HPT axis
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HPT axis. 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;

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Hpt axis

HPT axis


Hpt axis

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


Hpt axis

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)


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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)


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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

Colloid

Thyroglobulin

Follicular cell

Parafollicular cell “C-cell”

Capillary

TSH receptor


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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


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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 T4are released into the bloodstream


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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 20-50 times of that outside the cell


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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


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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


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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


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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


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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

http://www.anaesthetist.com/icu/organs/endocr/thyroid/images/t3t4.gif


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Thyroid Binding Plasma Proteins

http://en.wikipedia.org/wiki/Transthyretin

  • In cerebrospinal fluid, TTR is the primary carrier


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Thyroid Proteins in Plasma

http://en.wikipedia.org/wiki/Thyroid_hormone


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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

http://www.anaesthetist.com/icu/organs/endocr/thyroid/images/t3t4.gif


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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


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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


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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


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Effects on Lipid and Carbohydrate Metabolism

  • 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


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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


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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


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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


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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


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