The adrenal gland

The adrenal gland

1. Learning objectives:

   • medulla/cortex - steroid hormone synthesis, mechanism of action
   • Glucocorticoids - physiological effects, therapeutic use, HPA axis
   • Mineralocorticoids - effects on Na+ and water metabolism
   • Disfunctions of adrenal cortex; adrenal medulla
   • Adrenalin and noradrenaline - review of adrenergic receptors - fight or flight

2. Adrenal cortex and adrenal medulla

   • Adrenal cortex:
     • Outer part of adrenal gland—produces hormones, such as cortisol (helps regulate metabolism and bodies response to stress) and aldosterone (helps control blood pressure
     • corticosteroids
     • regulation of metabolic processes
     • regulation of K+ and Na+ blood levels
     • control of volume of extracellular fluid
     • adaptive changes over minutes, days, months
   • Adrenal medulla:
     • Inner part of an adrenal gland - controls hormones- help you cope with physical and emotional stress.  Main hormones secreted include epinephrine (adrenaline) and norepinephrine (noradrenaline), which have similar functions.
     • adrenaline and noradrenaline (epinephrine and norepinephrine)
     • responsiveness to stressors - fight or flight
     • regulation of metabolic processes
     • adaptove changes over within seconds to minutes

3. Adrenal gland - histology

   • different zones produce different hormones
     • CORTEX
       • Glomerulosa
         • mineralocorticoid
       • Fasciculata
         • glucocorticoids
       • Reticularis
         • androgens
       • MEDULLA
       • Glucocorticoids e.g. cortisol, corticosterone
         • Mineralocorticoids e.g. aldosterone
           • Androgens and Estrogens - small amount to replace loss of gonadal steroids - only needed in emergency situtation
             • All generated from CHOLESTEROL
               • closely related structures - different effects
               • cholesterol input = diet + formation from acetate w/in cell

4. Adrenal steroid synthesis

   • Cholesterol - absorbed from the GI tract or synth from acetate
     • Cholesterol is insoluble in water and transported with LDL
       • binds to LDL receptor and endocytosed
       • Steroids are NOT stored in cortical cells
         • hydrophobic - needs to bind to a protein to enter
           • so, cholesterol (steroid) CANNOT be stored but ACETATE precursor can be

5. Steroid action

   • Cytoplasmic receptor in multiple target tissues
   • translocates to the nucleus upon steroid building
   • modulates transcription of genes
   • steroid hormones are lipophilic - why they must bind to proteins

6. Glucocorticoids

   • Cortisol/corticosterone
   • secreted from zona fasciculata - widest zone of adrenal cortex
   • Diurnal rhythms
     • dogs and cats DO NOT have daily cortisol rhythms
     • Other species - secretion of CRH synchronised with sleep-wake-cycle
       • animals active during the day: high cortisol a.m
       • animals active at night: high cortisol at onset of darkness
       • stress induced secretion CRH can cause up to 20x increase in glucocorticoids and override circadian rhythms

7. Glucocorticoids output and effects

   • Control - acute and long term stress e.g. heat, trauma, cold, pain, fright, disease + CIRCADIAN rhythm generator
     • Stimulates CRH release from hypothalamus -> anterior pituitary
       • ACTH stimulates adrenal cortex - fasciculata cells (glucocorticoids) -> cortisol -> peripheral tissue and target cells
       • Corticotrophs, cells bound to anterior pituitary, produce ACTH
   • Physiological effects
     • Metabolism
       • CHO - stimulation of glucneogenesis
         • inhibit effects of insulin - decreased tissue uptake of glucose
       • Protein - stimulation catabolism of proteins -> glucneogenesis
       • Fat - during stress/starvation - shift metab from glucose -> fat
         • increased LIPOLYSIS (FA used as fuel - glucose sparing)
     • Hyperglycaemic
       • glucneogenesis = synthesis of glucose from amino acids

8. Glucocorticoids - physio effects

   • cardiac, skeletal and vascular smooth muscle
   • Insuffiency - muscle fatigue
     • cardiac insufficiency = failure
     • Vascular = loss of vasomotor tone
     • skeletal = general muscle weakness
     • mechanism ill defined
   • Nervous system
     • affects on mental function, insufficient = lethargy, apathy, inability to concentrate
     • Excess - hyperactivity, insomnia, euphoria, increased sensory acuity
     • mechanism also ill-defined

9. Response to stress

   • Metabolism
     • alertness
   • Cardiac, skeletal and vascular smooth muscle
     • muscle primed for escape
   • Nervous system
     • alertness

10. Inflammatory effect of glucocortisoid

    • anti-inflammatory and immuno-supressive
    • inhibit secretion of CYTOKINES
      • involved in immune response, produced by T-lymphocytes and mast cells
    • inhibit proliferation of immune cells
    • inhibit synthesis of antibodies
    • increase susceptibility to infection
    • Therapeutic use of glucocortisoid
      • low dose in adrenal insufficiency
      • suppress responses in autoimmune diseases

11. Mineralcorticoids

    • e.g. aldosterone
      • on release 60% bound to plasma protein TRANSCORTIN
    • released from ZONA GLOMERULOSA
    • HALF LIFE - 15-30mins
    • release mediated by - renin/angiotensin system, Na+/K+ concentration
    • regulate concentration of SODIUM and POTASSIUM in extracellular fluid
    • most important stimulation = changes in ELECTROLYTE levels and WATER BALANCE
      • major target = epithelial cells of COLLECTING TUBULES of KIDNEY - activate Na+ - K+ pumps
        • reabsorption of Na+ from fluid in renal tubules = excretion of K+ in urine. Restoration of blood Na+/K+ balance, blood volume and pressure increased

12. Control of mineralcorticoid output from adrenal cortex

    • Adrenal cortex - Glomerulosa cells
      • Aldosterone -> kidney tubules -> increased sodium reabsorption and K+ secretion = increased blood volume and pressure
      • Liver = Angiotensin - + renin = angiotensin 1 - + ACE = angiotensin 2 = stimulates aldosterone release from glomerulosa cells
        • ACE - lungs and kidney. Renin - JG cells when blood pressure low, Na+ low and blood volume low.
    • Disfunctions of the adrenal cortex:
      • HYPERADRENOCORTICISM - Cushing's disease
        • overproduction of glucocorticoids (overproduc of minerglc does not occur in dom. animals)
        • common endocrine disease in dogs, occasional in cats, rare in horses etc
        • Primary hypercorticism (15%) = adenomas of adrenal cortex = tumour of pituitary
          • Secondary (15%) = ACTH producing neoplasms of anterior or intermediate pitu
            • Latrogenic hypercorticism = widespread use of syntheitic glucocorticoids
    • Alopecia - muscle wasting + pot belly
      • Hirsutism = failure to shed seasonal coat

13. Disfunctions of the adrenal cortex

    • Hypoadrenocorticism (Addison's disease)
      • undersecretion of glucocorticoids and mineralcorticoids
        • RARE
      • Primary hypocorticism - ATROPHY of adrenal cortex
        • Latrogenic hypocorticism - abrupt withdrawl of steroid therapy
      • Symptoms
        • muscle weakness
        • poor CV function
        • Low BP
    • Therapeutic use of glucocorticoids
      • Anti-inflammatory and anti-allergic effects
      • Immunosuppresant in autoimmune disorders
      • NB: careful withdrawl and reduction of dose to avoid HYPOcorticism - negative feedback on endogenous cortisol

14. Adrenal medulla

    • CHROMAFFIN cells - catecholamine storage granules
      • Catecholamine - adrenaline + noradrenaline - secreted by ADRENOMEDULLARY CELLS
        • bind to receptors on adipose, CV, muscular and pancreatic tissue and CNS
        • 'emergency hormone' in response to adrenergic receptor nature
    • Synthesis of catecholamines
      • Tyrosine from diet (throglobulin and iodine)
        • =TH = DOPA -> DDC = Dopamine -> DBH = Norepinephrine -> PNMT -> Epinephrine
          • TH - thyroid hormone DOPA- DDC- DOPA DeCarboxylase PNMT- Phenylethanolamine N-methyltransferase
          • nor/epinephrine from storage granules
          • adrenal medulla is primary source of adrenaline
    • Secretion of catecholamines
      • Classic Ach pathway
        • depolarisation, calcium influx, granules fuse with chromaffin cell membrane - exocytosis and catecholamine release

15. Adrenergic receptors and physiological effect

    • a1, a2, B
    • Regulation
      • hormonal binding affinity
      • receptor concentration
      • receptor signalling -G-protein coupled receptors
        • ACTIVATION OF 2ND MESSENGERS
      • Regulate responsiveness of target cell to catecholamines
    • FIGHT OR FLIGHT
      • Vasoconstriction in viscera and skin = increased F/v of heart contraction - little effect on BF to CNS
        • shunt blood and nutrients to heart and muscles
        • dilation of coronary arteries + vessels in skeletal m
      • Contraction of pilomotor muscles - raise hair
        • liberation of nutrient
      • HYPERFUNCTION of adrenal medulla
        • Pheochromocytomas = tumours arising from chromaffin cells
          • rare and benign = secrete large quantites of catecholamines = elevated BP and HR

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