Hypothalamus-Pituitary-Thyroid Axis (HPT Axis) PDF

HYPOTHALAMUS- PITUITARY- THYROID AXIS TH TSH TRH  Thyrotropin-releasing hormone (TRH) stimulates the release of thyroid-stimulating hormone (TSH) synthesized within the paraventricular nuclei TRH travels to the anterior pituitary via the hypophyseal portal system where it binds to t...

HYPOTHALAMUS- PITUITARY- THYROID AXIS TH TSH TRH  Thyrotropin-releasing hormone (TRH) stimulates the release of thyroid-stimulating hormone (TSH) synthesized within the paraventricular nuclei TRH travels to the anterior pituitary via the hypophyseal portal system where it binds to the TRH receptor stimulating the release of thyroid-stimulating hormone The half-life of TRH in the blood is approximately 6 minutes. TRH is a tripeptide TRH has anti-depressant and anti-suicidal properties  Thyrotropin-releasing hormone receptor (TRHR) is a G protein-coupled receptor TRH it activates phospholipase C, which causes the formation of inositol triphosphate (IP3) and diacylglycerol (DAG). This leads to an increase in cytoplasmic calcium ion concentrations which stimulates the exocytosis of thyroid-stimulating hormone (TSH) into the blood. TSH stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism It is a glycoprotein hormone produced by thyrotroph cells in the anterior pituitary gland TSH is secreted throughout life but particularly reaches high levels during the periods of rapid growth and development, as well as in response to stress.  TSH receptors The TSH receptor is found mainly on thyroid follicular cells. The TSH receptor is a G protein-coupled receptor activates adenylyl cyclase and intracellular levels of cAMP rise. cAMP activates all functional aspects of the thyroid cell, including iodine pumping; thyroglobulin synthesis, iodination, endocytosis, and proteolysis; thyroid peroxidase activity; and hormone release Control of secretion The production of both TRH and TSH is under strict negative feedback control by the thyroid hormones  TSH concentrations in children are normally higher than in adults. RANGE: 0.4–2.5 µIU/mL Thyroid gland Thyroid gland ✴ One of largest pure endocrine glands in the body (≈ 20gms). ✴ Its size depends on: 1. age …↑ age α ↑ size. 2. sex … female > male. 3. physiological condition … (pregnancy, lactation) ✴ Site: Located in the neck just below the larynx, on either side of & anterior to the trachea. The Thyroid Gland Blood supply  Thyroid gland structure - Euthyroid (normal thyroid) 1. Multiple Follicles (Acini): ♦ Are the functional unit. ♦ Thousands in no. ♦ ≈ 100 to 300 µmeters in diameter. ♦ Each follicle is spherical in structure. ♦ Follicular wall is lined with a single layer of cuboidal epithelioid cells that secrete into the interior of the follicles. Thyroid Parafollicular cells, C cells Parafollicular cells, C cells (between follicles– produce Decreases blood Ca2+ calcitonin by depositing it in THYROID GLAND STRUCTURE  Structure of thyroid follicle – Euthyroid follicle ✴ Each follicle is filled with pink-staining proteinaceous material called colloid. When the gland is INACTIVE: colloid is abundant, follicles are large, & lining cells are flat. When the gland is ACTIVE: follicles are small, lining cells are cuboid or columnar, & the edge of colloid is scalloped, forming many small “reabsorption lacunae”. Structure of thyroid follicle - Euthyroid follicle 2. Colloid: Jell-like substance that contains large glycoproteins (proteins linked by carbohydrates) called thyroglobulin, which stores thyroid hormones within its molecules. 3. Parafollicular cells or “C-cells: - Spherical cell, which has no relation to colloid or cuboidal cells. - Secrete Calcitonin, which is involved in calcium homeostasis. Thyroid gland secretions 2 important thyroid hormones: Thyroxine (T4) or tetraiodothyronine Triiodothyronine (T3) - Secreted by Follicular cells. - Can be stored in thyroid gland for couple of months (2-3 months). - Having significant effect on ↑ metabolic rate of the body. Calcitonin - Secreted by Parafollicular cells. - Important hormone for Ca2+ metabolism & homeostasis.  Actions of Thyroid Hormones Increase basal metabolic rate Stimulate synthesis of Na+/K+ ATPase Increase body temperature (calorigenic effect) Stimulate protein synthesis Increase the use of glucose and fatty acids for ATP production Stimulate lipolysis Enhance some actions of catecholamines Increase activity of adrenal medulla  Heart: thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility. Lungs: thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion. Skeletal muscles: thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.  SYNTHESIS OF THYROID HORMONES  How thyroid hormones are synthesized? 1. Thyroglobulin formatiom: ▪ Thyroglobulin is a glycoprotein, made up of 2 subunits, & has a MW of 660,000. ▪ Synthesized in the thyroid cells following entry aa from ECF. ▪ Secreted into colloid by exocytosis of granules that also contain thyroid Peroxidase. ▪ Each thyroglobulin molecule contains approximately 100-120 tyrosine residues, but only a small number (20) of these are subject to iodination by thyroperoxidase in the follicular colloid. Therefore, each Tg molecule forms only approximately 10 thyroid hormone molecules. ▪  How thyroid hormones are synthesized? 2. Iodine formation: ▪ Iodine (Io) is a raw material essential for THs synthesis. ▪ Found in food, e.g. salt, & sea food, in the form of “iodide (I-)”. ▪ 120-150 µg of I- is needed daily to maintain normal thyroid fx in adults (or ≈1mg/wk). ▪ Iodide (I-) actively transported (trap) into the follicle (90 – 95%). ▪ (I-) will be 30X in thyroid cells > blood concentration. ▪ (I-) secreted into colloid along concentration gradient. ▪ Peroxidase enzyme found near apex of follicular cells. ▪ Peroxidase oxidize iodide (I-) to iodine (Io). Iodine Metabolism Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland (or removed from the body by the kidneys). The transport of iodide into follicular cells is dependent upon a Na+/I- cotransport system. Iodide taken up by the thyroid gland is oxidized by peroxidase in the lumen of the follicle: - peroxidase I I0 Oxidized iodine can then be used in production of thyroid hormones. How thyroid hormones are synthesized? 3. Iodination: ▪ Iodine attach to tyrosine within thyroglobulin chain. ▪ Iodinase enzyme is found in the apical membrane → Colloid → start iodination process. 1 Iodine + 1 tyrosine → Mono-iodo-tyrosine (MIT) iodinase 2 Iodine + 1 tyrosine → Di-iodo-tyrosine (DIT) Colloid How thyroid hormones are synthesized? 4. Condensation (coupling): ▪ MIT & DIT or 2 DIT molecules coupled together. MIT + DIT = T3 DIT + DIT = T4 - Not all DIT & MIT → thyroid hormones. - Only 25% of DIT & MIT give rise to thyroid hormones. How thyroid hormones are synthesized? 5. Thyroid hormones secretion: ▪ After formation of THs, they remain bound to thyroglobulin in the colloid until secreted. ▪ Hormones are surrounded in colloid by acid pool, then converted into ‘colloid droplet’. ▪ TSH stimulates pinocytosis of thyroglobulin into the follicular cell. ▪ Lysozome enzymes hydrolyze peptide bonds & release T3 & T4 from thyroglobulin. ▪ T3 & T4 will be discharged freely & secreted into the capillaries (blood), attaching to TBG. How thyroid hormones are synthesized? 6. Deiodination: ▪ Inside follicular cells, DIT & MIT which are NOT secreted into the blood. ▪ DIT & MIT will be deiodinized to (Io) & tyrosine. ▪ Deiodized tyrosine will recycled back to synthesize New MIT & DIT.  Thyroid hormones … (continued) ▪ T3 is the active form of T4. ▪ T3 ≈ 4 times > potent (active/important) than T4 in tissue, but it present in much smaller quantities in blood, & persists for a much shorter time than does T4. In an average human subject, T4 and T3 are secreted in a ratio of about 15:1, i.e., about 100 μg (130 nmol) T4 and 6 μg (9 nmol) T3 per day ▪ T3 has great affinity to nuclear receptors than T4.  TRANSFER OF THYROID HORMONES IN BLOOD  Transfer of thyroid hormones in blood ▪ Almost all THs are carried in the blood, mostly in an inactive form, bound to 3 different types of proteins: a. Thyroxine binding globulin … 80% b. Thyroxine binding pre-albumin … ≈ 10% c. Plasma albumin (serum albumin) … ≈ 10% T4 has greater affinity to bind proteins than T3. ▪ Only very little T3 (0.25-0.3%) & T4 (0.03%) are carried in the blood in the free active form. Thyroid hormones ▪ Amount secreted: - Thyroxine (T4) or tetraiodothyronine …93% - Triiodothyronine (T3) …7% ▪ Almost all T4 is converted to T3 in tissues. T4 T3 T4 T4 Capillary Reverse T3 (Rich blood supply) Target cell  Most T3 is produced by deiodination of T4 in peripheral tissues. mainly in the liver and kidneys.  Mechanism of action of thyroid hormones ▪ THs are lipophilic amino acid derivative hormones. ▪ Their receptors are located within the nucleus of target cells.  CONTROL OF THYROID HORMONES SECREATIONS Control of thyroid hormones secretions ▪ THs → also -ve feed back mechanism to Anterior pituitary gland in order to inhibit responsiveness to Hypothalamus (TRH). Normal thyroid hormone level In adults, the range should be 0.4 to 4.0 mIU/L(Milli International Units per Liter); levels lower or higher than this is risky. In children, thyroid hormone range should be: birth to 4 days- 1-39 mIU/L, in 2 to 20 weeks- 1.7-9.1 mIU/L, 21 weeks to 20 years- 0.7-6.4 mIU/L.  ABNORMAL THYROID HORMONES SECRETIONS Hypothyroidism : is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. Causes too little iodine in the diet is the most common cause of hypothyroidism. Hashimoto's thyroiditis is the most common cause of hypothyroidism in countries with sufficient dietary iodine. Less common causes include previous treatment with radioactive iodine, injury to the hypothalamus or the anterior pituitary gland, certain medications, a lack of a functioning thyroid at birth, or previous thyroid surgery. Symptoms Signs Fatigue Dry, coarse skin Feeling cold Cool extremities MyxedemaMyxedema Poor memory and concentration (mucopolysaccharide deposits in the skin) ConstipationConstipation, Hair loss dyspepsia Weight gain with poor appetite Slow pulse rate Shortness of breath Swelling of the limbs Hoarse voice Delayed relaxation of tendon reflexes In females, heavy menstrual periodsIn females, heavy menstrual periods Carpal tunnel syndrome (and later light periods) Pleural effusionPleural effusion, Abnormal sensation ascitesPleural effusion, ascites, pericardial effusion I: Hyperthyroidism (thyrotoxicosis) ▪ Hyperthyoidism: are due to an overproduction of thyroid hormones, but the condition can occur in several ways: ▪ Could be: 1ry hyperthyroidism … (diseases is in the gland), e.g. Grave’s disease 2ry hyperthyroidism … (disease in hypothalamus or pituitary gland) ↑ TRH → ↑ TSH → ↑ T3 & T4.  primary hyperthyroidism - Graves' disease: The production of too much thyroid hormone. - Toxic adenomas: Nodules that form in the thyroid gland, which are growths on your thyroid. They are usually benign (not cancer). But they may become overactive and make too much thyroid hormone. Thyroid nodules are more common in older adults. - Subacute thyroiditis: Inflammation of the thyroid that causes the gland to “leak” excess hormones. This leads to temporary hyperthyroidism that generally lasts a few weeks but may persist for months. - thyroid cancer - Too much iodine. Iodine is found in some medicines, cough syrups, seaweed and seaweed-based supplements. Taking too much of them can cause your thyroid to make too much thyroid hormone. symptoms of hyperthyroidism? The symptoms of hyperthyroidism can vary from person to person and may include: Nervousness or irritability Fatigue Muscle weakness Trouble tolerating heat Trouble sleeping Tremor, usually in your hands Rapid and irregular heartbeat (lead to blood clots, stroke, heart failure, and other heart problems) Frequent bowel movements or diarrhea Weight loss Mood swings Goiter, an enlarged thyroid that may cause your neck to look swollen. Sometimes it can cause trouble with breathing or swallowing. - An eye disease called Graves' ophthalmopathy. It can cause double vision, light sensitivity, and eye pain. In rare cases, it can lead to vision loss. - Thinning bones and osteoporosis - Fertility problems in women - Complications in pregnancy, such as premature birth, low birth weight, high blood pressure in pregnancy, and miscarriage hyperthyroidism diagnosed? - A medical history, including asking about symptoms - A physical exam - Thyroid tests, such as TSH, T3, T4, and thyroid antibody blood tests - Imaging tests, such as a thyroid scan, ultrasound, - radioactive iodine uptake test ( A radioactive iodine uptake test measures how much radioactive iodine your thyroid takes up from your blood after you swallow a small amount of it). treatments for hyperthyroidism - reduce iodine uptake - Medicines for hyperthyroidism include 1. Antithyroid medicines, which cause your thyroid to make less thyroid hormone. This is the simplest treatment, but it is often not a permanent cure. 2. Beta blocker medicines, which can reduce symptoms such as tremors, rapid heartbeat, and nervousness. They work quickly and can help you feel better until other treatments take effect. - Radioiodine therapy is a common and effective treatment for hyperthyroidism. It involves taking radioactive iodine by mouth as a capsule or liquid. This slowly destroys the cells of the thyroid gland. It does not affect other body tissues. Almost everyone who has radioactive iodine treatment later develops hypothyroidism. This is because the thyroid hormone-producing cells have been destroyed. But hypothyroidism is easier to treat and causes fewer long-term health problems than hyperthyroidism. - Surgery to remove part or most of the thyroid gland is done in rare cases. It might be an option for people with large goiters or pregnant women who cannot take antithyroid medicines (removal of thyroid gland will need to take thyroid medicines for the rest of your life. Some people who have part of their thyroid removed also need to take medicines. Secondary hyperthyroidism (less common) Pituitary adenoma: pituitary gland, produce excessive thyroid stimulating hormone (TSH) treatments may include surgical removal of the tumor, radiation therapy, or medication to shrink or control tumor growth. In primary hyperthyroidism, TSH levels are usually low because the pituitary gland reduces TSH production in response to high thyroid hormone levels. In contrast, free levels of T4 or T3 are high. Conversely, in secondary hyperthyroidism, excessive pituitary gland production elevates the TSH levels. The elevated TSH drives the thyroid gland to produce more T3 and T4, meaning free T4 and T3 levels may be high or at the upper end of their typical ranges.  I: Hyperthyroidism … ‘Grave’s disease’ ▪ 90% of hyperthyoidism is due to “Grave’s disease”. ▪ GD is an autoimmune disease → ↑ thyroid stimulating immunoglobulin (IgG) ▪ Symptoms of GD: - Exophthalmous (eye bulging), due to retro-orbital oedema (irreversible). - weakness of muscles (reversible). - Anxiety. - Sleeplessness. - ↑ appetite, ↓ weight & diarrhea. - Intolerence to heat. ▪ Treatment: - drugs to ↓ iodination process, such as PTU ‘Propylthiouracil’; MMI ‘methylmercaptoimidazole’.  a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry. Mechanism] Thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor (TSH receptor) which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3) Treatment of Graves' disease includes antithyroid drugs which reduce the production of thyroid hormone; radioiodine (radioactive iodine I-131); and thyroidectomy Thyrotoxicosis The term “thyrotoxicosis” refers to the clinical effects of excessive thyroid hormone levels in the bloodstream or tissues Graves’ disease is the most common cause of thyrotoxicosis. Excessive thyroid hormone levels due to taking too much thyroid medication for an underactive thyroid. Alternatively, thyroiditis, the thyroid can release stored hormones, resulting in high levels in the blood. Secondary hyperthyroidism is a rare cause of thyrotoxicosis, but it can happen as a result of high TSH levels. Hypothyroidism Primary hypothyroidism is due to decreased secretion of thyroxine (T4) and triiodothyronine (T3) from the thyroid. Serum T4 and T3 levels are low, and thyroid-stimulating hormone (TSH) level is increased causes of primary hypothyroidism Hashimoto's disease, an autoimmune disorder where your immune system attacks your thyroid. This is the most common cause. Thyroiditis, inflammation of the thyroid Congenital hypothyroidism, hypothyroidism that is present at birth Surgical removal of part or all of the thyroid Radiation treatment of the thyroid Certain medicines too much or too little iodine in your diet Secondary hypothyroidism Secondary hypothyroidism occurs when the hypothalamus produces insufficient thyrotropin-releasing hormone (TRH) or the pituitary produces insufficient TSH. Sometimes, deficient TSH secretion due to deficient TRH secretion is termed tertiary hypothyroidism. Subclinical hypothyroidism Subclinical hypothyroidism is elevated serum TSH in patients with absent or minimal symptoms of hypothyroidism and normal serum levels of free thyroxine (T4). symptoms of hypothyroidism? Fatigue Weight gain A puffy face Trouble tolerating cold Joint and muscle pain Constipation Dry skin Dry, thinning hair Decreased sweating Heavy or irregular menstrual periods Fertility problems in women Depression Slowed heart rate Goiter, an enlarged thyroid that may cause your neck to look swollen. Sometimes it can cause trouble with breathing or swallowing. Kids and teens who have hypothyroidism have the same symptoms as adults. In addition, they could have: Slow growth. Slow mental development. Delayed permanent teeth. Delayed puberty. Babies who are born without a thyroid gland or with a thyroid that doesn’t work may not have many symptoms at first. They may jaundice. Their face could be puffy and their tongue may be enlarged causing choking. As the disease progresses, infants can have trouble feeding and may not grow and develop normally. They also may be constipated, sleepy, and have poor muscle tone. If it is not treated, hypothyroidism in infants can lead to physical and an intellectual disability. Hypothyroidism can contribute to high cholesterol. In rare cases, untreated hypothyroidism can cause myxedema coma. This is a condition in which your body's functions slow down to the point that it becomes life-threatening. During pregnancy, hypothyroidism can cause complications, such as premature birth, high blood pressure in pregnancy, and miscarriage. It can also slow the baby's growth and development. hypothyroidism diagnosed? - A medical history, including asking about your symptoms - A physical exam - Thyroid tests, such as TSH, T3, T4, - thyroid antibody blood tests - Imaging tests, such as a thyroid scan, ultrasound, - radioactive iodine uptake test. treatments for hypothyroidism? Hormone replacement therapy (levothyroxine) Iodine (iodine deficiency) How goiter ‘swollen neck’ is formed? With lack of iodine … COLD Hypothalamus TRH + Anterior pituitary TSH + NO or low Thyroid Lack of feedback iodine gland inhibition Poor +++ Low T3 or T4 ↑ Growth of release the gland II: Hypothyroidism ▪ If there is absence of deionization enzyme → NO recycle synthesis of DIT & MIT → accumulate. ▪ DIT & MIT will not be used for new THs formation → ↓ THs.  Myxedema Myxedema is a medical term used to describe a rare but life-threatening situation caused by untreated hypothyroidism. swelling of your face, which can include your lips, eyelids, and tongue swelling and thickening of skin anywhere on your body, especially in your lower legs Shallow or slow breathing Low blood pressure Pulse below 60 beats per minute Slow or no reflex Low sodium levels Low blood sugar Decreased mental status  Hypothyroidism Children (Cretinism) ▪ Hypothyroidism in children→ ↓ THs. Hypothyroid from end of 1st trimester to 6 months postnatally, or in the 1st few years of life. ↓ T3 & T4 → reflex ↑ TSH. ▪ Additional Signs & Symptoms: - Severe mental retardation. - Short stature (due to ↓ growth of bones, muscle, & brain). ▪ Treatment: replacement therapy. jaundiced and has a large protruding tongue. Myxedema coma Myxedema coma is a life-threatening complication of hypothyroidism, usually occurring in patients with a long history of hypothyroidism. Its characteristics include coma with extreme hypothermia (temperature 24° to 32.2° C), seizures, and respiratory depression with carbon dioxide retention.