Thyroid + Adrenal Gland

• Colloid


  Stored thyroid hormones

  
• Thyroid Hormone Synthesis


  1. Uptake & concentration of iodide (I-) in the gland

  2. Oxidation & incorporation of I- into tyrosine's phenol ring

  3. Coupling of two iodinated tyrosines to form T4 or T3

  
• Iodine


  A critical micronutrient
• Thyroid hormone synthesis


  1. Uptake & concentration of iodide (I-) in the gland

  2. Oxidation & incorporation of I- into tyrosine's phenol ring

  3. Coupling of two iodinated tyrosines to form T4 or T3

  
• Iodide uptake

  Iodine is a critical micronutrient, few food sources are rich in it, minimum daily requirement is 80 µg, ~80 µg is taken up daily by the gland, stored I- within the gland is 100x greater than daily need, protected for 2 months from iodine deficiency, low levels of iodine intake decreases the rate of thyroid synthesis, high levels of iodine intake (>2 mg/day) suppresses thyroid synthesis (Wolff-Chaikoff effect)

  
• Iodide uptake mechanism


  • I- is actively transported into the thyroid gland vs an electrochemical gradient by a 2Na+ - 1I- symporter

  
• Tyrosine iodination


  1. is oxidized and incorporated into tyrosine by the enzyme thyroid peroxidase (TPO)

  
• Coupling of iodinated molecules with thyroglobulin

  Ratio of T4 to T3 synthesized is 10-20:1 (unless I- limited)

  
• Thyroid hormone secretion


  Thyroglobulin enters via endocytosis, lysosomal proteases hydrolyze the thyroglobulin, T4 and T3 is released, MITs and DITs are deiodinated and I- recycled

  
• Thyroid hormone secretion


  90% T4, 9% T3 (4x more potent than T4), 1% rT3

  
• Peripheral conversion of T4 to T3


  Important first step
• Fasting, malnutrition, physical trauma, drugs (PTU, DEX, propranolol, amiodarone), systemic illness, old age can decrease the conversion of T4 to T3
• Thyroid hormone transport in blood

  70% bound to binding protein thyroxine-binding globulin (TBG), 29.5% bound to prealbumin and albumin, free hormone levels are low but critical (0.03% of T4, 0.3% of T3), binding proteins create a reservoir of hormone and protect vs acute changes in thyroid gland function

  
• Bound and free T4 exist in equilibrium


  If free T4 decreases suddenly, the constant release and rebinding to binding proteins can replace the lost free T4
• If the liver makes more binding protein (pregnancy)


  Alterations in TBG do not disturb biological function (if thyroid gland normal)

  
• Regulation of thyroid hormone release

  Major stimulator is thyroid-stimulating hormone (TSH), which stimulates almost every step in the pathway of thyroid hormone synthesis

  
• Changes in thyroid hormone levels of only 10-30% are enough to change TSH in the opposite direction

  
• Feedback of T3 on the anterior pituitary

  Represses transcription of TSH gene, suppresses TSH release, down-regulates TRH receptors
• Reasons for treating hypothyroidism with synthetic T4 (Levothyroxine) instead of synthetic T3 (Liothyronine)

  Mimic true physiology, longer half-life (compliance), more stable, easier lab measurement, lower cost, lack of allergens

  
• T3's functions


  • Brain maturation, bone growth, β-adrenergic effects, increases basal metabolic rate
• Physiological effects of thyroid hormones

  • Regulate basal metabolic rate, cardiovascular effects (increases heart rate, stroke volume, contractility, blood pressure, vasodilation, decreases systemic vascular resistance), sympathomimetic effects, growth and development effects

  
• Symptoms of hyperthyroidism include nervousness, insomnia, anxiety, restlessness, sweating, heat intolerance, tremor, weight loss, palpitations, tachycardia
• Symptoms of hypothyroidism include fatigue, lethargy, weight gain, cold intolerance, muscle aches, stiffness, somnolence, thinning hair, dry skin, prolonged reflex times, depression, mental slowness, constipation, amenorrhea, puffy face (myxedema), goiter
• Causes of hypothyroidism


  Primary (thyroid failure, e.g. Hashimoto's thyroiditis), secondary (pituitary or hypothalamic failure), iodine insufficiency

  
• Causes of hyperthyroidism


  Primary: Graves' disease (autoimmune), secondary: excess TSH or TRH, hypersecreting thyroid tumor
• Adrenal Gland


  Endocrine gland that sits atop the kidneys and consists of a cortex (80%) and medulla (20%)

  
• Adrenal Gland


  • Combined weight: 6-10 g
  • One of highest blood flow rates per gram of tissue (from cortex to medulla)

  
• Prefrontal cortex shrinks during cram sessions, but grows back after a month off
• General adaptation syndrome


  Nervous and hormonal responses result in a state of intense readiness with fuel mobilized for use
• Stress response is coordinated by the hypothalamus

  
• ACTH stimulates all steps in synthesis of cortisol, adrenal androgens, & (slightly) aldosterone

  
• ACTH stimulates cell hyperplasia (via IGF-1)
• ACTH is synthesized from a large precursor, preproopiomelanocortin (POMC) which also gives rise to MSH

  
• Cortisol secretion is pulsatile


  Alternating bursts of modest secretion separated by silent periods of little to no secretion

  
• Cortisol secretion is diurnal

  One cycle every 24 hrs, with peak prior to awakening and lowest levels just prior to sleep
• The suprachiasmatic nucleus determines the diurnal rhythm of cortisol secretion

  
• Factors that can alter the setting of the suprachiasmatic nucleus

  • Lack of bright natural light during day
  • Exposure to artificial light at night
  • Chronic glucocorticoids (blunts morning peak)
• Negative effects of alternating shift work

  • Ulcers
  • Insomnia
  • Irritability
  • Depression
  • Impaired judgment
• Stress enhances the activity of the CRH-ACTH system and increases plasma cortisol in proportion to the intensity of the stressful stimuli

  
• Cortisol transport


  • 75% bound to corticosteroid-binding globulin (CBG, transcortin)
  • 15-20% bound to albumin
  • 5% unbound