Hypothalamus, Pituitary and Thyroid

Outline the anatomy of the hypothalamus and pituitary (1)

The hypothalamus in an areas on the base of the brain. Neurones send axons down from the hypothalamus which form the posterior pituitary (neuroendocrine organ that releases oxytocin and ADH)

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Outline the anatomy of the hypothalamus and pituitary (2)

Posterior pituitary has a neuronal development origin as a down-growth from the diencephalon (part of the brain). Anterior pituitary is ectodermal in origin.

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Outline the anatomy of the hypothalamus and pituitary (3)

Anterior pituitary has a developmental origin as an up-growth of ectoderm from the primitive oral cavity (Rathke'a pouch)

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Outline the anatomy of the hypothalamus and pituitary (4)

Neurones in the hypothalamus send axons to the median eminence. NP hormones released at the median eminence enter the portal vessels to control the release of hormones from the anterior pituitary

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Which hormones are secreted by the anterior pituitary gland (6)?

Growth hormone (GH), follicle stimulating hormone (FSH), luteinising hormone (LH), adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), prolactin (PL) - hormones released enter venous drainage to reach their target tissues

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Summarise the main pituitary hormones and their actions (1)

Posterior pituitary is neuronal, releases oxytocin and ADH. Anterior pituitary is ectodermal, secretes GH, FSH, LH, ACTH, TSH, PL

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Summarise the main pituitary hormones and their actions (2)

Cells in hypothalamus release peptide hormones (neurohormones) into portal blood vessels (at median eminence) which influence the release of hormones from the anterior pituitary

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What are the two types of hormones secreted by the hypothalamus (which affects the anterior pituitary)?

Releasing hormones and inhibiting hormones

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Give examples of releasing hormones (4)

Growth hormone releasing hormone (causes release of GH). Corticotropin releasing hormone (causes release of ACTH). Thyrotropin releasing hormone (causes release of TSH). Gonadotropin releasing hormone (causes release of LH and FSH)

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Give examples of inhibiting hormones (2)

Somatostatin (inhibits release of GH and TSH) and dopamine (inhibits release of PL)

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Describe features of the hormones FSH and LH (1)

Made in luteotrophs (gonadotrophs). Released in response to hypothalamus GnRH. Control production of steroid hormones by ovary oestrogen/progesterone. Control production of steroid hormones by testis (testosterone)

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Describe features of the hormones FSH and LH (2)

Gonadal steroids control sexual differentiation, behaviour and fertility

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What is the consequences of a loss in FSH/LH secretion (2)?

Loss of function in children preventing puberty. Calorie restriction in adults (anorexia, excessive exercise) causes loss of reproductive function

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The administration of which hormone can be used to manipulate reproduction?

GnRH

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Describe features of growth hormone (1)

Made in somatotrophs, released in response to hypothalamic GHRH, secretion inhibited by hypothalamic somatostatin. Direct anabolic effect in may tissues. Targets liver to produce somatomedins (insulin-like growth factors/IGFs)

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Describe features of growth hormone (2)

Somatomedins stimulate growth in many tissues

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What are the consequences for the lack of GH and for too much GH?

Lack of GH - short stature (treated by GH treatment). Too much GH - giantism (if secreted throughout growing period), acromegaly (if secreted after bones have fused, hands/feet/jaws continue to grow)

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What is acromegaly?

Over-secretion of GH in adult. Usually due to pituitary adenoma

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Describe features of prolactin

Made in mammotrophs. Release inhibited by hypothalamic dopamine. Stimulates lactation in post-partum period. Over secretion leads to loss of reproductive function

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Describe features of thyroid stimulating hormone

Made in thyrotrophs. Released in response to hypothalamic TRH. Acts on thyroid to generate triiodothyronine (T3) and thyroxine (T4). T3 and T4 regulate growth and development by multiple actions

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Outline thyroid anatomy

Located in anterior neck on trachea, inferior to larynx. Weighs 10-20 g, 2 lobes connected by isthmus. Highly vascular (supplied form carotid and subclavian arteries)

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Describe the structure and histology of the thyroid (1)

Composed of hollow follicles (thyroid follicles). Lined by epithelial cells (principal cells), responsible for synthesis/secretion of thyroid hormones, T3/4. Filled with thyroid colloid (stores T3/4 prior to secretion)

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Describe the structure and histology of the thyroid (2)

C cells (clear cells, parafollicular cells), responsible for synthesis/secretion of calcitonin (regulates Ca homeostasis)

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What are thyroid hormones? (1)

Amine hormones derived from tyrosine. Iodine is essential for the synthesis of thyroid hormones. Generated from iodination and coupling of tyrosine

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What are thyroid hormones? (2)

3,5,3'-tri-iodothyroinine (T3) and 3,3',5,5'-tera-iodothyronine (thyroxine/T4)

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Describe the synthesis and secretion of thyroid hormones (1)

Follicle (principal) cells make and secrete thyroglobulin into the colloid. Iodide absorbed from blood into follicle cells. I- oxidised to iodine at the apical membrane and released into colloid

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Describe the synthesis and secretion of thyroid hormones (2)

Iodine attached to tyrosine, forming mono-iodotyrosine (MIT) or di-iodotyrosine (DIT) which are incorporated into thyroglobulin (process catalysed by thyroid peroxidase)

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Describe the synthesis and secretion of thyroid hormones (3)

Tyrosine-iodine complexes joined together to form thyroxin (T4, two di-iodotyrosine molecules) or tri-iodothyronine (T3, one di-iodotyrosine and one mono-iodotyrosine). Colloid endocytosed and combined with lysosome

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Describe the synthesis and secretion of thyroid hormones (4)

T3 and T4 released into capillaries and bind to carrier proteins

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What is the mode of action for T4 and T3? (1)

T4 and T3 are strongly bound to serum proteins (Thyroid Binding Globulin - TBG) in circulation, <0.5% of each is present in free form (biologically active). T4 may be pro-hormone, T3 is most potent form (up to 10x as active as T4)

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What is the mode of action for T4 and T3? (2)

T3 is mainly produced by de-iodination of T4 within target cells outside the thyroid gland. Receptors for thyroid hormones are found in cell nucleus and are part of the super-family of nuclear receptors

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What is the mode of action for T4 and T3? (3)

They interact with DNA (as transcription factors) and produce changes in gene transcription and protein synthesis

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Describe features of thyroid hormone action - Thyroid receptor (1)

Thyroid receptor (TR/THR). Member of hormone responsive nuclear transcription factors. Consist of DNA binding domain and COOH terminal domain (mediates ligand interactions and binding of coactivators and corepressors)

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)Describe features of thyroid hormone action - Thyroid receptor (2)

Two primary isoforms TR alpha and TR beta. TR forms a heterodimer complex with retinoid X receptor (RXR)

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Describe features of thyroid hormone action - TR-Retinoid X Receptor (RXR) complex

Binds to thyroid response element (TRE). Activation of TRE stimulates or inhibits gene transcription

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Describe features of thyroid hormone action - nuclear receptor coregulators

Co-activators associated with liganded nuclear receptors and enhance gene transcription. Co-repressors bind to unliganded receptors and promote gene repression

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What are the actions of thyroid hormones (8)? - 1

Liver (increase gluconeogenesis), heart (increase HR/ionotropy/BP), CNS (increased growth/development of NS), muscles (increased protein catabolism), increased rbc formation (enhance O2 delivery)

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What are the actions of thyroid hormones (8)? - 2

Various endocrine tissue (increase activity in fat cells, pancreas, kidney), bones (increase turnover of minerals, linear growth and maturation of bones). Increased O2 consumption in tissues results in increased basal metabolic rate/heat production

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How is thyroid hormone secretion regulated?

Control of thyroid hormone - a classical negative feedback through the hypothalamic-pituitary-thyroid axis (HPT axis)

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How is thyroid hormone secretion regulated? - TRH

Thyrotropin releasing hormone. Produced by hypothalamus, down-regulated by T4 and T3, stimulated TSH formation

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How is thyroid hormone secretion regulated? - TSH

Thyroid stimulating hormone. Produced by anterior pituitary. Up regulated by TRH. Down regulated by T4 and T3. Stimulates iodine uptake, colloid endocytosis, number and secretory activity of thyroid cells (secretion of T4 and T3)

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What are the thyroid gland disorders?

Under-active (hypo) thyroid gland and over-active (hyper) thyroid gland

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What is hypothyroidism? (1)

Thyroid failure. Can be congenital (from birth) - produces severe developmental abnormalities if untreated

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What is hypothyroidism? (2)

Can be acquired in later like. Could also be the autoimmune destruction of the thyroid (Hashimoto's thyroiditis). Occurs 1 in 1000, 8-15x more common in women (40-60 yrs)

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What is hypothyroidism? (3)

Circulating antibodies against thyroid peroxidase, thyroglobulin/TSH receptors. TSH is increased as pituitary tries to compensate for decreased T4. Treated with T3/T4 replacement (oral). Lack of iodide in diet (common) - treat with (NaI in salt)

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What are the symptoms of hypothyroidism? (1)

Low metabolic rate, weight gain, cold sensitivity, deficient growth, slow mental processes, decreased cardiac activity. Lack of T3/T4 (no inhibition of TSH/elevated)/thyroid goitres form)

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Outline control of thyroid function (1)

TRH from hypothalamus stimulates TSH release from pituitary. TSH stimulates production/release of T4 and T3 from thyroid T4 de-iodinated to T3 at target tissues. TSH stimulates growth of thyroid. Most T4 plasma bound to TBG

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Outline control of thyroid function (2)

Free fraction biologically active. Free hormone (mainly T3) feedback back to inhibit TSH secretion at level of pituitary and hypothalamus

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What are the expected lab values for hypothyroidism?

Raised TSH (lack of negative feedback), low T4, presence of anti-thyroid peroxidase antibody/anti-thyroglobulin antibody, increased plasma cholesterol (effect of TH on lipid metabolism)

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What is the treatment for hypothyroidism? (1)

Life-long supplement of thyroid hormones. Oral thyroxine (Levothyroxine, synthetic T4). oral tri-iodothyronine (more potent but has shorter duration of action). Start with low dose of 25 mg/day

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What is the treatment for hypothyroidism? (2)

Slowly increase dose every 3-4 weeks until TSH levels are normal. S/E - weight gain, insomnia, muscle weakness, diarrhoea

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How is endemic dietary iodine-deficiency hypothyroidism treated?

With dietary supplement (NaI in salt)

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What is hyperthyroidism? (1)

Graves disease (most common form). Autoimmune disease with antibodies that stimulate thyroid to secrete T3 and T4 (agonist antibody). Antibody binds to TSH receptor (inappropriate secretion of T3/T4

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What is hyperthyroidism? (2)

High metabolic rate, weight loss, heat sensitivity, increased cardiac activity, hyperactive NS, tremor, anxiety, thyroid growth (toxic goitre) and exopthalamus. (Over production of thyroid hormones in adults

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What are the expected lab values for hyperthyroidism?

Raised free T4 (normal 12-26 pmol/L). Raised T3 (normal 1.4-2.6 nmol/L). Decreased TSH 0.18 mU/L (normal 0.5-5.0 mU/L). Presence of anti-TSH antibody

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What is the treatment for hyperthyroidism? (1)

Carbimazole or propylthiouracil - inhibit thyroid peroxidase and decrease thyroid hormone synthesis. Propylthiouracil - preventions conversion of T4 to T3. Partial ablation of thyroid with surgery or radioactive iodine

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What is the treatment for hyperthyroidism? (2)

(course of action only if carbimazole had not been effective). Beta blockers to counter cardiac effects

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Hypothalamus, Pituitary and Thyroid

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