Endocrine Communication

• Process of hormone transport involves:

  1. The regulated secretion of a hormone from a endocrine cell
  2. The diffusion of the secreted hormone into the vasculature
  3. Diffusion of hormone from vasculature into a target organ cell with a receptor to bind to it and induce a response
• The three types of hormonal pathways:

  • Autocrine signalling (endocrine cell has specific receptors)
  • Paracrine signalling (adjacent cells have receptors)
  • Endocrine signalling
• Hormones can act on target cells via:

  • controlling rate of enzymatic reactions
  • Controlling ion and molecular transport across membrane
  • Controlling gene expression and protein synthesis
• Cellular mechanism of action: the binding of a hormone to the target cell's receptor
• Hormones can be terminated through:

  • Limiting secretion in endocrine cell (negative feedback loops)
  • Remove / inactivate hormone through enzymic degradation in liver and kidneys
  • Terminating activity through receptor-hormone complex endocytosis and then digestion in lysosomes
• Tropic hormones: regulate the secretion of another hormone

  Non-tropic hormones instead act on non-endocrine tissues
• Three classes of hormones:

  • Amine hormones (removed COOH in either tyrosine or tryptophan)
  • Peptide hormones (an amino acid linked chain)
  • Steroid hormones (synthesised from chloresterol in either the adrenal cortex, gonads, skin or placenta)
• Steroid hormones are lipophilic and so pass through the phospholipid bilayer membrane. As a result, they have limited storage capabilities and so are synthesised when needed but can bind to molecules inside the target cell

  On the other hand, peptide and amine hormones are hydrophilic and so must be released through exocytosis, improving storage, and bind to membrane-bound receptors, worsening transport
• Steroid hormones are bound to carrier proteins (lipophobic - stay in plasma) to prevent enzymic degradation in liver
• In peptide hormone synthesis:

  1. mRNA on ribosome binds to amino acids into a peptide chain called preprohormone
  2. A signal sequence moves the preprohormone into the ER lumen
  3. ER enzymes chop off the signal sequence, forming an inactive prohormone
  4. Prohormone passes through Golgi complex
  5. Secretory vesicles contains the prohormone and enzymes which eventually chop the prohormone into active peptides which are released via exocytosis and moved into circulation
• Endocrine pathologies are either:

  Hypersecretion (excess hormone levels): leads to down-regulation of receptors due to resistance

  Hyposecretion (hormone deficiency)

  Abnormal target tissue responsiveness: mutations of protein sequence impacts binding efficiency or absent hormones
• What three glands (and their specifics) comprise the HPA axis?


  Hypothalamus

  anterior pituitary gland

  adrenal gland (adrenal cortex, zona fasciculata)
• Adrenal gland is comprised of:

  1. outer cortex (from superficial to deep):

  • Zona glomerulosa
  • Zona fasciculata
  • Zona reticularis

  2. inner medulla
• The long-loop negative feedback is the main mechanism that tropic hormone levels are maintained by homeostasis where an increase in non-tropic hormone inhibits secretion of hypothalamic and anterior pituitary tropic hormones
• The stress response (flight or flight) aims to increase blood-glucose levels by increasing the secretion of cortisol in the zona fasciculata:

  Cortisol acts in an opposite manner to insulin by:

  Skeletal muscle:

  • Decreasing glucose uptake
  • Decreasing glycogen stores
  • Decreasing protein synthesis
  • Increasing protein breakdown

  Liver

  • Increasing gluconeogenesis
  • Decreasing glycogenogenesis

  Adipose tissue

  • Increasing lipolysis
  • Increasing release of non-essential fatty acids and triglycerides
• Cushing Syndrome, an example of hypercortisolism, is induced by exogenous administration of steroid medication which results in an oversecretion of cortisol and thus, severe muscle, bone and skin breakdown as glucose uptake is restricted. It also dampens inflammatory and immune responses.
• The hormones secreted by the adrenal cortex can be broken down into:

  Zona glomerulosa: secretes mineralcorticoids (aldosterone)

  Zona fasciculata: secretes glucocorticoids (cortisol, corticosterone, cortisone)

  Zona reticularis: secretes androgens (dehydroepiandrosterone)

  Adrenal medulla: secretes catecholamines (epinephrine, norepinephrine)
• The type of hormones secreted in the adrenal medulla, catecholamines, are amine hormones
• The adrenal medulla is made up of neuronal cells called chromaffin cells, where the medulla is directly connected to the spinal cord through the preganglionic sympathetic neuron (chromatin is a modification of this in groups of nerve cells called ganglia). Chromatin cells secrete neurohormones including epinephrine to the blood
• Adrenaline (epinephrine) is the body's way to fight acute (short term) stress and achieves this by activating glycogenolysis. Whilst this reaction is relatively quick it is of little supply and thus cannot be used to respond to stress in the long term.
• DHEA is an example of a steroid hormone secreted in the zona reticularis of the adrenal cortex
• Renin-Angiotensin-Aldosterone system is the process of secreting aldosterone as well as its role to regulate blood pressure, volume and Na+ blood levels:

  Angiotensinogen released from the liver turns into angiotensin I in the presence of the renin enzyme released from the kidneys. Angiotensin I turns into angiotensin II in the presence of the enzyme angiotensin converting enzyme (ACE) which is released from the lungs. Angiotensin is the active form that causes vasoconstriction of blood vessels and travels to the adrenal cortex (zona glomerulosa) to secrete aldosterone.
• Aldosterone initially unbinds to the carrier protein attached to it. Then, it diffuses through the membrane of the P cell of the distal nephron since it's a steroid hormone. Once binding to a cytoplasmic receptor, forming a hormone-receptor complex, transcription and thus, translation is induced, producing proteins that modify the transporters to increase Na+ reabsorption and K+ secretion into the distal tubule lumen
• DHEA is a precursor, with weak adrenergic activity, of testosterone (promoting prostate growth, develops masculinisation and increases libido) and estrogen (promotes hair growth, sebum production and libido)
• The hypothalamus secretes the thyrotropin releasing hormone, stimulating the anterior pituitary to secrete the thyroid stimulating hormone which stimulates the secretion of T3 and T4 hormones from the thyroid gland, where T3 increases metabolic rate
• The thyroid gland consists of repeating units called thyroid follicles. This comprises of the follicular cells, responsible for T3 and T4 synthesis, and colloid (lumen), the site where thyroglobulin transforms tyrosine into T3 and T4.

  Alongside thyroid follicles, parafollicular cells exist which allows for calcium homeostasis
• Triiodothyronine (T3) and thyroxine (T4) are amine hormones that contain 3 iodo (T3) and 4 iodo halides.
• Thyroid hormone synthesis:

  Tyrosine gains an iodine to form monoiodotyrosine.

  Monoiodotyrosine gains an additional iodine to form diiodotyrosine.

  Diiodotyrosine either:

  • Adds with itself to form thyroxine (T4)
  • Adds with monoiodotyrosine to form triiodothyronine (T3)

  If T4 is synthesised, it de-iodises to form T3 (agonist) or rT3 (antagonist), decreasing metabolic rate.
• How T3 enters into blood:

  1. Follicular cell ER synthesises the enzyme thyroid peroxidase and the protein thyroglobulin which travel to the colloid
  2. Iodide from blood is cotransported with Na+ and transported into colloid
  3. Thyroid peroxidase catalyses the fusion of T3 and T4 onto thyroglobulin once T3 synthesis has occurred
  4. The protein undergoes endocytosis back into the follicular cell where lysosomes break T3 and T4 free from the protein
  5. T3 and T4 enter circulation
• Circulating T3 comes from:

  • Synthesis from T4 (80%)
  • 20% from direct synthesis in thyroid gland

  Circulating rT3 comes from T4 (100%)

  
  

  T3 and T4 are bound by carrier proteins in blood to prevent liver degradation but are only active when unbound.
• T3 increases mitochondrial activity, glucose oxidation (which increases basal metabolic rate and heat production) and growth and development through altering gene expression.
• Hyperthyroidism: oversecretion of thyroid hormones.

  Causes:

  Increased oxygen consumption rate and metabolic heat production

  Increased protein catabolism and thus, muscle weakness

  Muscle tremor

  An example is Graves' disease with thyroid stimulating immunoglobulin, mimicking the action of thyroid stimulating hormone. As immunoglobulins are disconnected from the long loop feedback loop, T3 secretion cannot be regulated, causing it to be over secreted.
• Hypothyroidism: Undersecretion of thyroid hormones.

  Three types:

  Primary hypothyroidism: under secretion of hormones due to thyroid gland (e.g. iodine deficiency).

  Secondary hypothyroidism: Lack of thyroid stimulating hormone due to anterior pituitary

  Tertiary hypothyroidism: lack of thyrotropin releasing hormone due to hypothalamus
• Hypothyroidism symptoms:

  • Decreased oxygen consumption and metabolic rate
  • Slow speech
  • Decreased protein synthesis
  • Slow heartbeat
  • Goiter

  If caused by an iodine deficiency:

  • This will decrease T3/T4 levels
  • Due to long loop negative feedback, this will increase the secretion of thyrotropin releasing hormone, thus increase thyroid stimulating hormone, enlarging the thyroid gland. However, since iodine is limiting the synthesis of T3/T4, they will remain in low amounts.
• Hypoglycemia: BGC < 4.0 mM

  Hyperglycemia: BGC > 7.0 mM
• Hypoglycemia symptoms are typically shaking, sweating, paleness and cognitive.

  Hyperglycemia symptoms are typically feeling thirsty due to excessive urination, blurred vision and diabetic complications
• Increase in BGC can be caused by:

  • Increased absorption from small intestines
  • Glycogenolysis
  • Glucose synthesis from fat and protein
  • Glucagon, steroids, GH, T3

  Decrease in BGC can be caused by:

  • Glucose oxidation in tissues
  • Glycogenesis
  • Decrease in gluconeogeneis (in liver) and increase in fat storage
  • Insulin
• The two types of Pancreatic Islets of Langerhans cells are the alpha (glucagon secreting) and beta (insulin secreting) cells
• Insulin production:

  • High BGC causes glucose diffusion into cell
  • Trapped in cell as G6P
  • Increase in glycolysis increases ATP:ADP ratio
  • Causes the closure of the ATP sensitive potassium channel
  • K+ is kept in the cell, increasing intracellular charge and causing membrane depolarisation
  • Voltage-gated calcium channel opens, increasing intracellular calcium concentration
  • Induces insulin granule exocytosis
• Incretin potentiates beta cell insulin secretion in the presence of high BGC