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Pituitary : the master gland Graduate Entry y Medicine Year 1 Endocrinology Review 26th May 2011 1. Pituitary gland 2. Thyroid gland 3. Adrenal gland Pituitary location and MRI appearance Organisation of the pituitary dura Pituitary fossa/sella Ant Post 1 Organisation of the pituitary hypothalamus Anterior pituitary five endocrine cell types each secrete different hormone(s) ‘neurosecretion’ Optic chiasm cell types can be differentiated by antibody labelling and cell structure internal carotid Anterior pituitary Posterior pituitary non-secretory supporting cell type ‘folliculo-stellates’ jugular vein Feedforward and feedback control - ve inhibitory feedback Hypothalamus R l Releasing i hormone h - ve Thyroid stimulating hormone (TSH) feedforward control Anterior pituitary Receptors: G protein coupled to cAMP Actions: in thyroid: stimulates thyroid production (metabolic ( rate)) hormone p Trophic hormone Endocrine gland Target Chemical type: glycoprotein α and β chains secreted by thyrotroph cells e.g. cortisol release from the adrenal increases iodine uptake by thyroid, stimulates thyroid growth 2 The hypothalamic-pituitary-thyroid axis hypothalamus cold Ch i l type: Chemical t polypeptide l tid hormone h from f POMC precursor, secreted by corticotroph cells TRH Inhibitory feedback anterior pituitary Adrenocorticotrophic hormone (ACTH) Released in pulses Receptor: G protein coupled receptor to cAMP Actions: stimulates secretion of cortisol (glucocorticoid hormone) from adrenal cortex in stress TSH thyroid T3 and T4 Pathology of TSH secretion is rare The hypothalamo-pituitary-adrenal axis hypothalamus Stress hypoglycaemia stimulates growth of adrenal cortex Diurnal rhythm of plasma ACTH and cortisol Inhibitory feedback anterior pituitary ACTH co ortisol CRH adrenal cortex glucocorticoids, cortisol 3 Gonadotrophins: LH and FSH ACTH pathology Chemical type: glycoproteins α, β subunits, from gonadotroph cells excess ACTH ACTH, and in turn excess glucocorticoid, - Cushing's disease Receptors: G protein coupled to cAMP Actions: reproductive deficiency of ACTH, in turn glucocorticoid deficient- Addison's disease Female: FSH follicle development and ovulation, LH synthesis of sex steroids by the ovary Male: LH controls testosterone production FSH stimulates sperm production Hypothalamo-pituitary-gonadal axis hypothalamus GnRH anterior pituitary gonadotrophs -ve LH + FSH ovary estrogen Pathology of LH and FSH LH = luteinising hormone FSH = follicle stimulating hormone Cyclical release in menstrual c cle cycle Deficit: infertility in adult life lack of sexual maturation Excess: precocious puberty testes testosterone 4 Prolactin Chemical type: Protein hormone secreted t d by b lactotroph l t t h cells ll Receptor: tyrosine kinase enzyme -linked Actions: stimulates development of breast and milk production inhibits reproductive function – lactational amenorrhaea Control of prolactin release Control of prolactin release hypothalamus suckling +ve dopamine -ve anterior pituitary lactotrophs PRL Breast growth and milk production Prolactin pathology PRL release is increased by suckling and stress Too much PRL secretion the only pituitary hormone whose principal control is inhibitory by prolactin secreting pituitary tumours - prolactinomas Dopamine agonists e.g. b bromocryptine, ti suppress lactation causes galactorrhoea, infertility, impotence in men PRL production is stimulated by estrogen during pregnancy 5 Growth hormone Growth hormone axis Hypothalamus Chemical type: Protein hormone secreted by somatotroph cells GHRH Anterior pituitary somatotrophs Receptor: enzyme-linked Actions: stimulates long bone and tissue growth direct and indirect actions via IGF’s stimulates protein synthesis raises blood glucose GH pathology Gigantism due to excess GH secretion Short stature if lack GH nb if prior to epiphyseal plate fusion at puberty Acromegaly: excess GH secretion after pp y plates p epiphyseal have fused Enlargement of hands and feet, Coarsening of facial features, Weight gain Li Liver GH -ve GH IGFs Long bone and muscle growth Posterior pituitary Formed by axons and terminals of h hypothalamic th l i neurosecretory t neurons Secretes peptide hormones antidiuretic hormone (ADH, also known as vasopressin) and oxytocin The hormones are made in the hypothalamus 6 Stimulation of posterior pituitary hormone release Stimuli of ADH release Plasma osmolality Blood volume hypothalamus Stimulus depolarises neuron axon Ca2+ posterior pituitary action potential exocytosis osmotic osmoreceptors detect ↑ plasma osmotic pressure and stimulate release. Vascular baroreceptors stimulate release when they detect ↓ in blood pressure Oxytocin Diabetes insipidus Chemical nature: peptide Too little ADH Receptors: PLC-coupled Two types: hypothalamic: lack of ADH production renal: lack of ADH action Actions: contraction of uterine muscle l in i childbirth hildbi th milk ejection by contraction of breast myoepithelium 7 Control of oxytocin release stretch of cervix/vagina at parturition suckling – nipple stimulation causes milk-ejection reflex Pituitary tumours hormonal effects: hormone-secreting tumours effects depend on cell type mechanical effects: affects vision as presses on optic chiasm Pathology deficit may cause prolonged labour knockout mice labour normal but no milk-ejection Normal Adenoma Anatomy of the Thyroid The Thyroid Gland 8 Thyroid structure Thyroid hormones the thyroid y p produces two unique q hormones: tri-iodothyronine (T3) and thyroxine (T4) T3 and T4 are the only iodine containing hormones in vertebrates the only source of iodide is dietary (veg, fish, salt) iodide is scarce and insufficient supply is a major health problem in many parts of the world Regulation of thyroid hormone secretion Hypothalamus TRH Peripheral metabolism of T4 stimuli e g cold e.g.cold, glucose Anterior pituitary Inhibitory feedback TSH Thyroid T3 and T4 metabolism iodothyronines are unusual in that the main thyroid product (T4) is not the active hormone (T3) metabolism T4 to T3 occurs in the liver and kidney T4 is converted to T3 by Type I deiodinase 9 Thyroid Receptor action Hyperthyroidism – ‘thyrotoxicosis’ restless, anxiety TR in i th the nucleus bind DNA and activate transcription Timescale - hours exophthalmos - eyes protrude goitre tachycardia and rapid pulse lose weight despite normal appetite intolerance of heat hot hands High T4 Low TSH metabolic effects exacerbate diabetes mellitus diarrhoea hand tremor Hyperthyroidism Most common cause is Graves’ disease Hypothyroidism Due to autoimmune production of antibody to the TSH receptor which acts like a superactive TSH cretinism in young young, myxoedema in adult failure of production by thyroid (‘burned-out’ Grave’s disease) failure of pituitary or hypothalamus to produce TSH or TRH thyroid hormone resistance – inactivating mutation of thyroid hormone receptor 10 Hypothyroidism Low T4 High TSH Prenatal thyroid deficiency (cretinism) apathy, tired goitre i heart slowing and slow pulse poor neural d development l t stunted growth muscle weakness weight gain constipation intolerance of cold muscle weakness treated by giving thyroid hormone at birth cold hands Calcitonin Drugs affecting the Thyroid • prevention of hypercalcaemia • no long term effect on serum Ca22+ Thyroxine (T4) is given for h hypothyroidism th idi • effects are over-ridden by PTH if in excess; CT receptor downregulation iodine: in large doses reduces the activity of the gland in hyperthyroidism Bone inhibits osteoclast breakdown of bone Gut helps control rise in Ca2+ due to meals, inhibits absorption radioactive iodine can be given to destroy thyroid tissue beta blockers used to alleviate symptoms in acute control of thyrotoxicosis 11 Stress: a change that disturbs or threatens to disturb homeostasis The Adrenal Gland Acute stressors Trauma Infection Intense heat or cold Starvation Surgery Severe blood loss Pain Dehydration Chronic stressors Anxiety Depression Adrenal structure Cortex Innervation of the adrenal gland adrenaline noradrenaline Medulla 12 Sympathetic activity in stress Rapid increase in adrenaline and noradrenaline in stress Preparation for emergency activity very rapid increase and then rapid decrease depletes only a small fraction of the stored catecholamine The adrenal cortex Maintenance of essential processes in chronic stress medulla cortex Control of cortisol production Hypothalamus capsule stress CRF Inhibitory feedback zona reticularis androgens zona fasciculata cortisol zona glomerulosa aldosterone Anterior pituitary ACTH Adrenal Receptors intracellular -GR glucocorticoids cortisol 13 Glucocorticoids preserve glucose for the brain Glucocorticoids also act on accelerate gluconeogenesis in liver central nervous system activity accelerate lipid and protein catabolism in liver and peripheral tissues (appetite, mood) increased red blood cell production maintenance of circulation reduce inflammation and the immune response- prevent it from becoming disruptive - Stress inhibits reproduction Clinical uses of glucocorticoids Hypothalamus Synthetic glucocorticoids eg prednisone GnRH glucocorticoids -ve Anterior pituitary PRL LH and FSH reproduction and lactation anti-inflammatory ti i fl t therapy th in i e.g. asthma, arthritis used topically in inflammation of skin, eye or ear prevent graft rejection in transplantation avoids risk of pregnancy - a drain on resources 14 Cushing’s disease ‘buffalo hump’ fat pads moon face bruising thin skin hypertension thin arms and legs trunkal obesity osteoporosis infertility poor wound healing Aldosterone Chronic stress and illness In utero stress of undernourishment or poor oxygen results lt iin llow bi birth th weight i ht and d is associated with hypertension, diabetes mellitus, lower life expectancy when adult Childhood chronic stress > retarded growth Adults continuing psychological stress is a major factor in ‘stress illnesses’ The renin-angiotensin system ‘mineralocorticoid’ regulates body sodium and fluid volume acts via nuclear mineralocorticoid receptors (MR) stimulates reabsorption of Na+ in the kidney in exchange for K+ (cortisol also binds MR) 15 Addisons disease - adrenal insufficiency Mineralocorticoid dysfunction Hypoaldosteronism H ld t i - sodium di loss, l low l blood volume, low blood pressure Lack of aldosterone and cortisol Hyperaldosteronism - excess sodium retention, water retention, increased blood pressure Pigmentation results from high circulating levels of Melanocyte stimulating hormone (MSH) Spironolactone – a MR antagonist is a diuretic drug used as an anti-hypertensive Low blood pressure Addisons disease pigmentation Addisons disease pigmentation hypothalamus hypothalamus CRH CRH no feedback anterior pituitary Inhibitory feedback anterior pituitary POMC ACTH adrenal cortex cortisol POMC MSH ACTH skin melanocytes pigmentation MSH skin melanocytes Melanocortin receptor pigmentation 16 Any questions: [email protected] To see slides in more detail see weblearn. You may find BM1 teaching materials helpful, see Organisation of the Body y Term ‘Endocrinology’ gy p pages g on Hilary weblearn. 17