L06 - Hormone synthesis and action PDF

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L02- Hormone Synthesis and Action Following this lecture, you should be able to: •

Understand the concept of glands, hormones and target tissues

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Name the three major groups of hormones and outline their synthesis, storage, transport to the target organs and how they react with specific receptors in or on the target organ

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Understand the role of feedback and endocrine axis in endocrine regulation

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Indicate the role of clinical observation in our understanding of hormone actions.

Hormones USED TO BE TAUGHT AS Comparative endocrinology  

Actions of hormones similar throughout evolution. o Look at a specific hormone and how it affects different species Hormones act Similarly across species – they are all controlling molecules, even if what they are controlling is different

Hormones are NOW TAUGHT AS Clinical endocrinology 

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Action of hormones related to pathology o How hormones affect different parts of the body  If you understand how the system works, you can understand the disease Hormones are still controlling molecules – just different examples

THE ENDOCRINE SYSTEM  

A system of ductless glands and cells which secrete hormones The endocrine system regulates many physiological processes e.g. metabolism, homeostasis and reproduction.

Glands  

ENDOCRINE GLANDS - release secretions (hormones) into blood directly from cells (they are ductless glands) EXOCRINE GLANDS - (not part of the endocrine system) release their secretions outside the body and may be ducted e.g. gut secretions (the gut isn’t part of the body, it’s just part of the digestive tract which is a tube that goes through you), sweat glands o

Exocrine glands are glands that produce and secrete substances onto an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, and mucous

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MIXED GLANDS - e.g. Pancreas produces digestive juice + insulin, glucagon and somatostatin.

The 2 main regulatory systems of the body Endocrine and Nervous systems •

Multicellular animals must monitor and maintain a constant internal and external environment. This is coordinated by two integrated systems: the nervous and the endocrine system. Feature

Endocrine system

Nervous system

Chemical coordinator

Hormone – many different types each affecting different specific tissue

Neurotransmitter – few types, secreted only onto target tissue.

Speed of effect

Generally slow

Generally rapid

Duration of effect

Generally long-lasting

Generally short-lived

Localisation of effect

Secreted into blood therefore widespread.

Secreted onto target cell so effect very localised.

HOWEVER – the boundaries blurred because some hormones are secreted from nerve endings: neuro-endocrine hormones. Can have a mixture of the characteristics of the endocrine and nervous system.

Mechanisms of Chemical Signalling in Endocrine/neuroendocrine systems An intracrine signal is generated by a chemical acting within the same cell (intracellular action) Autocrine signals are those in which a chemical acts on the same cell that it is secreted by A paracrine mechanism is defined as chemical communication between neighbouring cells within a tissue or organ. A chemical released by a specialized group of cells into the circulation and acting on a distant target tissue defines the ‘classical’ endocrine and neuroendocrine signalling mechanism. A neuroendocrine hormone would be secreted directly into the blood by a neurosensory cell through an axon. It is an electrical signal from the brain that causes the axon to release hormone.

The Endocrine System: Control of action at a distance Mainly controlled by negative feedback

Make sure you can understand what happens when one of these steps goes wrong.

Control of hormone release – Feedback Feedback - process by which body senses change and responds to it. Negative Feedback (most common) - process by which body senses change and activates mechanism to reduce it. The final product of an endocrine cascade acts to inhibit the release of hormones higher up the cascade. Positive Feedback - process by which body senses change and activates mechanism to amplify it.

Endocrine Axis 

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The target tissue for one hormone may be another endocrine gland o (a tropic hormone stimulates another endocrine gland) This functional grouping of endocrine glands is called an endocrine axis (e.g. Hypothalamopituitary-adrenal (HPA) axis) Faults may occur along this axis.

Hypothalamic-pituitary axis   

Neurons in the hypothalamus secrete thyrotropin releasing hormone (TRH), which stimulates cells in the anterior pituitary to secrete thyroid-stimulating hormone (TSH). v TSH binds to receptors on epithelial cells in the thyroid gland, stimulating synthesis and secretion of thyroid hormones, which affect probably all cells in the body. When blood concentrations of thyroid hormones increase above a certain threshold, TRHsecreting neurons in the hypothalamus are inhibited and stop secreting TRH. This is an example of "negative feedback".

The 3 types of Hormones 1. Protein and peptide hormones o o

 Most common type of hormone, made of chains of amino acids Mainly produced from pituarity and hypothalamus  Water soluble (i.e. hydrophilic) Transport in blood easily  Preformed and stored in membrane bound vesicles ready for release by exocytosis.  These hormones are produced on ribosomes (RER) as large precursor molecule - pre-prohormone  a pre-prohormone is a massive protein where the active hormone needs to be cleaved out

 PRE-PROHORMONE  PROHORMONE  HORMONE Active hormones get cleaved out of the pre-prohormones. This happens in the RER and in the Golgi This process is called proteolysis 

o

TSH, LH, FSH, hCG These glycoproteins are related    

All released from anterior pituitary Alpha subunit of amino acid is always the same Beta subunit are different, and can display selectivity Alpha subunit is cleaved off to activate these hormones

2.Steroid hormones 

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All made from cholesterol. o Cholesterol is required in correct amounts to produce steroidal hormones  Cholesterol is acted upon by CYP11A, an enzyme, which produces pregnenolone.  Pregneonoline has the capability to produce all steroidal hormones (depending on the enzymes and raw substances available) Steroidal hormones are produced from adrenal cortex Are sex hormones Lipid soluble o Need a transport protein to travel in the blood, as they are hydrophobic o However, can pass straight through membrane (i.e. Lipophilic) Synthesised as required and diffuse out of the cell immediately o Cannot be stored due to solubility in membrane. Synthesised in smooth ER from cholesterol derived from diet or from acetate.

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Cholesterol ester are near cell wall Hydrolysis of esters release cholesterol

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Cholesterol is transported within the adrenal cortex cell via the StAR protein (steroid acute regulatory protein), where ACTH regulates the activity of StAR and the processing of cholesterol.

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Star production is increased by ATCH

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Tissue-specific and cell-specific expression of the enzymes necessary for each steroid hormone e.g. in adrenal 3 cortical regions: o zona glomerulosa - aldosterone o zona fasciculata - cortisol o zona reticularis - adrenal androgens  e.g. zona glomerulosa contains cells expressing enzymes leading to aldosterone synthesis  Cells here do NOT express the enzymes necessary for cortisol synthesis or sex steroid synthesis

The first and rate-limiting step is the conversion of choles

H O

CYP 11A

Pregnenolone formed in mitochondrion b t moves to endoplasmic reticulum for processing to

Chhormones ol es t e r ol

Secretion and excretion   

Newly synthesized steroid hormones are rapidly secreted from the cell, with little if any storage. Increases in secretion reflect accelerated rates of synthesis. o Because steroidal hormones cannot be stored Steroid hormones are eliminated by inactivating metabolic transformations and excretion in urine or bile

3.Amine hormones Amines – mainly Thyroid Hormones (lipophilic)  

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Contain 2 tyrosine residues/derivatives bound together. Will either have: o Contain 4 iodine atoms (T4). o Contain 3 iodine atoms (T3). They are small, non-polar molecules. o hydrophobic o Soluble in plasma membranes

Synthesis of T4 in the thyroid

Hormone

Transport in Blood 

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Peptide hormones are hydrophilic - freely water soluble. o Have to bind to appropriate receptor on cell wall Steroid and amine hormones need to be transported in blood by carrier protein to: 1) increase solubility in blood 2) increase half-life 3) create a readily accessible reserve in blood.  Normally, these hormones can pass straight through cell membranes  Can bind to receptors in cytoplasm o Forms a complex o Goes into nucleus o Binds to hormone response element o This then has an effect of cell A LOT OF STERIOD AND THROID HOMROES HAVE a specific binding proteins e.g. Thyroid binding globulin (TBG) and cortisol binding globulin (CBG). o Non-specific binding proteins do this also e.g. Albumin - loose binding protein. Aldosterone binds to albumin.

Site of action of hormones 

Peptide

o

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Can’t pass through cell wall, therefore, they have to bind to cell surface receptors located on surface of target cell  Hormone binding activates second messenger cascade  Ultimately there is phosphorylation of proteins within the cell and the activated or deactivated proteins bring about a change in cellular function

Steroid o Can pass straight through, because they’re lipid soluble o Binds to Intracellular receptors – either located in the cytoplasm or nuclei  Forms a complex of the hormone-receptor. This complex binds to a section of DNA called the HRE, the hormone response element.

Clinical Endocrinology 

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Endocrine disorders: 1) Overproduction of a hormone 2) Underproduction of a hormone 3) Non-functional receptors that cause target cells to become insensitive to hormones Endocrine knowledge has come from: o Clinical observation o Experiments

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Surgical removal of gland. Grafting or injection of extracts after removal Administration of excess extract to normal.

Endocrine disorders Excess hormone production  Often caused by tumours  Or exogenous administration of hormone  Treatment - surgical removal of part of gland Deficiency in hormone production • The defiency with either be: • 1° - primary organ inadequate (removed/destroyed), tropic hormone  - feedback 

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A tropic hormone is a hormone that stimulates an endocrine gland to grow and secrete it's hormones

2° – another part of the endocrine axis isn’t producing something, which leads to the deficiency - tropic hormone deficient Autoimmune organ destruction most common cause Treatment - replacement therapy o Orally absorbed, long half-life e.g. steroid (corticosteroid), thyroid (thyroxine) hormones. o Injection e.g. GH, insulin – peptide hormones. Otherwise degraded in GI tract. But failure can occur at any point in chain from synthesis to initiation of response including at receptor level or cascade generation.

HORMONE

DEFICIENCY

Growth (GH)

(Dwarfism – proportionate)

EXCESS Gigantism (children) Acromegaly (adults)

Diabetes Insipidus Antidiuretic

Diabetes insipidus is a rare condition where you produce a large amount of urine and often feel thirsty. Diabetes insipidus isn't related to diabetes mellitus

Hypothyroidism (1° 2° 3°) Thyroid

Parathyroid

Hypervalemia (SIADH)

Hyperthyroidism

Hashimoto’s thyroiditis (1°) Congenital hypothyroidism (iodine deficiency)

(Graves’ Disease)

Hypoparathyroidism - tetany

Hyperparathyroidism (1° 2° 3°) bone resorption Coma

Insulin

Diabetes Mellitus

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin.

Cortisol

Adrenal Insufficiency

Cushing’s syndrome

(Addison’s Disease) 1° aldosteronism - Conn’s Aldosterone

Hypoaldosteronism 2° aldosteronism

Pro-opiomelanocortin(POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesizedin the pituitary from the 285-amino-acid-long polypeptide precursor pre-proopiomelanocortin(pre-POMC), by the removal of a 44-amino-acid-long signal peptide sequence during translation. Within pre-POMC is ACT and also MSH....