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Year 2 Revisio– Endocrine (Pituitary & Thyroid) Omar SalimPituitary LocationPituitary AnatomyPituitary Anatomy • Split into: • Posterior pituitary (neurohypophysis) • Band between anterior & posterior lobes = pars intermedia (often classed as part of anterior pituitary) • Anterior pituitary function is regulated by hypothalamus via hypophyseal portal system • Posterior pituitary is direct extension of hypothalamusPituitary Anatomy Blood supply from hypophyseal (pituitary) portal system: • Superior + inferior (primary/secondary) plexuses • Connected by long + short veins • Neurosecretory hormones released into superior plexus regulate adenohypophysis secretionPituitary Anatomy • Hypothalamus makes releasing hormones (GHRH, GnRH, CRH, TRH, dopamine) à stimulate hormone production by anterior pituitary • Anterior pituitary contains 5 types of cell, which secrete different hormones – somatotropes, corticotropes, thyrotropes, gonadotropes, lactotropes • Hypothalamus makes oxytocin & ADH à stored in posterior pituitaryOverview of Hypothalamus-PituitaryPituitary Hormones Hormone Major Target Organ(s) Major Physiologic Effects Anterior PituitaryGH Liver, Adipose Tissue Promotes growth (indirectly), control of protein/lipid/carbohydrate metabolism TSH Thyroid Gland Stimulates secretion of thyroid hormones ACTH Adrenal Gland (Cortex) Stimulates secretion of glucocorticoids FSH Ovary & Testis Control of reproductive function LH Ovary & Testis Control of reproductive function Prolactin Breast/Uterus Milk production Posterior Pituitary ADH Kidney Conservation of body water Oxytocin Ovary & Testis Stimulates milk ejection & uterine contractionsOverview of Hypothalamus-Anterior Pituitary Hypothalamus Pituitary Anterior pituitary cell Target organ type Growth Hormone Growth Hormone (GH) Somatotrophs Multiple Releasing Hormone (50%) (GHRH) Gonadotrophin Releasing Follicle Stimulating Gonadotrophs Ovaries/testes Hormone (GnRH) Hormone/Luteinising (10%) Hormone (FSH/LH) Corticotrophin Releasing Adrenocorticotrophic Corticotrophs Adrenal cortex hormone (CRH) Hormone (ACTH) (10-15%) Thyrotrophin Releasing Thyroid Stimulating Thyrotrophs Thyroid Hormone (TRH) Hormone (TSH) (5%) Dopamine Prolactin (negative) Lactotrophs Breast/uterus (20%)Pituitary HormonesPituitary Physiology Hormone secretion from anterior pituitary gland is regulated by releasing hormones secreted by neuroendocrine cells in hypothalamus, which project axons to median eminence, at base of brain. Hypothalamic releasing & inhibiting hormones are carried directly to anterior pituitary gland via hypothalamic-hypophyseal portal veins. Specific hypothalamic hormones bind to receptors on specific anterior pituitary cells, modulating the release of hormone they produce.Negative Feedback Loops When blood concentrations of stimulating hormones increase above threshold, neuroendocrine cells in hypothalamus are inhibited & stop secreting releasing hormone = "negative feedback".Growth Hormone AxisHypothalamic-Pituitary-Adrenal Axis * derived from POMC (pro- opiomelanocorticotrophin) * *Hypothalamic-Pituitary-Gonadal AxisHypothalamic-Pituitary-Thyroid AxisLactotroph Axis •Under negative hypothalamic control (dopamine) •Increases with stress •Only physiological action is in pregnancy (stimulates lactation)Hypothalamus-Posterior Pituitary Oxytocin • Important in labour and breast feeding: • Stimulates cervical dilatation & uterine contractions • ‘Let down’ reflex in mammary glands; suckling stimulates its production • Social bonding, reproduction Antidiuretic Hormone • Main role is in regulating water status. Produced in response to: –↓ plasma volume (sensed by baroceptors in atria/veins/carotids) –↑ plasma osmolality (sensed by osmoreceptors in hypothalamus) • Inserts aquaporin channels in basolateral membrane of renal collecting ducts à increased water reabsorption (AVPR2 receptor) • Also causes vasoconstriction & platelet aggregation (AVPR1 receptor)Clinical Disorders of Pituitary Gland • Anterior pituitary excess hormones • Prolactin • GH • ACTH • TSH • Posterior pituitary • Diabetes insipidus • Syndrome of inappropriate anti-diuretic hormone (SIADH) • Pituitary tumours • HypopituitarismDiabetes Insipidus – Lack of ADH • Passage of large volumes (>3 L/day) of dilute urine • Clinical features = polyuria, polydipsia, nocturia • Must exclude DM & hypercalcaemia • Causes: • Cranial = deficiency of ADH • Genetics, trauma, tumours, infections, inflammation of posterior pituitary • Nephrogenic = resistance to ADH • Genetics, drugs (e.g. lithium), metabolic disorders, renal diseaseDiabetes Insipidus – Lack of ADH Water Deprivation Tes= deprive patients of fluid for 8h à measure plasma & urine osmolality every 2-4h à then give synthetic ADH & reassess urine osmolalityDiabetes Insipidus – Lack of ADH Treatment: • Cranial = desmopressin (vasopressin/ADH analogue) • Given orally/nasal spray/injection • Monitor plasma sodium and osmolality • Nephrogenic = treat underlying cause • High doses of desmopressin (ddAVP) • Very difficultSyndrome of Inappropriate ADH (SIADH) • Excess ADH or inappropriate ADH for plasma osmolality • Common cause of low plasma sodium; due to increased body water • Multiple causes: • Cancer: lung/lymphoma/leukaemia • Chest infections: pneumonia • CNS disorders: infections, injury • Drugs: opiates, thiazides, anti-convulsants, PPIs, anti-depressantsSIADH Diagnosis and Treatment Diagnosis: • Hyponatraemia with inappropriately low plasma osmolality • Urine osmolality > plasma osmolality • Urine sodium> 20 mmol/l Treatment: • Treat underlying cause • Fluid restrict (1-1.5 L/day) • ADH (AVPR2) antagonists (‘vaptans’ e.g. tolvaptan)Non-Functioning Pituitary Adenomas • Pituitary adenomas found in 10% of population • Often asymptomatic (‘incidentalomas’) • Need to exclude hormone excess: • Check prolactin, IGF-1, thyroid function • Check cortisol production • Need to ensure no effect on visual fields: • Pituitary located just below optic chiasm • Tumour can expand upwards & push on chiasm à loss of peripheral vision (‘bitemporal hemianopia’)Secretory Pituitary Adenomas • Prolactin (commonest, 30%) – ‘Prolactinomas’ • ACTH (20%) – ‘Cushing’s Disease’ • Growth hormone (15%) – ‘Acromegaly’ • TSH (very rare, <1%) – ‘TSHomas’Prolactinomas • Clinical features • Galactorrhoea • Menstrual disturbance & subfertility in women • Reduced libido/erectile dysfunction in men • Management: • Dopamine agonists (cabergoline) • Surgery if large tumour with visual field effectsAcromegaly • Excessive production of GH (& IGF-1) in adults (in children ‘gigantism’) • Rare, UK annual incidence 4/million • Usually due to pituitary adenoma (often large) • Symptoms – as sweats, headache, tiredness, increased ring/shoe size, joint pains • Signs – coarse facial appearance, enlarged tongue/hands/feet, visual field loss • Complications – hypertension, diabetes/impaired glucose tolerance, increased risk of bowel cancer & heart failureAcromegaly Diagnosis: • Glucose tolerance test – glucose load fails to suppress GH; may reveal underlying DM or IGT • IGF-1 level – long half life, protein bound à more useful than plasma GH • Pituitary MRI – tumour usually large (macroadenoma, >1cm) & often extends into surrounding structures Management: • Surgery – transsphenoidal route, often not curative • Medical therapy – somatostatin analogues to inhibit GH secretion, given before & after surgery • Pituitary radiotherapy – to treat residual tumour; risk of hypopituitarism & long-term problems Pituitary MRI - GH producing macroadenomaHypopituitarism • Failure of (anterior/posterior) pituitary function • Can affect single hormonal axis (FSH/LH most commonly) or all hormones (panhypopituitarism) • Causes secondary gonadal/thyroid/adrenal failure • Need multiple hormone replacement (give cortisol first if all axes affected) • Controversy over need for GH in adults • Causes: o Tumours o Radiotherapy o Infarction (apoplexy) – if postpartum = Sheehan’s syndrome o Infiltrations (e.g. sarcoid) o TraumaPituitary Pathophysiology Pituitary located just below optic chiasm – tumour can expand upwards and push on chiasm causing loss of peripheral vision (bitemporal hemianopia) ACTH – increases production & release of cortisolThyroid Anatomy • Endocrine gland – produces T3, T4, calcitonin • Anterior neck (C5-T1), inferior to thyroid cartilage, anterior to tracheal rings • Lies deep to sternohyoid + sternothyroid • Composed of 2 lobes connected by isthmus • 3 Pyramidal lobe present in 10-30% – fetal remnant of thyroglossal duct • Surrounded by pretracheal fasciaThyroid Anatomy • Supplied by superior & inferior thyroid aa. (paired on L & R) • Superior thyroid artery – branch of external carotid a, supplies superior & anterior half • Inferior thyroid artery– from thyrocervical trunk (branch of subclavian a.), supplies postero-inferior part • Drained by superior, middle & inferior thyroid vv. • Superior/middle thyroid vv. à internal Jugular v. • Inferior thyroid v.à brachiocephalic v.Thyroid Anatomy • Lymph drainage to deep cervical nodes • Associated structures = recurrent laryngeal nerves & parathyroid glandsParathyroid Glands • aspect of thyroidroid glands, located on posterior • Number and position can vary • Supplied by inferior thyroid a. & thyroid branches of sympathetic cervical gangliaThyroid Histology • Main component = spherical follicles, store 25% of body’s iodide ions (need iodine for thyroid hormone production), composed of follicular cells & follicular lumen: • Follicular cells– secrete thyroid hormones T3 & T4 • Follicular lumen– contains colloid = reservoir for thyroglobulin & other substances needed for hormone synthesis • Parafollicular (C) cells between follicular cells, secrete calcitoninThyroid Histology 1. Oral iodine reduced to iodide (I ) by GI tract 2. Iodide trapping into follicle via Na/I symporter (TSH stimulates) 3. Iodide into colloid via pendrin transporter in apical membrane 4. Nucleus → ER→ thyroglobulin secretion à exocytosis from follicle into colloid 5. Thyroid peroxidase uses substrate hydrogen peroxide for oxidation of iodide à iodine & iodination of tyrosine residues on thyroglobulin (mono-/diiodotyrosine i.e. MIT/DIT). Coupling: • MIT + DIT à T3 (triiodothyronine) • DIT + DIT à T4 (thyroxine) 6. Conjugation of adjacent tyrosyl residues 7. Endocytosis of thyroglobulin into follicular cell 8. Proteolysis releases T3 + T4 molecules from thyroglobulin 9. Efflux of T3 & T4 to blood. Most bound to thyroid binding globulin, transthyretin and albumin 10. Uncoupled MIT & DIT deiodinated and used againThyroid Histology Colloid Follicular CellHypothalamic-Pituitary-Thyroid AxisThyroid Hormone T ransport • Transport – bind to 3 plasma proteins after leaving thyroid: 1. Thyroxine binding globulin –75% 2. Transthyretin (15-20%) 3. Albumin (5%) • Proportions: • T3 – 7% (main active hormone) • T4 – 93% • T4 deiodinatedàT3 in peripheral tissue (deiodinases) - delivered to target tissue • T3 & T4 have intracellular receptors found in nucleus à released from protein carrier & bind to intracellular receptor à alter gene transcription à synthesis of cell metabolism regulating proteinsThyroid Hormone Effects • Cellular effects: ↑ BMR of all tissues • ↑ rate of protein synthesis & catabolism • ↑ number & activity of mitochondria • ↑ active transport of ions across plasma membrane • ↑ ATP from carb & lipid metabolism à powers bodily Na+/K+ pumps à ↑ metabolic activity • Metabolic effects: • Carbohydrates: ↑ glycolysis, ↑ gluconeogenesis, ↑ glucose absorption • ↑ Lipid metabolism • ↑ Proteolysis • Growth – ↑ ossification of bone + maturation of growth plates • Development – important for development of nervous system in foetal life • CVS – upregulates β-adrenergic receptors à ↑ sensitivity to catecholamines • ↑ O 2onsumption • ThermogenesisThyroid Disorders • Primary causes = thyroid gland problem • Secondary causes = pituitary or hypothalamus problem • Hypothyroidism causes: • Hashimoto’s thyroiditis (anti-TPO Abs) • Thyroiditis (viral/postpartum) • Iatrogenic i.e. following treatment for hyperthyroidism – radiotherapy, thyroidectomy, anti- thyroid drugs (e.g. amiodarone, lithium) • Severe iodine deficiency • Hyperthyroidism causes: • Grave’s disease (anti-TSH Abs) • Toxic adenoma • Toxic multinodular goitre • Thyroiditis • TSH-secreting tumour Hypothyroidism – Primary Autoimmune Causes • Hashimoto’s thyroiditis • Anti-TPO antibodies often present (but also against thyroglobulin or TSH receptor) • Lymphocytic + plasma cell infiltration à thyroid atrophy à regeneration (painless goitre à often asymptomatic) • ~5% population, more women:men (7:1), typically 30-50y, more in younger women & older men • Potential complication – thyroid lymphoma (usually non-Hodgkin) • Usually genetic, other autoimmune associations e.g. vitiligo, pernicious anaemia, Addison’s, T1DM • Atrophic thyroiditis • Anti-thyroid antibodies à lymphocytic infiltration of thyroid à atrophy + fibrosis (no goitre) • Much more common in women, incidence increases with age • Associated with other auto-immune conditions • Postpartum thyroiditis – transient phenomenon observed after pregnancyHypothyroidism Bodily System Signs & Symptoms CNS Low mood, forgetfulness, psychosis, sleepiness CVS Bradycardia, hypertension (compensatory after ↓ BP ( RAAS)) Respiratory ↓ ventilatory drive, pleural effusion GI Constipation GU Menorrhagia MSK Delayed tendon reflexes, muscle stiffness & cramps, weakness Skin Dry skin, dry thin hair Metabolic ↓ BMR à weight gain, cold intolerance, fatigue Other Hoarse voice, goitre, carpel tunnel syndrome NB: generally everything decreases except GU!HypothyroidismHypothyroidism • Investigations – thyroid Function Tests • Serum TSH • Free T3 & T4 • Thyroid auto-antibodies: anti-thyroid peroxidase (anti-TPO), anti-thyrog) or anti-TSH receptor (TRAb) • Primary Hypothyroidism = ↓ T4 + ↑ TSH • Secondary Hypothyroidism = ↓ T4 + ↓ TSH • Treatment thyroxine Replacement Therapy with lifelongevothyroxine • Need monitoring of TFTs every 6 weeks on steady doseHyperthyroidism • Hyperthyroidism – overactive thyroid gland à excess thyroid hormone production • More common in women aged 20-40 • Thyrotoxicosis = syndrome (i.e. clinical effects) of hyperthyroidism • Causes • Autoimmune – Graves’ Disease = most common cause, thyroid stimulating immunoglobulins bind to & activate TSH receptors • Activating TSH receptor antibodies (TRAb) – specific for Graves’ (difficult to measure) • Anti-TPO present in 45-80% cases • Genetic, can be triggered bemotional/physical stress, pregnancy or smoking • Toxic mul-n i odular goitre – nodules which secrete thyroid hormone, seen in elderly & iodine deficient areas • Toxic adenom– solitary nodule producing T3 & T4, appears “hot” on isotope scanHyperthyroidism Bodily System Signs & Symptoms CNS Tremor hyerkinesis, irritability CVS Tachycardia/atrial fibrilla,ioll pulse, warm vasodilated peripheries GI Diarrhoea GU Oligomenorrhoea, infertility MSK Muscle wasting Skin Warm, moist skin, thin hair, Graves’ dermopathy (only in Grave’s disease) ↑ BMR à weight loss, increased appetite, heat Metabolic intolerance Other Exophthalmos, lid lag, goitre, bruit NB: generally everything increases except GU!Graves’ Signs & Symptoms • Grave’s ophthalmopathy – grittiness, redness, inflammation of conjunctivitis (chemosis), dry eyes, tearing, swelling of eyelids, photophobia, exophthalmos (i.e. proptosis), very rarely loss of vision • Grave’s dermopathy – reddening & thickening of skin, often on shins/tops of feet, rarely pretibial myxoedema • Often get thyroid bruitHyperthyroidism Investigations: • Bloods: • TFTs – serum TSH ↓, ↑ T3 & T4 • Thyroid autoantibodies – anti-TPO, TRAb (Graves’) • Nuclear imaging: • Thyroid scintigraphy scanning. Patterns: • Graves’ = diffuse uptake with suppression of background activity • Toxic multiodular goitre = irregular uptake • Toxic adenoma = hot noduleHyperthyroidism Management: • Anti-thyroid drugs: • β-blockers (e.g. propranolol) – for symptom management • Carbimazole & propylthiouracil(PTU) – inhibit TPOà reduces T3 & T4 production • Carbimazole usually used except in pregnancy (contraindicated) • Via block + replace or dose titration • Side effects inc. infections & rashes, agranylocytosis (rare but serious) • Radioactive Iodine (131-I) • Commonly used to definitively treat toxic multinodular goitre • Acts slowly, may induce hypothyroidism • Contraindicated in pregnancy, lactation, & active thyroid eye disease • Surgery – subtotal/total thyroidectomy • Complications – hypothyroidism, hypocalcaemia, recurrent laryngeal nerve palsyThyroid Function T ests Summary Free T4 TSH Diagnosis Low High Primary Hypothyroidism Low Low Secondary Hypothyroidism High Low Primary Hyperthyroidism High High Secondary Hyperthyroidism Low Low Sick Euthyroid Syndrome