• affect function of virtually every organ system
• in child, critical form normal growth and development
• in adult, 1º role is maintaining metabolic stability

• substantial reservoirs in the thyroid gland and blood provide constant availability
• the hypothalamic-pituitary-thyroid axis is very sensitive to small changes in circulating thyroid hormone [ ]s

• Hypothalamus secretes Thyrotropin releasing hormone (TRH) into pituitary portal venous system. 
• this stimulates the anterior pituitary to synthesis and release thyrotropin (thyroid stimulating hormone: TSH)
• TSH stimulates thyroid cells to ↑ synthesis and release of T4 and T3
• T4 and T3 act in a negative feedback fashion 

• in pituitary: block action of TRH
• in hypothalamus: inhibit synthesis and secretion of TRH

• formed in thyroid follicular cells when tyrosine is iodinated in thyroglobulin to form mono- and diiodotyrosine, which combine to form either T3 or T4.
• over 99% of each hormone is protein bound
• only unbound thyroid hormone is active
• T4 secreted solely from thyroid gland
• only 20% of T3 is produced in thyroid, remainder if formed in peripheral tissues from enzymatic breakdown of T4

• Positive inotropic and chronotropic effects
• lowers peripheral vascular resistance (leads to further ↑ in cardiac output)
• hyperthyroidism will cause jitters, heart palpitations, ↑ HR

• ↑ the # of β adrenergic receptors in heart and skeletal muscle, adipose tissue and lymphocytes

• ↑ hepatic gluconeogenesis and glycogenolysis 
• ↑ intestinal glucose absorption
• (all these ↑ glucose levels)

• ↑ metabolic clearance of many hormones, drugs, clotting factors...

• T4 enters target cell via active transport
• T4 converted to T3
• T3 moves into nucleus
• T3 binds thyroid receptor & activates gene transcription
• Takes hours to days to exert effects 
• (therefore missed dose does not have great effect)

• slowing of all body functions
• infants and children, retardation of growth and development resulting in dwarfism and irreversible mental retardation
• most common cause in US = hashimoto's thyroiditis (autoimmune condition)
• treat with replacement therapy

• Levothyroxine
• synthetic form of this is preferred choice for thyroid replacement

• Liothyronine
• Active form of thyroid hormone
• 3-4x more potent than T4
• use for replacement therapy NOT recommended 

• Synthetic levothyroxine (e.g. Synthroid) is preparation of choice due to its:
  • stability
  • content uniformity
  • low cost
  • lack of allergic foreign protein (not from animal source)
  • easy lab monitoring of serum levels
  • long t1/2 (7 days) allows QD admin
  • converted to T3 intracellularly, so produces both hormones

• shorter t1/2 (24 hrs), requires multiple daily doses
• higher cost
• greater difficulty monitoring via conventional lab tests
• greater risk of cardiotoxicity due to potency/activity 

• e.g Liotrix 
• because oral admin of T3 is unnecessary, use of combination products is never required

• Synthetic T4 (Synthroid, levothroid)
• initial dosage: start low and go slow
• normal starting dose: 25mcg/day
• increments of 15mcg every 2-3 weeks
• smaller starting in pts with myxedema, particularly if cardiovascular impairment suspected
• reduce dose if angina occurs

• on average 50-80% of oral dose is absorbed. 
• clinically, figure 50% is absorbed
  • if given IV only give 1/2 oral dose
• absorption affected by food, drugs, gastric acidity, and intestinal flora. 
  • abs. ↑ on empty stomach
  • stay consistent with when taken in relation to food

1. Thioamides
   • Propylthiouracil (PTU)
   • Methimazole (MMI)
2. Iodides
3. Radioactive Iodine
4. Adrenergic blockers (adjuncts only)

Estradiol: principal intracellular human estrogen

- converted to less potent estrone and estriol (to lesser extent) primarily in liver

Post menopause: androstenedione secreted by adrenal cortes is converted to estrone by peripheral tissues

1. oily preparations: slowly absorbed with prolonged duration of action (single IM injection absorbed over several weeks)
2. conjugated estrogens: well absorbed from GI
3. Transdermal: skin metabolizes estradiol only to small extent, so provides therapeutic serum levels of estradiol with lower levels of estrone and estrone conjugates (requires smaller total dose)