Endocrinology, lecture on the Thyroid Axis
XIII. Thyroid Axis
A. Hypothalamo-Hypophysial-Thyroid Cascade
1. TRH stimulates TSH
2. TSH stimulates T4
a. and T3
3. T4 converted into T3 at tissues
a. Transthyretin (TTR or TBPA thryroxine-binding prealbumin) = carrier protein
4. T3 binds to nuclear receptor
a. present in all tissues
i. including hypothalamus and pituitary - feedback
5. T3 predominantly responsible for negative feedback
B. TRH
1. 3 aa (pyroGlu-His-Pro-NH2)
pyroGlu = N-terminal glutamic acid closed into a lactam ring
a. preprohormone = 255 aa
i. 5 TRH molecules
ii. locations of the TRH sequences are conserved
between amphibian and mammalian
b. produced in the PVN, PVa, AH, POA, DMN, VMN and ARC
of the hypothalamus
i. primarily PVN and PVa
ii. stimulated by cold, inhibited by stress
(1) stimulated by NE, Epi, H (histamine)
and maybe ACh
(2) inhibited by GABA, DA, enkephalins, 5-HT
(of course negative feedback)
2. TRH stimulates TSH
a. TSH inhibited by somatostatin
3. TRH also stimulates PrL
4. one receptor
a. TRH-R up-regulated by estrogen
b. down-regulated by thyroid hormones
c. 2nd messengers: IP3, Ca++, PKC, cAMP
i. IP3/Ca++/PKC & cAMP
are involved in TSH & PrL release
(1) Ca++ is always involved
in endocytosis/release
C. TSH
1. 10% of all cells of the pars distalis
a. smallest cells of pars distalis
2. a subunit = 92 aa (also LH, FSH, CG)
a. single a-subunit gene for all glycoprotein hormones
i. 4 exons and 3 introns
ii. mRNA codes for 116 aa
- 24 aa signal peptide (N-terminal end)
3. b = 112 aa
a. gene is on different chromosome from gene for a-subunit
4. half-life = 60 min
a. inactivated in liver and kidney
5. one receptor type on thyroid cells and adipocytes
a. high affinity, low capacity
b. 2 subunits
6. Function = production and release of thyroid hormones
a. thyroid hormones are also regulated by stimulation from the
sympathetic nervous system and other nerves containing VIP
b. hypertrophy and vascularization of thyroid
c. ñ cAMP
i. ñ uptake of iodide
ii. ñ synthesis of thyroglobulin,
iodo- tyrosine and thyronines
iii. pinocytosis of thyroglobulin
iv. proteolysis of thyroglobulin
and release of T3 and T4
d. lipolytic
D. Thyroid
1. anterior portion of the neck
2. Follicle = functional unit
a. sphere of a single layer of cuboidal cells
i. surrounding the colloid
(1) made up of thyroglobin
- an iodinated glycoprotein
ii. height of follicular cells increases
with glandular stimulation
iii. classical secretory cells with well
developed rER and Golgi apparatus
b. microvilli of the apical plasma membrane extend
into the follicular lumen = pseudopods
3. thyroid also contains larger epithelial
clear or C cells which secrete calcitonin
E. Thyroid Hormones
1. Iodination
a. thyroid hormones are iodinated amino acids
b. while in the thyroid they are a part of the peptide
chain of thyroglobulin = 669kd
c. thyroid concentrates dietary iodide
i. iodide pump
d. tyrosine residues bind (up to two) oxidized iodines
i. oxidized by thyroid peroxidase
e. iodotyrosine residues couple to make iodothyronine
f. proteolysis releases free hormone
2. Thyroxine = T4 , 3,5,3'-Tri-iodothyronine = T3
a. half-life = 7 and 1 day respectively
3. Storage and Release
a. non-iodinated thyroglobulin is transferred to
(exocytosis) & stored in the lumen of the follicle
i. iodinated at the apical membrane
ii. not directly active and away from metabolic processes
b. thyroglobulin repenetrates the cell by pinocytosis
c. endocytotic vesicles fuse with lysosomes
containing proteolytic enzymes
d. proteolysis produces T3, T4,
MIT (monoiodinated tyrosine), and DIT
e. T3 and T4 are released
tyrosines and iodide recycled
f. carried in the blood by transthyretin (TTR)
i. transports thyroxine and retinol
ii. liver and choroid plexus (brain) secrete TTR
iii. TTR disociation, misfolding, and aggregation leads to
degeneration of post-mitotic tissue
1) associated with amyloid diseases, e.g. amyloid cardiomyopathy
2) may bind ß-amyloid, preventing Alzheimers
4. T3 Receptors
a. nuclear receptor superfamily (2 immediate-early genes)
i. tissue specific differences
(1) T3-Rb1 is everywhere,
T3-Rb2 in pituitary and CNS
(a) gene for T-Rb on chromosome 3
(2) T3-Ra1 in skeletal muscle and brown fat,
T-Ra2 doesn't bind T3 (may be inhibitory)
(a) gene for T-Ra on chromosome 17
ii. ~45,000 d
b. binds T3 (KD ~10-10 M = 0.1nM)
i. also T4, but with 10X lower affinity
(1) T4 converted to T3 intracellularly
c. induces gene transcription / mRNA synthesis
5. Thyroid Hormone, T3 - Function
a. receptors and function in almost all tissue
b. Development
i. differentiation and maturation of fetal tissue
(1) especially nervous and bone tissue
(2) lung surfactant
ii. growth
(1) ñ GH production and effectiveness
iii. stimulates amphibian metamorphosis
c. Metabolism
i. ñ metabolism of proteins, sugars, lipids,
H2O, N, and O2
ii. synergism with insulin, steroids, catecholamines
iii. heat production
