Endocrine System Notes PDF

**Content** Week 1........................................2 Week 2........................................14 Week 3........................................34 Week 4........................................43 Prac: 20772 PR02 Seminar: 21991 SE03 Week 1 1. hypothalamus and pituitary gland Pit...

**Content** Week 1........................................2 Week 2........................................14 Week 3........................................34 Week 4........................................43 Prac: 20772 PR02 Seminar: 21991 SE03 Week 1 1. hypothalamus and pituitary gland Pituitary gland: - also known as hypophysis - covered on the top by a layer of dura mater - 2 parts: anterior pituitary (adenohypophysis -\> made up of pars distalis and pars intermedia), posterior pituitary (neurohypophysis -\> made up of pars nervosa) - Located in the hypophyseal fossa on the sphenoid bone, posterior to the optic chiasm - Sphenoid sinus sits below the gland and is surrounded by the cavernous sinus Vasculature of the pituitary gland: - ICA -\> superior hypophyseal artery -\> adenohypophysis (predominantly) - Inferior hypophyseal artery -\> neurohypophysis (predominantly) - Portal system: superior hypophyseal artery first forms a capillary system around the hypothalamus, then forms a second capillary system around the anterior pituitary gland - Veins drains mostly to surrounding cavernous sinus Release of hormones: - Anterior pituitary: - Hormones released by epithelial cells - Controlled by the parvocellular neurons from the hypothalamus - Releases stimulating and inhibiting hormones to the hypothalamic artery - Hormones pass through the first capillary system and travel to the second capillary system through the portal vessel, then acting on the epithelial cells - Hormones released into veins then drained through the cavernous sinus then internal jugular vein. =\> gland controlling =\> direct controlling \*hormones are produced in the anterior pituitary - Posterior pituitary: - Controlled by paraventricular nucleus and magnocellular neurons in hypothalamus - Oxytocin and ADH are produced in magnocellular neurons and stored in vesicles in the magnocellular nerve terminal - Upon activation of the magnocellular neurons, ADH and oxytocin are released from terminals and taken up by adjacent capillaries. - The posterior pituitary is comprised primarily of glial-like cells called pituicytes - Function: milk ejection: aids contraction of the myoepithelial cells in the mammillary alveoli - Delivery: contraction of smooth muscle and reduce bleeding during labour - Tempering fear responses - Acts on collecting duct in kidney and induces an increase - Which increases BP and increases osmolality - Detected changes by baroreceptors in carotid and aortic bodies and osmoreceptors in hypothalamus - Negative feedback - Also increases the release of ACTH in anterior pituitary Anterior pituitary: arise from the oral ectodermal cells that forms the mouth cavity-\> sphenoid bone growth separates the oral cavity and the gland -\> cells proliferate and separates the connection with mouth cavity Posterior pituitary: Arise from neural ectodermal cells -\> extension of the 3^rd^ ventricle 2. pineal gland (also known as the epiphysis ceribri - Neuroendocrine organ - Innervated by the sympathetic fibres from superior cervical ganglion - Located around the diencephalon, inferior to the posterior part of the corpus collosum - Supplied by the PCA and drained into the - Great cerebral vein of Galen Function: - Release of Melatonin with the effects of the circadian rhythm - Melatonin cycle: increased production in the evening, levels peaks in the middle of the night then drops in the morning with daylight - Potentially help with jet-lag if taken orally 3. growth hormone and its regulation Definition of growth: - increasing size and complexity and the number of cells Growth hormones: - regulated by GHRH (growth hormone regulating hormone) and GHIH / somatostatin (growth hormone inhibiting hormone) - target tissues with fuel metabolism, primarily the liver - overall effects: promote protein synthesis by using up fat storage Insulin-like Growth Factors (IGFs) - peptide hormones that encourages mitosis - mediates the effects of growth hormone - IGF-I: affects most cells in the body. induce proliferation and inhibit apoptosis - IGF-II :growth hormone during gestation (from zygote to foetus) Growth hormone release pattern: - Irregular pulses, amplified by exercise and sleep - Regulated by GHRH and somatostatin Mech of GH: JAK/STAT: binding on surface membrane receptors -\> activating JAK enzymes and phosphorylates STAT - Turns on gene transcription and promote protein synthesis - On bone growth: - Stimulating growth of epiphyseal cartilage - Increases conversion from cartilage to new bone - Increasing osteoblast proliferation and bone remodelling Other endocrine factors affecting growth: - Thyroid hormone, insulin, gonadotrophins and glucocorticoid Hypersecretion of growth hormone : - In childhood -\> gigantism (body remains in proportion) - In adulthood -\> acromegaly (bone thickens and soft tissue proliferation increases) - More prominent bony features in the face, increased maxillary sinus size, enlarged lips and tongue - Could be caused by pituitary adenoma -\> surgery through the nose Hyposecretion of growth hormone: - Pituitary dwarfism - Causes: congenital, head trauma, - Treated by GH injection or cortisol 4. Hypothalamic-Pituitary-Gonadal (HPG) Axis GnRH and LH: - GnRH is secreted pulsatile, continuous secretion will lead to the desensitisation of GnRH receptors - LH secretion is positively related to GnRH release - The desensitisation of GnRH receptors will lead to castration -\> the destruction of reproductive tissues (e.g. prostate, mamillary gland) - Possible treatment options to sex organ cancer Glycoproteins - Examples: TSH, gonadotrophins (LH, FSH, HCG) - Protein with a sugar sharing a common alpha chain Structure of gonadotrophins: - alpha subunits are identical between the 2 gonadotrophins - specific differences exist in the beta subunits - a subunit -92 amino acids, b subunit -115 amino acids - overall molecular weight \~ 35 kDa -\> relatively large proteins-\> won't be suspectable in oral forms - several glycosylation sites exist on both chains - glycosylations have an important effect on half-life and biopotency LH and FSH control in male, - GnRH from hypothalamus triggers the release of LH and FSH - LH acts on Leydig cells -\> triggers release of testosterone - FSH acts on Sertoli cells in the testes -\> stimulates production of spermatozoa - Sertoli cells secrete inhibin to inhibit the release of GnRH and testosterone inhibits the release of GnRH in pituitary Female: - GnRH from hypothalamus triggers the release of LH and FSH - High levels of LH triggers ovulation -\> development of corpus luteum - Production of progesterone and oestrodiol inhibits the release of GnRH Effects of sex steroid: 1. Oestrogen - Trophic effects (nourishment) of female reproductive organs and breast tissue - Increasing bone density - Effects upon brain memory and mood, blood lipids 2. Progesterone - Maintains thickness of endometrium - Enhance nervous system on sexual behaviour 3. Androgens - Increase in muscle mass, decrease in fat mass, increased red blood cell mass, - increase in bone density (effect of Estrogens), effects on hair growth - Important effects on the male reproductive tract and sexual behaviour 5. Steroids - 4-ringed structured lipid hormone derived from cholesterol - Functions: maintaining homeostasis, stimulating tissue development, reproductive functions 5 groups of steroids: - Cholesterol: precursor of other steroids - Progestagens: maintaining pregnancy and female reproductive organs - Secreted from: ovarian follicles, corpus luteum, placenta - Corticosteroids: suppress cell-mediated immunity (glucocorticoid) and regulate the electrolytes in the body (mineralocorticoid -\> aldosterone) - Secreted from the adrenal cortex - Androgens: male sexual differentiation, male reproductive organs functioning, anabolic effects - Secreted from Leydig cells, ovary, adrenal cortex - Oestrogens: female secondary sexual differentiation, maintenance of female reproductive organ - Secreted from ovarian follicles, placenta, fat tissues Steroid synthesis: - Inside mitochondria - Mediated by steroid acute regulatory protein -\> controlled the amount of acetate or cholesterol entering the mitochondria - The type of steroid synthesised depends on the enzyme in the cell - E.g. different enzyme levels in the adrenal cortex regulate the amount of aldosterone, androgens, and glucocorticoid released. - Congenital adrenal hyperplasia: lack of the enzyme that converts the precursor to aldosterone and glucocorticoid -\> increased secretion of androgens Oestrogen synthesis in ovary: - From high levels of LH -\> cholesterol is taken up into mitochondria to synthesise androgens -\> androgens then re-enter the ovarian follicles and synthesise into oestrogens -\> circulation Steroid transportations: - Hormones binds into a transport protein -\> with weak associations so it can easily disassociate and enters target cells in capillaries - The binding protein protects the hormone from renal filtrations and enzyme attacks -\> prolongs the half life of the hormone - It also allows the hormone to be evenly distributed into the target cells as free-flowing hormones would be all solely taken up by the distal part of the cells Tissue-specific regulation of steroid action: - Cortisol and aldosterone has similar structure and shares the same mineralocorticoid receptors - Cortisol concentration is 100 times of that of aldosterone - Therefore cortisol is temporarily disabled into cortisone until blood circulates back to the liver, where cortisone can be converted back to cortisol for its use - Such that aldosterone can still be taken up in the kidneys and act as the primart mineralocorticoid Transport of thyroid hormones: - Binded to TBG (Thyroxine binding globulin), albumin, and TBPA(thyroxine binding pre-albumin) - Factors: - Pregnancy, Estrogen Treatment, - Liver disease, major illness, nephrotic syndrome - Other related drugs (anti-epileptics, anti-inflammatories) Peripheral deiodination of T4 - Majority of thyroid hormone is T4, but T3 is more biologically active - T4 has a better half-life then T3 - Deiodination of T4 in the outer ring gives T3 - Maintaining half life while also maintaining the activity of the hormone 6. pituitary gland pathology: tumours in the pituitary gland: 1. pituitary adenomas: - most common cause of hyperpituitarism - hyperpituitarism can also be caused by hyperplasia, carcinomas, secretion by extra pituitary tumours, or hypothalamic disorders - the excess hormone might vary from the location of the tumour - if tumour is present in the prolactin-producing part it will lead to increased prolactin secretion - can also be plurihormonal tumour (involving multiple hormones) - sometimes present with no clinical significance - autosomal dominant inheritance - Histology: usually benign: with functional cells, relatively uniform cells arranged in sheets and cords, functional status does not correlate with the histological findings, with unpredictable growth rate Specific adenomas: Prolactinomas: most frequent type of hyperpituitary adenomas - Most common within women in child-bearing age - Subdivided into weak acidophillic (more common and sparsely granulated) and strong acidophillic (less common and densely granulated) - Hyperprolactinaemia can also be caused by other secondary causes - Head trauma, pregnancy, hyperplasia, drugs(inhibit the dopamine control of prolactin inhibition from dopamine), other disorders Growth hormone adenomas: - Second most common - Subdivided into - densely granulated - slow-growing and well-differentiated tumour - sparsely granulated - in younger patient, more aggressive and potential to be invasive - sometimes prolactinomas and growth hormone adenomas are mixed and presented in the same tumour Corticotrophs cell adenomas: - underlying cause of cushing's disease - also be subdivided into sparsely and densely granulated - usually monohormonal - usually associated with hyperprolactinaemia pituitary apoplexy: - sudden haemorrhage to the adenoma - clinical features: sudden onset of severe headache with diplopia and hypopituitarism - could even cause loss of consciousness or death Null cell adenomas (non-functioning pituitary adenomas) - commonly presented in elderly patient with visual problems pituitary carcinoma - primary tumour with metastasis potential - non-functioning and very rare secondary tumour - most commonly metastasise from breast, lung, GI Tract ischaemic necrosis: - during pregnancy as the pituitary gland enlarge to secrete more prolactin to prepare for lactation - usually not accompanied with increased blood supply -\> more susceptible to ischaemia Craniopharyngiomas: - slow growing - a bimodal distribution, common in children present in 5-15 years old and adults over 50 with visual problems - presented with hypopituitarism and diabetes incidius - usually with calcification on X-rays and cysts containing viscous oil with sparkling cholesterol crystals SBL prep: Differentials: Galatorrhoea: - prolactinomas -\> hypersensitivity of pituitary gland - drugs: anti-depressants, oral contraceptives, methyldopa(anti-hypertensive) - pituitary gland disorder: pituitary adenomas Amenorrhoea: - congenital adrenal hyperplasia -\> too much testosterone - FSH and LH deficiency - Mental health disorder Prolactin control and regulation: - Dopamine inhibits the release of prolactin 2.1 Thyroid and parathyroid gland Thyroid gland: - 2 lobes and an isthmus (bridge), a pyramidal lobe in (10-30% of individuals) - Females have larger thyroid glands - Medial to the common carotid artery, internal jugular vein and vagus nerve - T3 (triiodothyronine, 20%), T4 (thyroxin, 80%)-\> controlled by hypothalmus - Hypothalamus (Thyrotropin releasing hormone) -\> anterior pituitary (Thyroid stimulating hormone) - and calcitonin secreted here -\> released when blood Ca2+ level is high - supplied by the autonomic nervous system - sym: post ganglionic fibres enter via arteries - para: vagus nerve enter via superior pharyngeal nerve Blood supply: - Superior thyroid artery: - First branch from the external carotid artery - Enters via superior poles - Inferior - Originates from thyrocervical branch from subclavian artery - Enters inferiorly and posteriorly - 3-10% of individuals have an unpaired thyroidea ima artery 3. main veins: - superior thyroid veins, middle thyroid veins: both drain into internal jugular veins - inferior thyroid veins: drain into brachiocephalic veins Activation of T4 to T3 in individual organs - then T3 is converted into other hormones in individual - follicle - follicular epithelial cell -\> release T3 and T4 -\> requires iodine - parafollicular C-cells -\> calcitonin thyroid gland development: - first gland to develop (starting from week 4) - connected to the tongue by thyroglossal duct - From week 11 epithelial cells - From week 20 on TSH kicks in and T3/T4 are produced Parathyroid gland: - 2 superior and 2 inferior gland: - superior: superiorlateral part of the thyroid gland. - Inferior: 1-2cm from the entry of the inferior thyroid gland - Blood supply via thyroid arteries and veins - Produce parathormone (PTH) -\> produced by chief cells - Produced when calcium levels are low - Also regulates vitamin D levels Anatomical Variations of the Thyroid and Parathyroid Glands: - Most humans (\>80%) have four parathyroid glands - 1-12 parathyroid glands can be present - most common deviations are three glands and five glands - more commonly seen in the inferior glands - less commonly for the superior parathyroids, 2.2 Thyroid hormones Thyroid hormone stimulation: - Regulation in the hypothalamus -\> Thyrotropin releasing hormone (TRH) - Released by anterior pituitary -\> release thyroid stimulating hormone (TSH) - Stimulating thyroid to release T3 (triiodothyronine )and T4 (thyroxin) - Levels of TSH, T3 and T4 increase during early morning (12-3) and drops as the day goes on, shows circadian rhythm as with all other hormones released in the anterior pituitary - T3 and T4 provide negative feedback and inhibits TSH and TRH Thyroid hormone synthesis: - Amino acids form peptides in rough ER - Peptides and carbohydrates forms thyroglobulin (large protein without iodine) in golgi apparatus - Vesicles are formed and the thyroglobulin are released via exocytosis - At the same time, iodide is taken up by Na+/I- symporter when activated by TSH - Iodide is oxidized into iodine before entering the colloid - Iodine is then attached to thyroglobulin with the presence of thyroperoxidase (TPO) into monoiodotyrosine (MIT) and diiodotyrosine(DIT) - MIT and DIT then form T3 and T4 - T3 and T4 are then endocytosed into follicular cells - Proteolytic enzymes then cleaves T3 and T4 from the thyroglobulin - T3 and T4 are then released into blood stream Transport of thyroid hormones: - T3 and T4 are lipophillic -\> require protein transporter thyroxine-binding globulin (TBG), transthyretin, and albumin. - T3 and T4 can dissociate from binding proteins to enter - T3 or T4 then bind to intracellular receptors and cause - Thyroid hormone is then degraded in the liver Effects of thyroid hormone: - **Cardiovascular system** - have a permissive effect on catecholamines; increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.  - **Lungs** - thyroid hormones stimulate the respiratory centres and lead to increased oxygenation because of increased perfusion.  - **Nervous system** -- important for the development and operation of the central nervous system; helps with brain maturation by axonal growth and the formation of the myelin sheath; also important for maintaining excitability of autonomic and enteric nerves.  - **Skeletal muscles** - increases development of type II (fast twitch) muscle fibres.  - **Bone **- act synergistically with growth hormone to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts.  - **Gastrointestinal system** -- lack of thyroid hormone leads to reduced GI motility due to diminished activity of enteric neurons and GI smooth muscle. Live Lecture: Anatomy and histology of the endocrine system: Endocrine gland are derived from epithelium, surrounded by capillaries - Hormones and factors - Factors: molecules produced outside of glands from many different cell types and released next to the cells but also present in blood Control: Cortex -\> hypothalamus -\> anteior pituitary gland -\> target organ (GH and prolactin) from acidophil cells or target gland (ACTH, TSH, FSH, LH,) from basophil cells / posterior pituitary gland -\> target organ (ADH and oxytocin) - Hormones produced from hypothalamus are stored in herring bodies in posterior pituitary cells Or Metabolic signal (change in ion levels or glucose levels) -\> detected by receptors in glands -\> target organ Or Autonomic nervous system -\> glands -\> target organs Hypothalamus: - Circadian rhythm, Hunger/thirst, Body temp, Cortical arousal - Mediated by different nuclei in the hypothalamus Adrenal gland: - Left gland is pyramidal and hidden behind liver and IVC - Right gland is semilunar and usually larger - Cortex: produce corticosteroid hormones - Medulla is neuronal and for receiving preganglionic sympathetic innervation and releases adrenalin and lower levels of noradrenalin Ovaries: - Bloody supply via ovarian artery running in suspensory ligament - Theca external cells: fibroblast and smooth muscle cells - theca internal cells: sensitive to LH and produce androgen - granulosa cells: sensitive to FSH and convert androgens into estrogens 2.3 Thyroid disorder Negative feedback loop of thyroid hormone: - TRH from hypothalamus - TSH from anterior pituitary - T3 and T4 from thyroid gland - Inhibits TRH and TSH Summary of disorders Signs and symptoms of thyroid disorder: In short: - Hyperthyroidism: increased sympathetic drive, - hypo -\> reduced sympathetic drive Causes of hyperthyroidism: - graves disease - Toxic nodules - Thyroiditis -\> breakdown of thyroid tissue -\> increased release of preformed thyroid hormones in follicles - Important to differentiate between increasing release of thyroid hormone or preformed hormones stored in follicles \*Thyroid storm: - life-threatening situation - storm of thyroid hormones leading to severe signs and symptoms such as hyperpyrexia, cardiovascular compromised, altered mental state - rare condition (\