Documente Academic
Documente Profesional
Documente Cultură
Both act by raising cAMP in the target cells. In men, FSH acts on Sertoli cells to initiate and maintain spermatogenesis whilst LH stimulates interstitial cells (of Leydig) to secrete testosterone. Released in pulses with cyclical variation through the menstruation cycle. Release is stimulated by hourly pulses of GnRH (Gonadotrophin releasing hormone) from the hypothalamus. Inhibited by oestrogen/testosterone by negative feedback. Switches to positive feedback at ovulation to give an LH surge. Ovarian peptides (inhibin and follistatin) inhibit FSH release. Hypergonadotrophinism can cause precocious puberty whilst hypog. Can cause infertility due to a lack of spermatogenesis.
14.2.2.4 Prolactin/mammotrophin
A protein made in Lactotroph cells which matches the receptor tyrosine kinase found in the breast. It promotes growth and development of breast and milk production Is inhibited by the release of dopamine by the hypothalamus, stimulated by circulating oestrogen, stimulated by suckling and during pregnancy. There is a large increase in the number of Lactotroph cells so that the pituitary almost doubles in size during pregnancy. Hypersecretion can be caused by a tumour (prolactinomas) and result in galactorrhoea, infertility (infertility stops the production of a new foetus whilst the first is still suckling) and impotence. Dopamine agonists (e.g. bromocryptine) are used to suppress PRL release.
Diabetes insipidus can be caused by an irregularity in ADH action. Hypothalamic DI is caused by a lack of ADH production (e.g. due to a tumour suppressing the action of the cells). Renal DI is caused by a lack of kidney function (e.g. due to a mutation in the receptors of the kidney).
14.2.3.2 Oxytocin
Has a role in parturition and milk-ejection. 14.3 Thyroid Gland and Iodothyronines, Calcitonin Thyroid diverticulum forms from the midline of the mouth floor between the 1st and 3rd brachial arch components of the tongue. Grows caudally over developing larynx to the anterior aspect of the trachea. Then associates with parathyroids which develop from the 3rd and 4th pharyngeal pouches and the neural crest cells that develop into the parafollicular C cells (calcitonin cells). Has two lateral lobes and a central isthmus. Most of the tissue along the developmental line disappears but some can remain resulting in ectopic thyroid tissue being found in the tongue. The isthmus is the central part of the thyroid found between the 2nd and 4th rings of the trachea and the lateral lobes extend up on either side of the trachea and larynx. Its enclosed in a pre-tracheal fascia which anchors it to the airway resulting in it moving when swallowing occurs. Big arterial and venous blood supply via system in diagram to right. Microstructure: made of circles of follicular cells around a colloid. Comes up pink on an H and E stain with the surrounding cells showing up due to purple staining nuclei. Active follicles have tall cells and small colloids with spaces where vesicles have released thyroglobulin back into the follicular cells where it is converted into T3 and t4. C cells (parafollicular cells) that release calcitonin are located at the base of the follicle epithelium. Calcitonin lowers plasma calcium The hypothalamus releases TRH in response to an increase in plasma glucose and cold. This then stimulates the release of TSH by the pituitary gland. This then travels in the blood supply to the thyroid to stimulate the release of T3 and T4. Also a negative feedback of T3 and T4 on TSH production. An Na/I symporter on the basal follicular membrane traps iodine from the plasma into the follicle where it is then used to make thyroglobulin. These are NIS and there are pendrine on the apical surface which pump I into
the colloid. This means that there is a very large store of I in the colloid to smooth out T3 and T4 production when I is low in the blood. Thyroperoxidase (TPO) is found on the apical membrane and this is the enzyme that converts thyroglobulin into T3 and T4 Production: Transport I- into cell via NIS, transport into colloid by pendrine and then convert I- to I2 and iodinate thyroglobulin by TPO. The molecule is iodinated at its tyrosine residues for storage. The colloid is then exocytosed by a TSH mediated process and proteases in lysosomes digest the thyroglobulin to produce T3 and T4 from the combined iodinated tyrosine residues. TSH stimulates TH release but also stimulates thyroid growth by binding to a GPCR linked to adenylyl cyclase which ends up activating PKA which phosphorylates transcription factors, making them stimulate DNA replication and so cell growth. T3 and T4 are transported around the body in the blood bound to certain proteins that then give them a longer half life than expected. These include thyronine-binding globulin (TBG) (higher affinity for T4 than T3), transthyretin (lower affinity) and albumin (very low affinity but high capacity). This results in T4 having a longer half life despite it being the inactive form. Peripherally, T4 is degraded to T3 by type 1 and 2 deiodinase and rT3 by type 3. Type 1 is located in the liver and kidneys and provides T3 for the blood plasma. Type 1 can also convert it to the inactive rT3 form to be cleared from the body. Type 2 is found in target tissues like the brain, adipose and pituitary and provides intracellular T3. Type 3 inactivate both T3 and T4. Iodothyronines are cleared through the kidneys as thyronine after deiodination and the iodine is salvaged for reuse by the kidneys. Deiodinases are found throughout the body in different forms: D1 and 2 produce T3 and D3 produces rT3 or T2 for inactivation and removal from the body. Thyroid hormones either work by interacting with certain enzymes, glucose transport and mitochondrial proteins, or by T3s interactions with nuclear receptors which act on response elements (TREs) which are found in gene promoter regions. Works by stimulating or inhibiting the production of different mRNAs. Sensitivity to T3 is regulated via a number of nuclear receptors. T3 actions: o Metabolic: increase protein breakdown (but RNA polymerase I and II is also stimulated, leading to an increase in protein synthesis initially), glycogenolysis, gluconeogenesis, cholesterol breakdown and lipolysis. This results in there being more substrate available for respiration. o Cardiovascular: increase cardiac output, rate and force by increasing production of myosin, beta1 receptors and Ca2+ ATPase, thus increasing contractility. o Developmental: essential for postnatal growth of CNS (stimulates production of myelin, neurotransmitters and axonal growth), bone (linear growth by chondrocyte activity) and hair, teeth and epidermis. o Others: stimulates gut mobility, increases skeletal muscle activity and increases betaadrenergic sympathetic stimulating of the heart, adipose tissue, skeletal muscle and the liver. Abnormal thyroid activity: Goitre could be caused by: o Iodine deficiency leads to lower levels of T3 and T4 secretion which means a lack of negative feedback on the hypothalamus and pituitary leading to high levels of TRH and TSH. If the enlarged thyroid then traps enough iodine then T3 and T4 levels can be normal despite the goitre.
o Graves disease when autoimmune antibodies attach to TSH receptors permanently activating them, leading to very high TH levels. o Tumour which may be functioning or non-functioning. Hyperthyroidism causes a raised BMR, raised heart rate and cardiac output, heat intolerance, weight loss despite a large appetite, increased sympathetic drive. And eye protrusion. Can be caused by graves disease or a tumour. Hypothyroidism is called cretinism which leads to mental retardation and stunting of postnatal growth if not treated correctly. It is called myxoedema in adults and results in a reduced BMR, slow mentation, hypothermia and constipation. Can be caused by many different things: o Mutation in the gene for NIS, pendrine, TPO or thyroglobulin. o Tumour in the thyroid or the pituitary (can be distinguished diagnostically by looking at TSH levels which will be low if the pituitary is affected or high if the thyroid is the problem). o Mechanical damage e.g. from a car accident o Mutation in the gene for thyroid, TSH or TRH receptors. o Damage to capillary system that transports TRH. o Iodine deficiency o Failure in development e.g. due to a mutation in the thyroid transcription factor (most common cause of cretinism in the UK) o Autoimmune destruction (most common) o With a MCT8 mutation, T3 is unable to enter cells leading to cretinism despite normal levels of thyroid hormones. o Burnt out Graves disease: if the disease is untreated, the thyroid is overworked and will eventually shut down. Treatment: hypothyroidism is treated by hormone injections (called thyroxin or T4) at different times of the day with hyperthyroidism being treated using radioactive iodide or surgery. Euthyroid sick syndrome is when there are abnormal levels of thyroid hormones (usually low T3 and T4 and high TSH and rT3) despite there being no disease in the thyroid gland. This can be due to many chronic and acute diseases such as GI, cardiovascular and pulmonary diseases which all affect the metabolic rate and stress exerted on the body and so the feedback system that controls TRH output.
Wilms tumour (WT1) and steroidogenic factor 1 (SF1)). The fetal adrenal zone is very prominent and is made up of two sections: the fetal and definitive zones. The second is very similar to the adult adrenal gland whilst the foetal zone produces weak androgens which the placenta then aromatizes to make oestrogen. The adrenal medulla is made of groups of chromaffin cells packed with catecholamine-containing cells which store large amounts of adrenaline and noradrenaline. The adrenal cortex is made up of three layers of types of cells arranged in balls and sheets interspersed with capillaries: the zona glomerulosa, fasciculate and reticularis. The adrenal gland is well vascularised by branches from the phrenic artery, the renal arteries and direct from the aorta. They drain into a single adrenal vein in each gland which then drains into the inferior vena cava on the right or the left renal vein. These blood vessels dilate under stress unlike all other blood vessels. The chromaffin cells are innervated by thoracic preganglionic sympathetic nerves that release Ach onto nicotinic receptors.
14.5.2.2 Cortisol
Produced by the zona fasciculata with receptors present in almost all cells. The glucocorticoid receptors are in the cytoplasm and when activated will them migrate into the nucleus. When inactivated in the liver it is converted to cortisone. Cortisol release is stimulated by CRF stimulating ACTH which then raises cAMP levels in the medulla and this happens within seconds though it doesnt have an effect for a couple of hours. Actions:
o Protects the body in prolonged stress so as to preserve glucose for the brain. o Stimulates the metabolism of carbohydrates (glycolysis) and so opposes insulins actions, lipids (lipolysis and ketogenesis) and proteins (protein breakdown and gluconeogenesis). This is all done through the stimulation of production of the enzymes involved. o Maintains the circulation by increasing heart contractility and increasing vascular tone. o Maintains plasma volume by preventing increased capillary permeability. o Maintains ability of skeletal muscles to produce prolonged contractions. o Promotes Na+ retention so excess cortisol can lead to too little water being excreted out of the body. o Suppresses REM sleep o Increases surfactant production in the lungs. o Increases haemopoesis o Inhibits leukocyte translocation from blood to sites of tissue damage, stimulates lymphocyte destruction. As a result, glucocorticoid selective drugs are used to treat inflammatory diseases such as asthma. o Inhibits reproduction and lactation.
14.5.3 Aldosterone
Aldosterone is produced in the zona glomerulosa and its receptors are only present in the nuclei of a few cell types (including kidney collection tubule epithelia, salivary and sweat glands, colon and some brain neurons). Cortisol also binds to mineralcorticoid receptors so in aldosterone targets, cortisol is inactivated by 11-hydroxsteroid dehydrogenase to protect the MRs from normal cortisol levels. Aldosterone regulates ion transport and so water retention in the kidney collecting tubules by stimulating Na+ reabsorption in exchange for potassium, hydrogen and ammonium ion secretion. There is a 2hr lag in response to aldosterone secretion whilst Na/K ATPase transcription is increased. In the glands and colon aldosterone also causes the retention of sodium. Aldosterone is stimulated by the renin-angiotensin system. This system is stimulated by low plasma sodium or low renal blood pressure. These stimulate the juxtaglomerular apparatus (JGA, distal tubule and mesangial cells) to release rennin which breaks down plasma angiotensinogen to produce angiotensin 1 which is then converted to angiotensin II by ACE. AII stimulates the release of aldosterone, arteriolar constriction and drinking in response to thirst. High plasma potassium can also stimulate aldosterone release and sympathetic activation can stimulate renin secretion by the JGA. Hyperaldosteronism results in sodium loss, low blood volume and low blood pressure. Hypoaldosteronism results in the opposite and is called Conns syndrome. Spronolactone can therefore be used as an anti-hypertensive since it is an aldosterone antagonist and so can ACE inhibitors. Very high levels of cortisol can also mimic this condition since this will overwhelm the deactivating enzyme and so reach the MRs.
(dehydroepiandrosterone) sulphate (as opposed to DHEA that is made in adults) is produced in copious amounts since it then travels to the placenta where it is converted into oestrogen.
14.6.1 Insulin
Insulin has the general effect of promoting anabolic reactions by: increasing glucose and amino acid uptake, suppressing glycogenolysis, suppressing lipolysis and proteolysis and supporting growth and proliferation. It is synthesised as proinsulin which is then broken down by proteolysis to form C peptide and insulin. It is released in response to high blood glucose or amino acid concentrations, GI hormones (e.g. Glucagon-like peptide/GLP which are released in response to nutrients like carbohydrates being sensed in the gut lumen. Glucose-dependent insulinotropic peptide/GIP also anticipates the arrival of more glucose. Type 2 diabetics are often not responsive to GIP. The mechanism by which glucose levels are sensed is as follows: blood glucose rises, more glucose is co-transported with Na+ into the cells through Glut2 proteins, more glucose is metabolised, more ATP produced, ATP binds to K+ channels and Na+/K+ pumps to inhibit K+ current, depolarises membrane, opens Ca2+ channels, Ca2+ bids to insulin granules and causes exocytosis. Sulphonylureas are a class of drugs used to treat some Type 2 diabetics and neonatal diabetes and works by The receptor that detects insulin is called tyrosine kinase which has two peptide tails inside the cell that cross phosphorylate each other (this is why any mutations in this gene are dominant) for activation. They then phosphorylate other molecules which set off cascade reactions e.g. phosphorylate Glut4 proteins which migrate to the cell membrane and so increase glucose transport into the cell. Insulinoma is a tumour of the beta cells. Causes unregulated release of insulin leading to hypoglycaemia.
MEN or multiple endocrine neoplasia is a class of autosomal dominant genetic conditions predisposing someone to develop multiple endocrine tumours. o MEN 1 is caused by a mutation in the MEN1 gene and usually causes tumours in the islets and the rest of the GI endocrine system, parathyroid and pituitary. o MEN 2 is mostly caused by a mutation in the RET proto-oncogene leading to phaeochromocytoma (chromaffin cells of adrenal medulla) and medullary thyroid carcinoma as well as sometimes parathyroid hyperplasia, gastrointestinal symptoms, Marfans and muscular hypotonia. Diabetes mellitus: Type I: o caused by a total loss of insulin due to an autoimmune reaction destroying cells. Treated with insulin injections which are now being developed into an artificial pancreas that will release the insulin all by itself and give more constant release to allow for better control. o 0.5% prevalence with onset usually occurring during childhood and is fatal if left untreated. o Symptoms: polyurea, thirst, dehydration, weight loss and ketosis. o If an insulin dose is missed/before the condition is diagnosed, cells are no longer able to take up glucose so switch to metabolising fats. This leads to a dangerous build up of ketone bodies which are acidic and toxic at high levels, causing ketoacidosis. Symptoms include Kussmaul breathing, dry skin and mouth, flushed face, fruity breath and vomiting. Type II: o Caused by a resistance to insulin or a disordered secretion of insulin. o 4-5% prevalence usually with mature onset and in those who are obese. o Can be caused by pancreatic amyloidosis which is when amyloid (an insoluble pleated sheet protein produced from amylin which is secreted at the same time as insulin and works to inhibit nutrient release into the blood. If the pancreas is subjected to very high levels of glucose, some of the usually soluble protein is converted into insoluble plaques instead of being passed out of the body via the kidneys as is normal.) aggregates in the pancreas causing cyotoxicity which kills the islet cells and reduces insulin production 14.6.2 Glucagon See biochem notes for detail. Polypeptide synthesized by -cells released in response to hypoglycaemia. Acts on liver via cAMP pathway to promote glycogenolysis and gluconeogenesis and promotes lipolysis in adipose tissue. Day to day glucagon stimulates glycogen release and use but during prolonged fasting it stimulates fatty acid breakdown so glucagons affects depend upon the dose. Glucagonoma causes hyperglycaemia and weight loss. Is synergistic with GH, catecholamines and glucocorticoids (cortisol opposes insulins effects so as to preserve glucose for the brain. 14.6.3 Somatostatin Paracrine peptide produced in -cells (and the stomach and intestines) which inhibits insulin and glucagon release. It also has negative effects in the gut, salivary glands and pituitary and decreases all metabolic activity in the liver. It is used to treat giantism and Acromegaly since it inhibits GH secretion.
Pandreatic polypeptide Released in response to meals and vagal stimulation (hypoglycaemia, exercise and starvation). It inhibits the secretion of pancreatic enzymes and gall bladder contraction and may suppress appetite.