1. HPT axis

2. Review of HPA
Hypothalamus receives multiple signals from various regions of the brain
Hypothalamus can directly release hormones into bloodstream in posterior pituitary via neurons or;
Secrete hormones via portal system (blood vessels) to anterior pituitary that regulate hormone secretion from anterior pituitary

3. HPT axis Hypothalamic-pituitary-thyroid axis
Thyrotropin releasinng hormone (TRH) is released from paraventricular nucleus of hypothalamus
TRH stimulates cells in the anterior pituitary, called thyrotropes, to release thyroid stimulating hormone (TSH)
TSH stimulates the thyroid gland to synthesize the thyroid hormones (T3 and T4)

4. Anatomy of thyroid gland
Thyroid gland is an unpaired endocrine gland surrounding anterolateral (front and sides) surface of trachea in the neck
Consists of two lateral lobes with a connecting isthmus (narrow strip)

5. Histology and Composition
Composed of spherical follicles
Follicles are surrounded by a single layer of epithelial cells called follicular cells
Inner space is called follicular lumen and is filled with a colloid rich in thyroglobulin protein
Parafollicular cells, or “C-cells”, can be found scattered among follicular cells or in spaces between follicles
TSH receptors are found on the surface of follicular cells
Thyroglobulin
Parafollicular cell “C-cell”
Follicular cell
Colloid
Capillary
TSH receptor

6. Thyroid hormone synthesis
Thyroglobulin (Tg) is made in the follicular cells and released into the follicular lumen
Tg has a number of exposed tyrosine residues
An enzyme called thyroperoxidase (TPO) oxidizes an iodide (I-) to I+ and adds it to the tyrosine rings of Tg to get MIT and can do it a second time and form DIT
TPO can fuse a DIT and an MIT to form T3 or DIT and a DIT to get T4

8. Thyroid hormone synthesis
Tg, along with the attached T3, T4, DIT, and MIT, is engulfed by the follicular cell
Tg is broken down and the T3 and T4 are released into the bloodstream

9. Iodide in thyroid hormone synthesis
Iodide is essential to the synthesis of TH
On the external (non-lumenal) surface of follicular cells are iodide pumps that actively transport iodide into cell at concentrations times of that outside the cell

10. Effect of TSH Has multiple roles in increasing TH release
Increases activity of iodide pump such that the ratio of [I-]IC:[I-]EC is 500:1
Affects DNA to increases production of the iodide pump
Activates TPO
Stimulates breakdown of Tg and release of T3 and T4

11. Where are thyroid hormones stored?
Thyroid hormones are stored in the colloid inside the follicle
Stored in the form of iodinated thyroglobulin
Thyroid gland can store enough hormones to serve the body for 2 – 3 months

12. Thyroglobulin Glycoprotein (10% carbohydrate)
660 kDa, dimeric protein produced by and used only within the thyroid gland
Produced by the follicular cells of the thyroid
During storage, T3 and T4 are attached to thyroglobulin
When thyroglobulin is endocytosed  hormones are released
Hydrolysis releases thyroid hormones

13. Release of Thyroid Hormones
When TSH is released, thyroglobulin molecules form colloid droplets and are taken back up into follicular cells by endocytosis
Colloid droplets fuse with lysosomes  hydrolysis of Tg T3 and T4 are released
About 10% T4 converted to T3 before secretion
T4 and T3 containing vesicles are excreted out to blood stream

14. Delivery of Thyroid Hormones to Tissues
T3 and T4 are water-insoluble
Need to bind to a transport protein in the serum to be transported to tissues
Thyroid Binding Globulin (TBG) = produced by the liver
Transthyretin (TTR) = also secreted by liver
Albumin = main protein in blood
T4 and T3 are cleaved from TBG to become free T4 and free T3 when they reach the tisssues  bind to thyroid hormone receptors 14

15. Thyroid Binding Plasma Proteins
Binding strength
Plasma concentration
Thyroid Binding Globulin (TBG)
highest
lowest
transthyretin (TTR)
lower
higher
Albumin
poorest
much higher
In cerebrospinal fluid, TTR is the primary carrier

16. Thyroid Proteins in Plasma
Type
Percent
bound to Thyroxin Binding Globulin (TBG)
70%
bound to transthyretin (TTR)
10-15%
Albumin
15-20%
unbound T4 (fT4)
0.03%
unbound T3 (fT3)
0.3%

17. Conversion of T4 to T3 All T4 is converted to T3 in peripheral tissues
More T4 is secreted by thyroid
But T3 works better than T4
This conversion is done by Iodothyronine Deiodinase

18. Mechanism of Thyroid Hormones
Thyroid hormones are hydrophobic  readily cross lipid bilayer
Bind to receptor in cytoplasm
Enter nucleus
Bind to DNA in the nucleus
Change DNA expressions  change specific mRNA level  change protein level
Similar mechanism for all hydrophobic hormones. i.e. estrogen 18

19. Physiologic Effects of Thyroid Hormones
Almost all cells in the body are targets for thyroid hormones
Important for development, growth and metabolism
Deficiency and excess state lead to abnormal health state

20. Thyroid Hormone and Metabolism
Stimulate metabolic activities in most tissues → lead to increase in BMR (Basal metabolic rate)
BMR = the amount of energy a person expends daily while at rest
Thyroxine increases the number and activity of mitochondria in cells → increased body heat production → increased oxygen consumption and rates of ATP hydrolysis

21. Effects on Lipid and Carbohydrate Metabolism
Low amounts  glycogen synthesis (enhance insulin dependent entry of glucose into cells)
High amounts  glycogenolysis and gluconeogenesis to generate free glucose
Lipid metabolism
Deficient  serum cholesterol levels increase
High amount → fat mobilization and oxidation of fatty acids in tissues → serum cholesterol levels decrease 21

22. Effects on Growth and Development
Thyroid hormones are needed for normal growth in children and young animals
Thyroid deficiency → growth-retardation
Tadpoles deprived of thyroid hormone → unable to undergo metamorphosis into frogs
Normal levels of thyroid hormones are essential for proper development and growth of fetus and neonatal brain 22

23. Other Effects Cardiovascular system
Thyroid hormones → increase heart rate, cardiac output, and vasodilation → more blood flow to organs
Increase transcription of myosin protein genes in cardiac muscle → increased cardiac contractility
Central Nervous System
Too little → mentally sluggish
Too much → anxiety and nervousness
Reproductive System
Too little → infertility
Cardiac contractility depends on the relative ratio of different types of myosin proteins in cardiac muscle 23

25. Dysregulation - Hyperthyroidism
Too much = HyPERthyroidism = increased thyroid hormones in blood
Non-functional negative feedback system
Graves Disease = autoimmune disease → antibodies bind to and activate the thyroid-stimulating hormone receptor → continuous stimulation of thyroid hormone synthesis
Common symptoms:
Nervousness, high heart rate, anxiety, weight loss but increased food ingestion
Treatment: anti-thyroid drugs → suppress synthesis of thyroid hormones by blocking thyroid peroxidase
Thyroid peroxidase = needed for iodination of thyroglobulin

26. Dysregulation - Hypothyroidism
Too little = HyPOthyroidism
Primary: Problem with the thyroid → part of the thyroid is destroyed (95% cases) = Hashimoto's thyroiditis
Secondary: problem with pituitary → decreased TSH secretion → decreased production of T3 and T4
Tertiary: problem with hypothalamus → decreased TRH hormone
Iodine deficiency → not enough thyroid hormones are made
Common symptoms:
Lethargy, fatigue, weakness, cold intolerance, reproductive failure, weight gain but appetite decrease
Treatment = synthetic thyroid hormone