Endocrinology, lecture on the Thyroid Axis
USD Department of Biology
Endocrine Glands
2nd Messengers
Nuclear Receptors
Genetic Regulation
Hormone Synthesis
Receptor Regulation
Hypothalamo-Hypophysial Communication
Tropic Hormones
Neurohypophysial Nonapeptides
Thyroid Axis
Adrenal Axis
Adrenal Medulla
Osmotic-Pressure Balance
Reproductive Endocrinology
Somatic Axis
Growth Factors
Immune Factors
Ca++, PO4 Homeostasis
Pancreatic Hormones
GI Hormones
Guts 'n Brains
Brain Hormones
Endocrine Evolution
Figures for Endocrionology
text:Vertebrate Endocrinology5th Edition - David O. Norris:
Read pages 207-229 for this lecture
acronyms    end
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. 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


		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 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


		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. 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.  cAMP

				i.  uptake of iodide

				ii.  synthesis of thyroglobulin,
				     iodo- tyrosine and thyronines

				iii. pinocytosis of thyroglobulin

				iv. proteolysis of thyroglobulin
				     and release of T3 and T4

			d. lipolytic

		6. one receptor type on thyroid cells and adipocytes

			a. high affinity, low capacity

			b. 2 subunits

	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 thyroid binding proteins

		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. 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)  GH production and effectiveness

				iii. stimulates amphibian metamorphosis

			c. Metabolism

				i.  metabolism of proteins, sugars, lipids,
				    H2O, N, and O2

				ii. synergism with insulin, steroids, catecholamines

				iii. heat production

XIV. Steroids