Corticotropin-releasing hormone (CRH) is a neurotransmitter and peptide hormone. It is generated by cells in the hypothalamic paraventricular nucleus (PVN) and released into the hypothalamo-hypophyseal portal system at the median eminence through neurosecretory terminals of these neurons. Stress causes the release of CRH.The CRH is carried to the anterior pituitary through the hypothalamo-hypophyseal portal system, where it activates corticotrophs to release adrenocorticotropic hormone (ACTH). Cortisol, glucocorticoids, mineralocorticoids, and DHEA are all produced in response to ACTH.Excessive CRH production causes the size and quantity of corticotrophs in the anterior pituitary to expand, which can lead to the creation of a corticotrope tumour that generates too much ACTH.

The adrenal glands produce too little steroid hormones, which causes Addison’s disease. The production of glucocorticoids, mineralocorticoids, and sex steroids are all altered. The most prevalent cause is autoimmune adrenalitis, which accounts for 70-80 percent of cases.It affects more women than males and occurs most frequently between the ages of 30 and 50.The following are some of the clinical signs and symptoms of Addison’s disease:Weakness and sluggishnessHypotension is a condition in which the blood pressure (notably orthostatic hypotension)Vomiting and nauseaLoss of weightAxillary and pubic hair lossDepressionHyperpigmentation is a condition in which a person’s (palmar creases, buccal mucosa and exposed areas more commonly affected)The following are the classic biochemical hallmarks of Addison’s disease:HyponatraemiaHyperkalaemiaHypercalcaemiaHypoglycaemiaAcidosis metabolicaWhen ACTH levels are combined with cortisol levels, it is possible to distinguish between primary and secondary adrenal insufficiency:In primary insufficiency, levels rise.In secondary insufficiency, levels are low or low normal.

Hypothyroidism occurs when there is a deficiency of circulating thyroid hormones. It is commoner in women and is most frequently seen in the age over 60.Iodine deficiency is the commonest cause of hypothyroidism worldwide.In the UK and other developed countries, iodine deficiency is not a problem and autoimmune thyroiditis is the commonest cause.

Cushing’s syndrome is a group of symptoms and signs brought on by long-term exposure to high amounts of endogenous or exogenous glucocorticoids.Iatrogenic corticosteroid injection is the most prevalent cause of Cushing’s syndrome. Cushing’s illness is the second most prevalent cause of Cushing’s syndrome. Cushing’s disease is distinct from Cushing’s syndrome in that it refers to a single cause of the illness, a pituitary adenoma that secretes high quantities of ACTH, which raises cortisol levels.Because cortisol enhances the vasoconstrictive impact of endogenous adrenaline, patients with Cushing’s syndrome are usually hypertensive.Hyperglycaemia (due to insulin resistance) rather than hypoglycaemia is a common symptom.Cortisol levels fluctuate throughout the day, with the greatest levels occurring around 0900 hours and the lowest occurring at 2400 hrs during sleep. The diurnal swing of cortisol levels is lost in Cushing’s syndrome, and levels are greater throughout the 24-hour period. In the morning, levels may be normal, but they may be high at night-time, when they are generally repressed.A dexamethasone suppression test or a 24-hour urine free cortisol collection can both be used to establish the existence of Cushing’s syndrome.

Hormones can be classified into three categories depending on their chemical composition: amines, peptides (and proteins), and steroids. Amines are made up of single amino acids (for example, tyrosine), peptide hormones are made up of peptides (or proteins), and steroid hormones are made up of cholesterol.The table below lists some prominent instances of each of these three hormone classes:1. Peptide hormone: Adrenocorticotropic hormone (ACTH)Prolactin VasopressinOxytocin GlucagonInsulin SomatostatinCholecystokinin 2. Amine hormone:Adrenaline (epinephrine) Noradrenaline (norepinephrine)Dopamine3. Steroid hormone:Mineralocorticoids (e.g. aldosterone)Glucocorticoids (e.g. cortisol)ProgestogensAndrogensOestrogens

Insulin, a peptide hormone, is produced in the pancreas by the beta-cells of the islets of Langerhans.The beta-cells first synthesise an inactive precursor called preproinsulin which is converted to proinsulin by signal peptidases, which remove a signal peptide from the N-terminus. Proinsulin is converted to insulin by the removal of the C-peptide.Insulin has a short half-life in the circulation of about 5-10 minutes.Glucagon and parasympathetic stimulation stimulates insulin release.

Parathyroid hormone (PTH) is a polypeptide containing 84 amino acids. It is the principal controller of free calcium in the body.PTH is synthesised by and released from the chief cells of the four parathyroid glands that are located immediately behind the thyroid gland.PTH is released in response to the following stimuli:Decreased plasma calcium concentrationIncreased plasma phosphate concentration (indirectly by binding to plasma calcium and reducing the calcium concentration)PTH release is inhibited by the following factors:Normal/increased plasma calcium concentrationHypomagnesaemiaThe main actions of PTH are:Increases plasma calcium concentrationDecreases plasma phosphate concentrationIncreases osteoclastic activity (increasing calcium and phosphate resorption from bone)Increases renal tubular reabsorption of calciumDecreases renal phosphate reabsorptionIncreases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (via stimulation of 1-alpha hydroxylase)Increases calcium and phosphate absorption in the small intestine (indirectly via increased 1,25-dihydroxycholecalciferol)

Glucagon is a peptide hormone that is produced and secreted by alpha cells of the islets of Langerhans, which are located in the endocrine portion of the pancreas. The main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading to increases in glycaemia. It provides the major counter-regulatory mechanism to insulin in maintaining glucose homeostasis.Hypoglycaemia is the principal stimulus for the secretion of glucagon but may also be used as an antidote in beta-blocker overdose and in anaphylaxis in patients on beta-blockers that fail to respond to adrenaline. Glucagon then causes:GlycogenolysisGluconeogenesisLipolysis in adipose tissueThe secretion of glucagon is also stimulated by:AdrenalineCholecystokininArginineAlanineAcetylcholineThe secretion of glucagon is inhibited by:InsulinSomatostatinIncreased free fatty acidsIncreased urea productionGlycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy released by this process is used to form ATP and NADH. Glycolysis is inhibited by glucagon, and glycolysis and gluconeogenesis are reciprocally regulated so that when one cell pathway is activated, the other is inactive and vice versa.Glucagon has a minor effect of enhancing lipolysis in adipose tissue. Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into glycerol and free fatty acids. It makes fatty acids available for oxidation.

Glucagon, secreted from the pancreatic islet alpha cells, is considered to be the main catabolic hormone of the body. It raises the concentration of glucose and fat in the bloodstreamThere are five different pancreatic islet cells:Alpha cells (20%) – produce glucagonBeta cells (70%) – produce insulin and amylinDelta cells (<10%) – produce somatostatinGamma cells (<5%) – produce pancreatic polypeptideEpsilon cells (<1%) – produce ghrelin

Parathyroid hormone (PTH), a polypeptide containing 84 amino acids, is the principal hormone that controls free calcium in the body.Its main actions are:Increases osteoclastic activity Increases plasma calcium concentrationDecreases renal phosphate reabsorptionDecreases plasma phosphate concentrationIncreases renal tubular reabsorption of calciumIncreases calcium and phosphate absorption in the small intestineIncreases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol

Cushing’s syndrome is a group of symptoms and signs brought on by long-term exposure to high amounts of endogenous or exogenous glucocorticoids. Cushing’s syndrome affects about 10-15 persons per million, and it is more common in those who have had a history of obesity, hypertension, or diabetes.Cushing’s syndrome has a wide range of clinical manifestations that are dependent on the degree of cortisol overproduction. The appearance might be vague and the diagnosis difficult to detect when cortisol levels are just somewhat elevated. On the other hand, in long-term cases of severely increased cortisol levels, the presentation might be colourful and the diagnosis simple.Cushing’s syndrome has the following clinical features:Obesity and weight growth in the true senseSupraclavicular fat pads are fat pads that are located above the clavicle.Buffalo humpFullness and plethora of the face (‘moon facies’)Muscle atrophy and weakening at the proximal levelDiabetes mellitus, also known as impaired glucose toleranceHypertensionSkin thinning and bruisingDepressionHirsutismAcneOsteoporosisAmenorrhoea or oligomenorrhoeaCortisol levels fluctuate throughout the day, with the greatest levels occurring around 0900 hours and the lowest occurring at 2400 hrs during sleep. The diurnal swing of cortisol levels is lost in Cushing’s syndrome, and levels are greater during the whole 24-hour period. In the morning, levels may be normal, but they may be high at night-time, when they are generally repressed. As a result, random cortisol testing is not an effective screening technique and is not advised.The following are the two most common first-line screening tests:Cortisol levels in the urine are measured every 24 hours.A diagnosis of Cushing’s syndrome can be made if more than two collections measure cortisol excretion more than three times the upper limit of normal.Physical stress (e.g., excessive exercise, trauma), mental stress (e.g., sadness), alcohol or drug misuse, complex diabetes, and pregnancy can all cause false positives.Renal dysfunction, inadequate collection, and cyclical Cushing’s disease can all cause false negatives.The overnight low-dose dexamethasone suppression test (LDDST) involves giving 1 mg of dexamethasone at 11 p.m. and measuring blood cortisol levels at 8 a.m. the next day.Cushing’s syndrome is diagnosed when cortisol is not suppressed to less than 50 nmol/L.It might be difficult to tell the difference between mild Cushing’s disease and normal cortisol production.False positives can occur as a result of depression, severe systemic sickness, renal failure, prolonged alcohol misuse, old age, and the use of hepatic enzyme-inducing medicines, among other things.False negatives are extremely uncommon in Cushing’s disease patients.A characteristic biochemical picture might also be helpful in confirming the diagnosis of Cushing’s syndrome. The following are the primary characteristics:HypokalaemiaAlkalosis metabolique

Cushing’s syndrome is a collection of symptoms and signs caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids.The most common cause of Cushing’s syndrome is the iatrogenic administration of corticosteroids. The second most common cause of Cushing’s syndrome is Cushing’s disease.Cushing’s disease should be distinguished from Cushing’s syndrome and refers to one specific cause of the syndrome, an adenoma of the pituitary gland that secretes large amounts of ACTH and, in turn, elevates cortisol levels. This patient has a diagnosis of Cushing’s disease, and this is, therefore, the underlying cause in this case.The endogenous causes of Cushing’s syndrome include:Pituitary adenoma (Cushing’s disease)Ectopic corticotropin syndrome, e.g. small cell carcinoma of the lungAdrenal hyperplasiaAdrenal adenomaAdrenal carcinoma

Glucagon is a peptide hormone that is produced and secreted by alpha cells of the islets of Langerhans, which are located in the endocrine portion of the pancreas. The main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading to increases in glycaemia. It provides the major counter-regulatory mechanism to insulin in maintaining glucose homeostasis.Hypoglycaemia is the principal stimulus for the secretion of glucagon but may also be used as an antidote in beta-blocker overdose and in anaphylaxis in patients on beta-blockers that fail to respond to adrenaline. Glucagon then causes:GlycogenolysisGluconeogenesisLipolysis in adipose tissueThe secretion of glucagon is also stimulated by:AdrenalineCholecystokininArginineAlanineAcetylcholineThe secretion of glucagon is inhibited by:InsulinSomatostatinIncreased free fatty acidsIncreased urea productionGlycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy released by this process is used to form ATP and NADH. Glycolysis is inhibited by glucagon, and glycolysis and gluconeogenesis are reciprocally regulated so that when one cell pathway is activated, the other is inactive and vice versa.Glucagon has a minor effect of enhancing lipolysis in adipose tissue. Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into glycerol and free fatty acids. It makes fatty acids available for oxidation.

The hormone-active metabolite of vitamin D is 1,25-dihydroxycholecalciferol (commonly known as calcitriol). Its activities raise calcium and phosphate levels in the bloodstream.The following are the primary effects of 1,25-dihydroxycholecalciferol:Calcium and phosphate absorption in the small intestine is increased.Calcium reabsorption in the kidneys is increased.Increases phosphate reabsorption in the kidneys.Increases the action of osteoclastic bacteria (increasing calcium and phosphate resorption from bone)Inhibits the action of 1-alpha-hydroxylase in the kidneys (negative feedback)Thyroid hormone (parathyroid hormone) Calcium reabsorption in the tubules of the kidneys is increased, but renal phosphate reabsorption is decreased.

Cortisol levels fluctuate throughout the day, with the greatest levels occurring around 0900 hours and the lowest occurring at 2400 hrs during sleep.The diurnal swing of cortisol levels is lost in Cushing’s syndrome, and levels are greater throughout the 24-hour period. In the morning, levels may be normal, but they may be high at night-time, when they are generally repressed.

The anterior pituitary gland produces and secretes a peptide hormone called adrenocorticotropic hormone (ACTH) (adenohypophysis). It is secreted in response to the hypothalamus’s secretion of the hormone corticotropin-releasing hormone (CRH).ACTH promotes cortisol secretion via binding to cell surface ACTH receptors in the zona fasciculata of the adrenal cortex.ACTH also promotes the production of beta-endorphin, which is a precursor to melanocyte-releasing hormone (MRH).

When there are excessive levels of aldosterone independent of the renin-angiotensin aldosterone axis, primary hyperaldosteronism occurs. Secondary hyperaldosteronism occurs due to high renin levels.Causes of primary hyperaldosteronism include:Conn’s syndromeAdrenal hyperplasiaAdrenal cancerFamilial aldosteronismCauses of secondary hyperaldosteronism include:Renal vasoconstrictionOedematous disordersDrugs – diureticsObstructive renal artery diseaseAlthough patients are usually asymptomatic, when clinical features are present, classically hyperaldosteronism presents with:HypokalaemiaSodium levels can be normal or slightly raisedHypertensionMetabolic alkalosisLess common, clinical features are:LethargyHeadachesIntermittent paraesthesiaPolyuria and polydipsiaMuscle weakness (from persistent hypokalaemia)Tetany and paralysis (rare)

When there are excessive levels of aldosterone outside of the renin-angiotensin axis, primary hyperaldosteronism occurs. High renin levels will lead to secondary hyperaldosteronism. The classical presentation of hyperaldosteronism when symptoms are present include:HypokalaemiaMetabolic alkalosisHypertensionNormal or slightly raised sodium levels

Glucagon binds to class B G-protein coupled receptors and activates adenylate cyclase, increasing cAMP intracellularly. This activates protein kinase A. Protein kinase A phosphorylates and activates important enzymes in target cells.

Hypocalcaemia occurs when there is abnormally low level of serum calcium ( >2.2 mmol/l) after correction for the serum albumin concentration.Rhabdomyolysis causes hyperphosphatemia, and this leads to a reduction in ionised calcium levels.Patients with rhabdomyolysis are commonly cared for in a high dependency care setting. Addison’s disease, hyperthyroidism, thiazide diuretics and lithium all cause hypercalcaemia.

A history of recent weight loss is very suggestive of an absolute deficiency of insulin seen in type I diabetes mellitus.An age of onset of less than 20 years makes a diagnosis of type I diabetes mellitus more likely. However, an increasing number of obese children and young people are being diagnosed with type II diabetes.Microalbuminuria, peripheral neuropathy, and retinopathy all occur in both type I and type II diabetes mellitus. They are not more suggestive of type I DM.

Hyperthyroidism results from an excess of circulating thyroid hormones. It is commoner in women, and incidence increases with age.Hyperthyroidism can be subclassified into:Primary hyperthyroidism – the thyroid gland itself is affectedSecondary hyperthyroidism – the thyroid gland is stimulated by excessive circulating thyroid-stimulating hormone (TSH).Graves’ disease is the most common cause of hyperthyroidism (estimates are that it causes between 50 and 80% of all cases).Although toxic multinodular goitre, thyroiditis,TSH-secreting pituitary adenoma and drug-induced hyperthyroidism also causes hyperthyroidism, the commonest cause is Graves’ disease.

Insulin is an anabolic hormone. Its actions can be broadly divided into:Lipid metabolismProtein metabolism andCarbohydrate metabolismFor lipid metabolism, insulin:Stimulates lipogenesisInhibits lipolysis by lipaseFor carbohydrate metabolism, insulin:Decreases gluconeogenesisStimulates glycolysisPromotes glucose uptake in muscle and adipose tissuePromotes glycogen storageIncreases glycogenesisDecreases glycogenolysisProtein metabolism:Stimulates protein synthesisAccelerates net formation of proteinStimulates amino acid uptakeInhibits protein degradationInhibits amino acid conversion to glucose

Glucagon is a peptide hormone that is produced and secreted by alpha cells of the islets of Langerhans, which are located in the endocrine portion of the pancreas. The main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading to increases in glycaemia. It provides the major counter-regulatory mechanism to insulin in maintaining glucose homeostasis.Hypoglycaemia is the principal stimulus for the secretion of glucagon but may also be used as an antidote in beta-blocker overdose and in anaphylaxis in patients on beta-blockers that fail to respond to adrenaline. Glucagon then causes:GlycogenolysisGluconeogenesisLipolysis in adipose tissueThe secretion of glucagon is also stimulated by:AdrenalineCholecystokininArginineAlanineAcetylcholineThe secretion of glucagon is inhibited by:InsulinSomatostatinIncreased free fatty acidsIncreased urea productionGlycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy released by this process is used to form ATP and NADH. Glycolysis is inhibited by glucagon, and glycolysis and gluconeogenesis are reciprocally regulated so that when one cell pathway is activated, the other is inactive and vice versa.Glucagon has a minor effect of enhancing lipolysis in adipose tissue. Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into glycerol and free fatty acids. It makes fatty acids available for oxidation.

Hypothyroidism is diagnosed using the results of thyroid function tests (TFTs). In the early stages of the disease, the earliest biochemical change noticed is a rise in thyroid-stimulating hormone (TSH) levels. Free triiodothyronine (T3) and thyroxine (T4) levels are usually normal.In primary hypothyroidism, the serum TSH level is usually greater than 10 mU/L, and free T4 levels are below the reference range.Subclinical hypothyroidism is diagnosed when the serum TSH level is above the reference range, and the free T4 levels are within the reference range. The test should, however, be repeated after 3-6 months to exclude transient causes of raised TSH.In summary, how to interpret TFTs in cases of suspected hypothyroidism is shown below:Subclinical hypothyroidismTSH is raisedFree T4 is normalFree T3 is normalPrimary hypothyroidismTSH is raisedFree T4 is loweredFree T3 is lowered or normalSecondary hypothyroidismTSH is lowered or normalFree T4 is loweredFree T3 is lowered or normal

​Primary hyperparathyroidism the commonest cause of hypercalcaemia. It is commonest in women aged 50 to 60.The commonest cause of primary hyperparathyroidism is a solitary adenoma of the parathyroid gland (approximately 85% of cases). Primary hyperparathyroidism may present with features of hypercalcaemia such as polyuria, polydipsia, renal stones, bone and joint pain, constipation, and psychiatric disorders.In primary Hyperparathyroidism:PTH is elevatedCalcium is elevatedPhosphate is loweredIn secondary Hyperparathyroidism:PTH is elevatedCalcium is low or low-normalPhosphate is raised in CRFIn tertiary Hyperparathyroidism:PTH is elevatedCalcium is elevatedPhosphate is lowered in CRF

Osteoclasts are a type of bone cell that breaks down bone tissue. This is a critical function in the maintenance, repair and remodelling of bones. The osteoclast disassembles and digests the composite of hydrated protein and minerals at a molecular level by secreting acid and collagenase. This process is known as bone resorption and also helps to regulate the plasma calcium concentration.Osteoclastic activity is controlled by a number of hormones:1,25-dihydroxycholecalciferol increases osteoclastic activityParathyroid hormone increases osteoclastic activityCalcitonin inhibits osteoclastic activityBisphosphonates are a class of drug that slow down and prevent bone damage. They are osteoclast inhibitors.

A negative feedback mechanism involving the hypothalamic-pituitary-thyroid axis controls the release of T3 and T4 into the bloodstream. When metabolic rate is low or serum T3 and/or T4 levels are decrease, this triggers the secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus.TRH goes to the anterior pituitary gland and stimulates secretion of thyroid-stimulating hormone (TSH). An increased serum level of T3 and T4 inhibits the release of TRH.

Dopamine is a neurotransmitter and amine hormone that is derived from the amino acid tyrosine. It is made in a number of places throughout the human body, both inside and outside the central nervous system. The adrenal medulla, dopamine neurons in the arcuate nucleus of the hypothalamus, the substantia nigra, and other areas of the brain produce dopamine.The tuberoinfundibular pathway refers to the dopamine neurons in the arcuate nucleus of the hypothalamus’ tubeal region. Dopamine is discharged into the hypothalamo-hypophyseal portal system from these neurons’ neurosecretory terminals at the median eminence.The major function of dopamine produced from the hypothalamus is to suppress prolactin production from the anterior pituitary, and it is released in reaction to excessive levels of prolactin secretion. Modulation of motor-control centres and activation of reward centres are two more crucial activities of the brain.Dopamine-secreting cells can also be found in other areas of the body, where they perform mostly paracrine functions (acting on nearby cells).

A thyroid function test is used in the diagnosis of hyperthyroidism.Serum TSH should be the first-line investigation for patients with suspected hyperthyroidism as it has the highest sensitivity and specificity for hyperthyroidism. A normal TSH level almost always excludes the diagnosis, though there are rare exceptions to this.Antithyroglobulin antibodies are commonly present in Graves’ disease, but the test has a sensitivity of 98% and specificity of 99, and is not widely available.Radioactive iodine uptake scan using iodine-123 – shows low uptake in thyroiditis but high in Graves’ disease and toxic multinodular goitre. It is however, not first-line investigation in this caseThyroid ultrasound scan – is a cost-effective and safe alternative to the radioactive iodine uptake scan.