Week 3

• Endocrine system


  Communication system in the human body that allows for simultaneous control across many cells and tissues via hormones
• Endocrine glands


  • Produce cell signalling molecules called hormones
  • Hormones are secreted into circulation before being transported to other parts of the body
  • Hormones are recognised by specific receptors
  • Association of a hormone with a receptor induces a physiological change in the target cell
  • Aberrations in hormone secretion and/or action are the main causes of endocrine diseases
• Classic endocrine glands


  • Pineal gland
  • Hypothalamus
  • Pituitary gland
  • Thyroid gland
  • Parathyroid glands
  • Adrenal gland
  • Pancreas
  • Testes
  • Ovaries
• Other endocrine tissues

  • Gastrointestinal tract
  • Liver
  • Heart
  • Kidneys
  • Skin
  • Adipose tissue
  • Skeletal muscle
  • Bone
• Types of hormones


  • Peptide hormones
  • Amino acid derivatives
  • Lipid derivatives
• Peptide hormones


  Comprised of amino acids, including small peptides, short polypeptides, small proteins and glycoproteins
• Amino acid derivatives


  Derived from the amino acids tryptophan or tyrosine
• Amino acid derivative hormones

  • Melatonin
  • Thyroid hormone
  • Dopamine
  • Noradrenaline
  • Adrenaline
• Lipid derivatives


  Derived from arachidonic acid or cholesterol
• Lipid derivative hormones


  • Eicosanoids (leukotrienes, prostaglandins, thromboxanes, prostacyclins)
  • Steroid hormones (oestrogens, progesterone, androgens, cortisol, aldosterone, calcitriol)
• All steroid hormones are produced from cholesterol
• Hormone


  Signalling molecule secreted by an endocrine gland into circulation and acts on a distant target cell
• Hormones


  • Can act throughout the body, often on multiple tissues at the same time
  • Specificity of action depends on whether cells express receptors for that hormone
  • Cells without the appropriate receptor will be unaffected by the hormone
• Short distance cell signalling


  Cell signalling molecules are secreted into interstitial fluid and act on neighbouring cells or the secreting cell itself
• Autocrine signalling


  Signalling molecule acting on its secreting cell
• Paracrine signalling


  Signalling molecules acting on neighbouring cells
• Physiological response to hormones

  • Depends on the concentration of the free, biologically active fraction of the hormone
  • Depends on the sensitivity of the target cell, including the presence of receptors, receptor activation and intracellular signal transduction
• Causes of too much hormone activity

  • Hypersecretion
  • Reduced plasma protein binding
  • Reduced clearance
  • Excessive response at tissue target (rare)
• Causes of too little hormone activity

  • Hyposecretion
  • Increased clearance
  • Tissue resistance or insensitivity (common)
• Neurohormones


  Hormones that originate from neurons, instead of endocrine glands
• Hypothalamus


  • Part of the central nervous system
  • Connected to the pituitary gland by the infundibulum or pituitary stalk
  • Made up of nuclei and nerve tracts that surround the third ventricle
  • Regulates behaviours and homeostasis
  • Integrates stimuli from external and internal sources
  • Outputs neural and humoral signals
  • Both neural tissue and an endocrine gland
  • Secretes neurohormones
• Anterior pituitary


  • Contains 5 endocrine cell types, each producing their own hormones
  • The gonadotrophs produce two hormones, FSH and LH
• Hypothalamic-pituitary axes


  • Hypothalamic-pituitary-thyroid (HPT) axis
  • Hypothalamic-pituitary-gonadal (HPG) axis
  • Hypothalamic-pituitary-adrenal (HPA) axis
• Hypothalamic releasing factors


  • Neurohormones from the hypothalamus that stimulate the release of anterior pituitary hormones
  • Small peptides that rapidly metabolise in blood and are not measurable in peripheral systemic blood
• Thyroid gland


  Sits at the front of the neck area
• Thyroid gland


  • Should not be confused with the parathyroid glands
  • Fairly small ductless alveolar gland, measuring approximately 5cm in width
  • Mostly composed of epithelial cells arranged in thyroid follicles (about 300 follicles, which vary in size from 0.02 to 0.3mm)
  • Thyroid follicles possess a central cavity that is filled with a sticky fluid called colloid (a protein-rich reservoir of thyroid hormone production)
  • Within the spaces between the thyroid follicles are the parafollicular cells (C cells) which secrete calcitonin
• Goitre


  A prominent bulge that can occur when too much hormone being produced by the gland (hyperthyroidism) or too little hormone being produced (hypothyroidism)
• T4


  Inactive thyroid hormone
• T3


  Active thyroid hormone
• Thyroid hormones


  • T4 and T3 are synthesised by the thyroid follicles
  • Only about 20% is T3 (active hormone) and the remaining 80% is T4 (inactive hormone)
• Thyroid gland


  One of the main regulators of metabolic processes including basal metabolic rate, gluconeogenesis, glycogenolysis, protein synthesise, lipogenesis and thermogenesis
• T3


  • Increases the size and number of mitochondria within the cells, increases the turnover of various endogenous macromolecules by increasing their synthesis and degradation
  • Increases the basal metabolic rate, thereby increasing the body's oxygen and energy consumption
  • Stimulates the production of RNA polymerase 1 and 2, thereby increasing the rate of protein synthesis and turnover
  • Increases the rate of protein degradation
  • Potentiates the effects of the beta-adrenergic receptors on the metabolism of glucose, increases the rate if glycogen breakdown and glucose synthesis in glucogenesis
  • Stimulates the breakdown of cholesterol and increases the number of LDL receptors, thereby increasing the rate of lipolysis
  • Increase the heart rate and force of concentration, thereby increasing cardiac output by increasing beta-adrenergic receptor levels in myocardium
  • Has profound effect upon the developing embryo and infants, affects the lungs and influences the postnatal growth of the central nervous system
  • May increase serotonin in the brain, in particular in the cerebral cortex, and down-regulate 5HT-2 receptors
• Calcitonin


  A 32 amino acid peptide hormone secreted in humans by the parafollicular cells (known as c-cells) of the thyroid gland
• Calcitonin


  • Regulates calcium levels in the blood by decreasing it, opposing the actions of parathyroid hormone which increases blood calcium levels
  • Inhibits the activity of osteoclasts (cells that break down bone), reducing the amount of calcium that enters the blood
  • Decreases the amount of calcium that the kidneys reabsorb and release back into the bloodstream, thus causing lower blood calcium levels
• Thyroid hormone synthesis


  1. ATE ICE process (6 key steps, not important to remember details)

  2. Iodine is incorporated into T4 and T3 hormones as part of their structure
• Iodine


  Rarely occurs as the trace element, usually occurs as a salt and therefore is referred to as iodide
• Iodine


  • Essential element that can only come from diet
  • Without sufficient iodine, the thyroid gland cannot make hormones
  • Iodine deficiency is the most common cause of thyroid disorders worldwide
  • A low iodine diet can cause hypothyroidism, an enlarged thyroid gland (goitre) and can affect fertility, pregnancy and neurodevelopmental disorders in newborns
• Hypothalamus pituitary thyroid axis

  1. T3 levels in the pituitary gland regulate the secretion of thyroid-stimulating hormone (TSH)

  2. TSH, produced in the anterior pituitary, is the chief player in thyroid gland function and morphology

  3. TSH provides negative feedback by decreasing synthesis of thyrotropin-releasing hormone (TRH) from the hypothalamus as well as blocking the action of TRH that stimulates TSH release

  4. Release of TSH fuels uptake of iodide by thyroid gland and accelerates many steps in thyroid hormone synthesis

  5. Release of TSH also increases growth and vascularisation of the thyroid gland itself

  6. Both T3 and T4 provide negative feedback to TSH secretion, while TRH determines the setpoint
• Thyroid hormones


  • Thyroid stimulating hormone (TSH) increases T4 and T3 in the blood circulation
  • Thyroid hormones are lipophilic, meaning they are relatively insoluble in blood plasma
  • The vast majority of circulating thyroid hormones (>99%) are bound to plasma proteins, such as thyroxine binding globulin (TBG), thyroxine-binding prealbumin (TBPA) and albumin (A)
  • It is only the unbound or "free" fraction of hormones that are able to bind to thyroid hormone receptors within cells to exert a physiological action
  • T4 and T3 are transported into cells by specific carrier-mediated mechanisms
  • Once inside the cell cytoplasm T4 can be deiodinated to T3 or rT3 depending on the enzyme expression
  • The hormones move into the nucleus and bind to thyroid hormone receptors
  • There are various receptor subtypes (e.g. TRalpha1, TRbeta1 and others)
  • Thyroid receptors are nuclear receptors that function as ligand-dependent transcription factors, with the thyroid hormone-receptor complex binding to "response elements" in the promoter regions of genes to regulate the expression of target genes
• Physiological effects of thyroid hormones

  • Calorigenic or thermogenic effects: Stimulate oxygen consumption in many cells of the body, resulting in increased metabolic rate and heat production
  • Stimulate the basal metabolic rate, in particular through endorsement of ATP production and generation and maintenance of ion gradients
  • Cross the BBB and act on the hypothalamus to increase sympathetic nervous system (SNS) activation
  • Can modulate the heat-generating capability of brown adipose tissue via uncoupling protein 1 (UCP1)
  • Growth and developmental effects: Required for normal somatic growth and neural development, skeletal development and linear bone growth, development of the nervous system
  • Fuel metabolism effects: Higher levels of TH favour catabolism, with glycogenolysis, proteolysis and lipolysis being observed
  • Cardiovascular or sympathomimetic effects: Increase the cardiovascular response to catecholamines, increase heart rate and force of concentration, increase blood pressure
  • Reproduction: Normal TH levels are required for reproduction, with thyroid disorders impacting on fertility in both sexes