Physiology and Testing

Cells and Effectors

Most of the basic sciences will be included with each endocrine gland and its disorders. However it's not a bad time to recap some basics

Cells can make use of methods of transport between cells to make things happen remotely. A small tripeptide released by the hypothalamus acts on the anterior pituitary to release Thyroid stimulating hormone which then acts on the thyroid to release thyroxine. Thyroxine inhibits the hypothalamus and pituitary. These things can only happen if the molecule released has some way to alter target cell behaviour. There are several different ways in which this can be done. The ultimate target is the nucleus and modifying protein synthesis.

Types of hormones

  • Amines: e.g. Thyroxine forms T3 peripherally which bind with nuclear receptors. Amines generally have a short half life and rapid action.
  • Peptides: e.g. Prolactin which bind with cell surface receptors and act via secondary messengers. Short half life and rapid action.
  • Steroids: Cortisol, aldosterone, sex hormones. These can freely pass across the cell membrane and pass through to the nucleus where they alter gene expression and protein synthesis
  • Cell surface receptors

    For those molecules which do not pass across the cell membrane the challenge is how to convert a surface interaction into an intracellular response. Molecules can interact with several types of cell surface receptor. The means of response can be by various mechanisms

    7TM (7 transmembrane) receptors

    These are composed of a polypeptide chain with 7 membrane-spanning serpentine or snakelike helices. They are important in a wide variety of biological process including response to chemical messengers "hormones". For instance all Adrenergic receptors are 7TM receptors coupled to G proteins. The 7TM helix receptors change conformation in response to ligand binding and activate G proteins. The transduction of the signal occurs within seconds. This class of membrane proteins can respond to a wide range of agonists, including photons (retina), amines, hormones, neurotransmitters and proteins. Some agonists bind to the extracellular loops of the receptor, others may penetrate into the transmembrane region.

    G proteins can be involved in endocrine disease most notably some cases of GH overproduction by the pituitary causing acromegaly. Do not confuse this with the fact that works through tyrosine kinase. G protein related endocrine disorders include

    • Some cases of Acromegaly
    • Albright McCune syndrome
    • Pseudohypoparathyroidism

    These receptors once activated stimulate the formation of secondary messengers such as cAMP and calcium but there are several more.

    • cAMP
      • Generation of cAMP is by the stimulation of adenylate cyclase.
      • Almost all hormones acting at 7TM receptors cause a rise in cAMP except somatostain which lowers cAMP.
    • Intracellular Calcium
      • Intracellular calcium can be elevated by a G protein activated secondary messenger. The G protein activates the enzyme phospholipase C which releases Inositol triphosphate (IP3) from membrane phospholipids
      • IP3 binds endoplasmic reticulum receptor releasing Calcium ions. This binds calmodullin.

    Tyrosine Kinase receptors - phosphorylates target protein

  • The TK receptor has a G-protein linked transduction mechanism. However it is not a metabotropic receptor as it does not have the full 7 TM serpentine structure as is seen with metabotropic receptor.
  • The ligand binding site exists on the membrane surface and within the cell lies the tyrosine kinase and there are at least 4 types with different ligand binding domains.
  • Binding of the ligand stimulated the action of the TK which then phosphorylates target proteins.
  • Binding and subsequent protein phosphorylation can set up a chain of events with activation of factors important in cell growth and differentiation such as ras and Mitogen activated protein(MAP) kinases.
  • G proteins may also be involved but this is not the same as with a metabotropic receptor. Mutations involved here may play a role in some cancers.
  • Tyrosine kinase mediate activity is usually seen hormones involvd with "growth"
    • Insulin
    • Insulin like growth factors
    • Growth hormone
    • Prolactin
    • Epidermal growth factor (EGF)
    • Insulin Growth factor (IGF)
    • Fibroblast growth factor (FGF).
  • Steroids

    Steroid hormones are formed from cholesterol. There are five major classes
    • Progestagens - made in corpus luteum and prepares endometrium for ovum implantation
    • Glucocorticoids - made in adrenal cortex causes gluconeogenesis, formation of glycogen, breakdown of fat and protein, inhibit inflammation, stress response
    • Mineralocorticoids - made in adrenal cortex. Aldosterone causes sodium uptake and potassium loss in distal convoluted tubule
    • Androgens - made in testes, needed for male secondary sexual characteristics
    • Oestrogens - made in the ovaries, female secondary sexual characteristics
    • Molecule
      • Often contains four rings A,B,C,D as for cholesterol.
      • Binds and activates receptors which acts as transcription factors regulating gene expression
      • Pregnenolone is a precursor of many steroid hormones and is formed from cholesterol
    • Synthesis
      • Cholesterol is released from lipids by cholesterol esterase (+ ACTH and + AgII)
      • Cholesterol converted to pregnenolone in mitochondria.
      • Pregnenolone -> Progesterone ->(C11/17/21 Hydroxylation) cortisol
      • Progesterone -> -> (C21 hydroxylation) Aldosterone
      • Progesterone -> -> Testerosterone -> Oestradiol
      • Progesterone -> -> Oestradiol

    Vitamin D

    Vitamin D is formed from cholesterol and shares similar properties with steroids

    • 7 dehydrocholesterol + UV light -> -> Cholecalciferol (D3)
    • Cholecalciferol (D3) -> Calcitriol (1,25(OH2) Cholecalciferol)
    • 1-hydroxylation in kidneys, 25- hydroxylation in liver
    • Binds to a receptor to form a complex which acts as a transcription factor regulating gene expression

    Testing in Endocrine disease

  • General approach
    • Most endocrine diseases present with often vague patterns of changed appearance and symptomatology
    • Ask could this be endocrine.
    • If you have reasonable suspicion then perform a sensitive screening test and then back a positive result with a selective test
    • Is this hormonal excess or deficiency and where does it fit into he feedback centres that control endocrine physiology
  • The tenets of testing in Endocrinology
    • If a gland is suspected to be over active - try and suppress it
    • If a gland is underactive then try and stimulate it