, non-genomic vasodilation of vascular smooth muscle ( not regulating gene expression, just a direct effect Other Effects - Promotes normal growth and function of muscles and skeleton o Permissive effect on GH - Regulates GI motility and tone  also gastric acid secretion - Promotes normal female reproductive activity and lactation o Hypothyroidism in women of child bearing age can impair fertility

Thyroid Disorders Goitre - An enlarged thyroid gland - Can occur in both hypo- and hyperthyroid states o Hypo  gland working in over drive to find all of the iodine that it can o Hyper  overdrive of hormone = enlarged gland - Some drugs and food components are goitrogenic o Lithium carbonate therapy in bipolar disorders and amiodarone  decrease the synthesis of TSH o Substances in turnip...