Thyroid Hormone

Thyroid Hormone Synthesis and Secretion

Thyroid hormone is a biogenic amine consisting of two iodinated tyrosine residues – hormone is 65% iodine by weight

minimum iodide requirement is 150 m g/day, of which 80 m g is used for hormone synthesis (rest excreted in urine)

extracellular iodide pool is 400-500 m g; thyroid contains 7500 m g to protect from iodide deficiency for at least 2 months

Forms of Thyroid Hormone:

Thyroxine (T₄) – main secreted form (90% of gland output), contains four iodine atoms

Triiodothyronine (T₃) – main active form (10x as potent as T₄), made from deiodination of T₄ in liver and kidney

Reverse T₃ (rT₃)(inactive metabolite) – antagonist to T₄ activity, produced by metabolism of T₄

Site of Synthesis – epithelial follicular cells of thyroid gland (bilobed, 20 grams); stored in follicles as colloid

Steps of Synthesis – under control of TSH:

(1) Production of Thromboglobulin – a huge glycoprotein (670 kD) with tyrosines that will be used to make hormone

thromboglobulin is produced within thyroid epithelial follicular cells and stored in the colloid

(2) Iodide Trap –iodide cotransported with Na⁺ across the basolateral plasma membrane (energy from Na⁺/K⁺ ATPase)

efficiency of trap is inversely proportional to amount of iodide in blood – called the Wolff-Chaikoff effect

comp anion inhibitors block iodide uptake – thiocyanate, perchlorate, pertechnetate

(3) Oxidation of iodide to iodine, which is added to tyrosines of thromboglobulin – catalyzed by thyroid peroxidase

uses H₂O₂ and NADPH – details are not well understood
this produces monoiodotyrosine (MIT) or diiodotyrosine (DIT) having 1 or 2 iodine atoms, respectively

(4) "Coupling" of Tyrosines – DIT + DIT Þ T₄, MIT + DIT Þ T₃ – also catalyzed by thyroid peroxidase

coupled tyrosines may be separated by a considerable distance on thyroglobulin – thyroglobulin forms loops

Secretion begins with endocytosis of colloid from follicular lumen – vesicle is transported to basolateral membrane

lysosomal proteases release free T₄ and T₃ from thyroglubulin, and hormones diffuse into bloodstream

deiodinase – recycles unused iodine by removing it from MIT and DIT that has become "uncoupled"

Regulation of Thyroid Hormone Synthesis and Secretion

Thyroid Stimulating Hormone (TSH) – only known stimulator of thyroid

regulated by thyroid releasing hormone (TRH) from hypothalamus

regulates all steps in formation of thyroid hormone via Ý cAMP

causes hypertrophy and hyperplasia of the follicular epithelium, Ý volume of ER, Ý # ribosomes, Ý DNA and RNA synthesis, Ý capillary proliferation, Ý blood flow to thyroid

interacts with thyroid via specific membrane receptor – acts primarily via cAMP, also Ca⁺⁺ and phosphoinisotide

negative feedback – T₃ and T₄ reduce both TSH and TRH secretion (fig. A below)

if T₃ and T₄ synthesis ß , TRH and TSH will Ý – can lead to goiter (fig. B below)

Thyroid Hormone Action

Peripheral metabolism affects target cell exposure to hormone more than secretion of thyroid hormone

since T₃ is the more active hormone, it is the intracellular production of T₄Þ T₃vs. T₄Þ rT₃that counts

T₄ Þ T₃: (+) overnutrition; (-) fetus, illness, starvation, drugs

T₃ results from Ý caloric intake(esp. carbohydrates), rT₃ results from fasting, infection, surgery, psychiatric illness, stress

Thyroid Binding Globulin (TBG) – binds thyroid hormone in circulation, and buffers acute changes in hormone level

only 30% of T₄ binding sites on TBG are occupied – still, 0.025% of T₄ (2ng/dl) and 0.3% of T₃ (.28ng/dl) are in free form

free form fractions are what exert biological activity

albumin and transthyretin (thyroid binding prealbumin) also bind T4/T3

Three Major Actions of Thyroid Hormone:

(1) Stimulation of whole body metabolic rate – especially Ý O₂ utilization, Ý CO₂ production, Ý ventilation

Ý O₂ delivery due to heart effects: Ý cardiac output= Ý stroke vol. + Ý heart rate (Ý sarcolemma reticulum Ca⁺⁺ATPase), Ý contractility (Ý myosin a heavy chain, ß b chain), Ý systolic BP, ß diastolic BP (ß peripheral vascular resistance)

Ý thermogenesis – Ý sweating and ventilation; body weight ß by excess thyroid horm and vice versa

controls BMR: ß size of animal = Ý BMR, but (calories/SA of animal) remains constant in all sizes!

(2) Stimulation of growth, differentiation and development of numerous tissues

Bone – Ý linear growth of bone, maturation of the epiphyseal bone centers, Ý activity of chondrocytes in cartilage growth plate (via growth hormone and somatomedin), Ý bone turnover by Ý bone resorption (ß in total bone mass)

Subcutaneous tissues – inhibits synthesis of mucopolysaccharides and fibronectin in intracellular ground substance; increase in nail and hair turnover

Central Nervous System – improves wakefulness, alertness, responsiveness to stimuli, learning capacity, emotional tone, nerve reflexes

Deficiency in utero and early infancy: Cretinism – severe mental retardation (cretin = "Christlike" since these children were considered to be incapable of sin)
in newborn – growth of cerebral and cerebellar cortex, proliferation of axons, branching of dendrites, myelinization

(3) Augmentation of the activity of the sympathetic nervous system

Ý transcription of b -adrenergic receptors – does not Ý production or plasma levels of catecholamines

T₃ binds thyroid hormone receptor (steroid/Vitamin D/retinoid family related to c-erbA oncogeny products)

hormone-receptor complex binds to a cis-acting thyroid regulatory element which stimulates or inhibits transcription