Thyroid gland
(glandula thyreoidea)
Bi1100en Hormones – Cellular and Molecular Mechanisms
▪ frontal side of the neck, attached to the larynx and trachea
▪ two lobes connected by isthmus; lobus pyramidalis present in some
individuals
▪ larger in women, geographically further from the sea and at higher altitudes
▪ blood and lymphatic circulation highly developed
Thyroid gland - anatomy
▪ fibrous septa divides the gland into lobes (lobuli), which consist of follicles,
50 – 500 μm) separated by ligaments and capillary and lymphatic vessels
▪ follicles composed of one layer of cubic follicular cells and filled with colloid
(viscous and homogeneous fluid, thyroglobulin)
▪ parafollicular cells (C-cells producing calcitonin) of neuroectodermal origin
(neural crest)
Thyroid gland - microanatomy
▪ derived from amino acid tyrosine
▪ essentially double tyrosine with three or four iodine atoms
▪ lipid soluble
Thyroid hormones:
triiodothyronine (T3), tetraiodothyronine/thyroxine (T4)
▪ modification of thyroglobulin-bound tyrosines
▪ posttranslational iodine-binding
▪ proteolytic cleavage
▪ released as T3 or T4
▪ binding to globulins and transport
Thyroid hormones - synthesis
▪ protein 660kDa
▪ synthesis on follicular cell ribosomes
▪ glycated in the Golgi apparatus
▪ packed in granules
▪ exocytosis from follicular cells to colloid
Thyroid hormones - synthesis of thyroglobulin
▪ secondary active iodine transport into follicular cells (two Na+ to one I-)
▪ concentrated app. 25x (TSH stimulation via cAMP > 250x concentrated)
▪ competition with other anions
▪ transported to colloid by pendrin protein (transported against Cl-)
▪ further processing by iodine peroxidase/thyroperoxidase on microvilli of
follicular cells (oxidation of I- to I0)
Thyroid hormones - synthesis
▪ thyroglobulin iodination stimulated by TSH via IP3
▪ iodinated tyrosines on thyroglobulin react with each other > T3/ T4
▪ stored in the colloid (in the form of T3 and T4)
Thyroid hormones - synthesis
▪ thyroglobulin transferred to follicular cells by endocytosis
▪ forming of phagolysosomes
▪ T3 and T4 cleaved from thyroglobulin by proteases
▪ T3 and T4 released to the blood
▪ monoiodotyrosine (MIT) and diiodothyrosine (DIT) residues used for iodine
recycling
Thyroid hormones - secretion
Thyroid Hormones:
Summary of the synthesis and secretion
▪ hypothalamic-pituitary axis (stimulation by thyroliberin-thyrotropin, TRHTSH;
inhibition by somatostatin, SIH)
▪ stimulated by a decrease in thyroxine (T4 deiodinated to T3 in target cells),
decreased BMR, hypothermia
▪ negative feedback (exercise > increase in body temperature > inhibition)
▪ globulin binding (thyroxine-binding globulin, TBG - primarily T4); in smaller
quantities bound to prealbumin and serum albumin
▪ free T3 and T4 transported in trace amounts (0.3 %), however, they are active
Thyroid hormones - regulation and transport
▪ T3 3x - 8x more efficient than T4 which is considered a storage form
▪ T3 acts faster
▪ half-life 1 day (T3) and 7 days (T4)
▪ 80 % of T3 is formed by cleaving iodine from T4 in the liver, kidneys and other
tissues (brain, pituitary gland, placenta, brown adipose): 5'-deiodinase
▪ 5-deiodinase produces inactive reverse T3 by cleaving out iodine on the
inner ring > regulation of TSH production during starvation
▪ active transport to target cells (ATP) and binding to nuclear receptors
Thyroid hormones - action
5'-deiodinase
5-deiodinase
▪ hormone + nuclear receptor (monomer or dimer TR/RXR) > binding to DNA
response elements (co-activator, RNA polymerase) > gene expression
▪ increase basal metabolism (increase the number of mitochondria, cristae,
stimulates cholesterol processing)
▪ ↑ energy metabolism - ↑ oxygen consumption - ↑ heat production
(moreover supports lipolysis of brown fat by regulating the expression of
necessary enzymes)
▪ synergy with growth hormone
▪ T3 stimulates growth (skeleton, brain) and maturation, increases heart rate
and activity, supports catabolism of proteins and carbohydrates, increases
sensitivity to other hormones and their effects (insulin, glucagon,
somatotropin, adrenaline)
Thyroid hormones - activity
▪ the disorder can occur in any of the steps of T3 and T4 synthesis or at the
level of their transporters and receptors
▪ disorders may be manifested by the enlarged thyroid gland (goitre) - release
T3 and T4may be both increased (e.g. thyroid proliferation due to
autoantibody binding) and decreased (e.g. iodine deficiency > decreased T3
and T4 > increased TSH production > proliferation of follicular cells)
Thyroid hormones - pathophysiology
Causes:
▪ tumors
▪ inflammation of the thyroid gland (thyroiditis)
▪ increased TSH secretion (for instance its release increases under stress)
▪ autoantibodies that bind to TSH receptors (Graves-Basedow disease)
Symptoms:
▪ increased metabolism (weight loss, hyperventilation)
▪ increased heat production (increase in basal metabolism up to 2x)
▪ patients experience heat intolerance and increased sweating
▪ increased lipolysis and proteolysis (muscle degradation and osteoporosis)
▪ saccharide metabolism > reversible diabetes mellitus (hyperglycemia)
▪ growth can be accelerated in children
▪ increased cardiac output and systolic blood pressure
▪ increased glomerular filtration in the kidneys and intestinal muscle function
(diarrhea)
▪ increased neuromuscular irritability (tremor, muscle weakness, insomnia)
Thyroid hormones - hyperthyroidism
Thyroid hormones - excess
Graves-Basedow disease (disease Basedowi)
▪ swelling of the soft tissues behind the bulb causes exophthalmos, double vision,
tearing
▪ increased serum T3, T4, reduced TSH levels, antibodies against TSH-receptors
hyperthyroidism
Causes:
▪ iodine deficient in the diet
▪ inflammatory damage or thyroid removal
▪ less often due to insufficient action of the TRH-TSH axis
▪ thyroid suppressors: thiouracil, thiocyanate, glutathione and others
Symptoms:
▪ opposite to hyperthyroidism: decreased basal metabolism, cold intolerance,
lipolysis, kidney function (swelling), anemia, hypoglycemia etc.
▪ irreversible brain damage in newborns!
Thyroid hormones - hypothyroidism
▪ 32 amino acids
▪ calcitonin-like protein family (alternative splicing of the gene product; for
instance to calcitonin gene-related peptide > vasodilatory effect)
▪ parafollicular thyroid cells (C-cells) with Ca 2+ receptors
Regulation:
▪ hypercalcemia > induction of CT production; hypocalcemia > inhibition of CT
production
▪ stimulating effect of gastrin and other gastrointestinal hormones on CT
secretion
Calcitonin (thyrocalcitonin, CT)
▪ G protein > adenylate cyclase > cAMP
▪ reduces increased Ca2+ concentration in the blood (antagonist of the
parathyroid hormone)
▪ 99 % of Ca2+ in the bones; 1% in body fluids (60 % diffusible and 40 % bound
to albumins and other plasma proteins)
▪ total calcium in serum 2.1-2.6 mmol/l; normal concentration of ionized Ca2+ is
1.25 mmol/l
▪ Ca2+ for neuronal transmission, muscle contraction and blood clotting
▪ calcium regulated together with phosphate > precipitate in high
concentrations
▪ regulation through the intestine, kidneys and bones
▪ suppresses osteoclasts in bones
▪ reduces Ca2+ absorption in the intestine
▪ increased Ca2+ deposition in the bones
▪ increases Ca2+ and phosphates secretion by the kidneys
▪ prevents hypercalcemia after eating
▪ acts to protect bones during pregnancy and lactation
Calcitonin (thyrocalcitonin, CT)
Parathyroid glands
(glandulae parathyroideae)
▪ usually 4 lenticular bodies on the back of the thyroid gland (common blood
and lymphatic supply)
▪ collagen ligaments, septa with adipocytes appearing with increasing age)
▪ Ca2+ receptors
▪ chief cells silver stainable (secretory granules, produce parathyroid
hormone) and oxyphil cells (without secretory granules, a lot of mitochindria
and glycogen > paracrine regulation)
Parathyroid glands - structure
▪ 84 amino acids, dimer with helical structure
▪ synthesis and release are controlled by Ca2+ concentration in parathyroid
glands (↑ Ca2+ > ↓ PTH)
▪ half-life approximately 4 minutes
▪ target organs: mainly bone, kidney and intestine (parathyroid hormone 1
receptor), CNS, pancreas, testes, placenta (parathyroid hormone 2 receptor)
Parathyroid hormone (PTH)
▪ increase in Ca2+ concentration after its decline:
→ activation of osteoclasts (release of calcium and phosphates from bones)
→ increases calcitriol synthesis in kidneys > Ca2+ resorption in kidneys and
intestine
→ inhibits phosphate resorption > hypophosphataemia > Ca2+ released from
bones
Parathyroid hormone (PTH)
Calcium management
in other tissues
▪ steroid, the active form of vitamin D
▪ multi-organ dependent synthesis (skin, liver, kidneys)
Calcitriol (1,25-(OH)2-cholecalciferol)
ineffective form
▪ synthesis in the skin from 7-dehydrocholesterol after irradiation by UVB
(270-300 nm)
▪ via provitamin D, which is converted to vitamin D3
▪ vitamin D3 (cholecalciferol) in animals, vitamin D2 (ergocalciferol) in plants
▪ in the liver conversion to 25-OH-cholecalciferol (calcidiol; storage form with
a half-life of about 15 days)
▪ in the kidneys (and placenta) conversion to 1,25-(OH)2-cholecalciferol
(calcitriol; catalysed by 1-α-hydroxylase)
▪ 24-hydroxylase produces an inactive form of the hormone
▪ regulation via enzymes catalyzing synthesis in the kidneys
Calcitriol (1,25-(OH)2-cholecalciferol)
stratum spinosum
stratum basale
▪ targets primarily intestine, bones, kidneys, placenta, mammary glands
(prolactin > lactation), skin and more
▪ binding to nuclear receptors (VDR > transcription factor)
▪ induced expression of calcium-binding protein and Ca2+-ATPases
▪ stimulates Ca2+ resorption in the intestine
▪ Ca2+ resorption in the kidneys
▪ promotes bone mineralization
▪ calcitriol is also produced by monocytes/macrophages, where it acts as a
cytokine and thus stimulates the innate immune system
Calcitriol (1,25-(OH)2-cholecalciferol)