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38 Cards in this Set
- Front
- Back
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On which chromosome are the growth hormone genes located? Specify the area.
Which 2 variants are most common (by %)? How do they differ? |
CHR 17q in the GH-hCs cluster.
Variants: 1) the hGH-N gene product (normal) 75% at 22k and hGH 10% at 20 k, made by alternate splicing. |
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How is GH held in the body?
What is the half-life of GH? What is the most common signalling pathway activated by GH? What other hormone uses this pathway? |
50% of GH is bound to a plasma protein that is a fragment of the GH receptor (i.e. extra-membrane portion cleaved off).
T1/2: 6-20 minutes Activates the JAK2-STAT pathway after making contact with a receptor that is a member of the cytokine family. Prolactin also uses this pathway. |
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What does GH stimulate the liver to produce? What are the 2 main ones?
Where are these found in plasma? Who gets the most? |
Insulin-like growth factors. IGF1 and IGF2.
Found bound to plasma proteins, of which there are 6: IGFBP 1-6. IFGBP-3 binds the most (95%) |
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Insulin, IGF-1 and IGF-2:
Bind to? Source? Regulated by? Plasma-binding Protein? Job? |
Bind to: IGF 1 and 2 bind to IGF 1 and 2 receptors, and to insulin receptors. Insulin binds to insulin receptor and IGF-1 receptor.
Source: I: pancreatic B cells, 1. liver and other tissues, 2. diverse tissues Regulated by: I. glucose, 1. GH, nutrition status, 2. ? Binding Protein: 1 and 2 = yes, I. = no. Job: I. control of metabolism, 1. skeletal and cartilage growth, 2. growth during fetal development. |
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How is GHRH release described?
How is Somatostatin (SS) release described? How is growth described? |
GHRH: Episodic (pulsatile).
SS: tonic (constant). Growth is episodic, not continuous. |
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What are the primary actions of GH? (6).
What are the primary actions if IGF-1? (4) Big role? |
GH:
1. Na+ retention 2. Decreased insulin sensitivity (mm) = less glucose into muscle 3. Lipolysis (ketogenic) = f.a. production 4. Stim. liver to make IGF-1. 5. Protein synthesis 6. Epiphyseal growth (LINED-P) IGF-1: 1. Insulin-like activity 2. Antilipolytic activity 3. Protein synthesis 4. Epiphyseal growth (AEIP) Big role: Increase hepatic glucose output, causing hyperglycemia. |
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How do GH and IGF-1 act on bone in the proximal, intermediate, and distal zone?
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- GH binds to a receptor on prechondrocytes to cause differentiation in the proximal zone.
-IGF stimulates proliferation of chondrocytes in intermediate zone via clonal expansion -IGF again stimulate maturation of chondrocytes in distal zone. |
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What does too much GH result in after closure of the epiphyseal plate?
Major cause of this? What co-occurs? What are the effects of this? (6) What occurs in 25% of cases? |
Acromegaly.
Pituitary tumors are the major cause. Prolactin is also increased in 20-40% of cases, causing breast development and lactation. Effects: 1. osteoarthritic vertebrae 2. bilateral hemiopia 3. prognathism and acromegalic facies 4. hirsutism 5. gynecomastia and lactation 6. enlarged hands and feet. Diabetes occurs in 25% of cases, insulin insensitive. This decreases glucose uptake and increases hepatic glucose output. |
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What increases GH secretion? (6)
How is this tested? |
1. Deficiency of E substrates: (hypoglycemia, exercise, fasting).
2. Increases in circulating aa (e.g. protein meal, arginine). 3. Stressful Stimuli 4. Going to sleep 5. Hormones and drugs (L-dopa and alpha-adrenergic agonists), dopamine agonists, estrogen, androgens 6. Glucagon Tested with a glucagon test, so this increases GH |
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What decreases GH secretion? (6)
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1. REM sleep
2. Glucose 3. Cortisol 4. Free fatty acids 5. Medroxygrogesterone 6. GH |
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Outline the Growth Hormone Axis.
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GHRH is released episodically from hypothalamus, + stimulating the anterior pituitary to release GH.
GH release is - stimulated by Somatostatin. GH stimulates the liver and other tissues to produce Insulin like growth factors. It also + blood glucose and promotes bone and tissue growth. Insulin-like GF stimulate cartilage growth, and provide negative feedback on the anterior pituitary, and positive feedback on somatostatin. |
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Outline the Hypothalamo-Pituitary thyroid axis.
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Tonic release of TRH from the hypothalamus stimulate the anterior pituitary to release TSH. Stress is negative feedback.
TSH stimulate the thyroid to produce T3 and T4, which are released into the blood flow. T4 is converted to T3 (largely). Systemic metabolic effects. -Tissue metabolism -O2 consumption -CHO and lipid metabolism -Normal growth and development |
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Describe the structure of the the thyroid gland.
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Composed of multiple follicles, each surrounded by a single layer of cells and filled with colloid. These are enclosed in a connective tissue capsule.
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Describe the structure of the 2 hormones secreted by the thyroid.
Which form is more active? |
Thyroxine (T4): tyrosine is conjugated with 4 iodine attached to the tyrosine ring.
Triiodothyronine (T3): the first tyrosine ring only contains 1 I in the top position. If it is on the lower position, reverse T3 (RT3), an inactive form is made). T3 > T4 |
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Explain how iodine is metabolized and the thyroid hormones are made.
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Iodine is converted to I- (iodase) and transported from the blood, across the thyroid follicle cell, into the colloid.
In the colloid, I- is combined with thyroglobulin (TG) made in the follicle cell and secreted into the colloid. I- is added to the tyrosine aa portion of TG. This is moved back into the follicle cells. Thyroid hormones remain attached to TG until secreted. at which time the peptide bonds are hydrolysed. |
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What are the 2 products made in the thyroid colloid?
What are the 3 ways these are assembled? |
Monoiodotyrosine (MIT) made first by adding iodine to 3' position.
Diiodotyrosine (DIT) is made by adding a second I to the 5' position. DIT + DIT = T4 with release of alanine. MIT + DIT = T3 with alanine release. DIT + MIT = RT3. |
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How is iodine transported into the thyroid cell?
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Transported in by an Na+/I' symporter against an electrochemical gradient. I' by diffusion in, Na+ taken out by Na+/K+ ATPase deficiency. 500 ug/d of Na+ required for this, and 150 ug/d I-
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Which hormone is produced in greatest quantities?
Which hormone is more effective? |
T4. Only a small amount of T3 is actually secreted by thyroid.
T3 (3-5X > potent) |
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How is T4 converted to T3 (or RT3) in blood and peripheral tissues?
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The enzyme iodotyrosine deiodinase removes I- from MIT and DIT.
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What are the normal plasma levels of T4 and T3?
Half-life of plasma-bound T4? What are the 3 plasma proteins used to bind thyroid hormones? |
T4 8.0 ug/dL, 99.98% bound.
T3 0.15 ug/dL, 99.8% bound. Half-life: 6-7days. 3 proteins: T binding globulin (TBG): 4: 67% 3: 46% Transthyretin: 4: 20% 3: 1% Albumin: 4: 13%, 3: 53%. Note TBG is the largest BP for T4, Albumin is largest for T3. Free T4 = 0.002 ug/dL. |
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What factors up regulate TBG?
Down regulate? Decrease binding capacity/affinity? |
Up:
estrogen tx and pregnancy methadone, heroin tranquilizers Down: glucocorticoids androgens anti CA drugs Decreased Affinity/Binding capacity: anti CA drugs anticonvulsants. |
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How much of T4 is converted to T3?
What are the 3 deiodases involved in this conversion and where do they operate? |
1/3. 87% is made by conversion of T4 --> T3, only 13% is secreted by thyroid.
D1: plasma formatpion of T3 D2: local formation in tissues D3: placenta and brain |
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Where are T4 and T3 diodinated and conjugated?
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In the liver to form sulfates and glucoronides which can enter the bile and then intestines. The conjugates are hydrolyzed and some are reabsorbed via the enterhepatic circulation, some are excreted in stools.
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Name the TR genes, their location, splicings, and distribution.
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2 TR genes: alpha (C17) and beta (C3).
By alternate splicing, each form has at least 2 mRNAs, therefore 2 idfferent receptor proteins: TRalpha1, TRalpha2, TRbeta1, TRbeta2 (only found in the brain; rest are widely distributed). TR alpha2 does not bind T3 and is an orphan receptor. |
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Function of TRs?
How can their function be altered? |
A TR activated receptor binds DNA as a monomer, homodimer, heterodimer with other nuclear receptors, expecially the retinoid X receptor (RXR).
Function can be altered by co-activator and co-repressor proteins, yielding many effects on the body. |
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Outline the functions of the thyroid hormones.
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1. Up basal metabolic rate:
-Increased Na/K ATPase -Increased O2 consumption, but not in brain, testes, uterus, lymph or spleen -Heat generation and sweating -Weight loss -Increased respiration -Increased CV function on beta-adreneric receptors), which affects myosin type in myocytes, increasing contraction speed -Increased metabolism 2. CNS/SNS -development of cerebral cortex, cochlea -Increased beta-adrenergic receptors -Increased reflex times 3. Growth -Required for fetal+neonatal skeleton and CNS -Involved in pubertal growth spurt -Permissive for GH 4. Reproduction -Required for mild production -Required for normal menstrual cycles and fertility |
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TSH:
How many subunits? Gene location? T1/2? Inhibited by? |
2 subunits - alpha and beta. Alpha on CHR 6, beta on CHR 1. Beta is specific for TSH, alpha is identical to subunits for other hormones.
T1/2: 60 min. Inhibited by somatostatin, DA, GC (dopamine? glucocorticoids?). |
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When does hypothyroidism occur?
How does hypothalamo-pituitary access reflect this? Symptoms? |
When there is less than 50 ug/d of iodine.
Low dietary iodine results in: -Decreased T3 and T4 production -No negative feedback to stop TRH and TSH, so these increase -Too much TSH = thyroid hypertropy Symptoms: goiter, mental deterioration and poor memory. |
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List other causes of hypothyroidism other than iodine insufficiency.
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Myxedema - edema - results from prolonged hypothyroidism.
Problem may occur at the level of the thyroid, pituitary or hypothalmus, hence test TSH and TRH levels to resolve. |
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What is cretinism?
Causes? |
Congenital hypothyrodism. Results from:
-maternal iodine deficiency -fetal thyroid dysgenesis -errors of thyroid hormone synthesis -maternal antithryroid antibodies crossing placenta -fetal hypopituitary hyothyroidism |
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What is Graves's Dx?
Signs? Symptoms? (6) Causes? |
Hyperthyroidism.
Signs: exopthalmosis, goiter! Symptoms (6): -Increased BMR -Weight loss -Hyperphagia (munch...munch...) -Heat intolerance -A fib Causes: -antibody-mediated autoimmune rxn: body produces antibodies to recetor or TSH, antibodies bind to TSH receptor and chronically stimulate it. This creates strong negative feedback. |
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Outline the patterns of hormone levels in terms of primary and secondary pituitary tumors.
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Primary defect: the primary target (e.g. the organ secreting hormone) is OVER or undersecreting target hormone. Pituitary will respond with positive or negative feedback.
Secondary defect: the problem is at the level of the pituitary gland, and the primary target will respond accordingly. (KEY - Both move in same direction). |
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What are the 3 presentations for pituitary lesions?
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1. Mass effect - due to the size of the lesion. Present with headaches, visual field defects, effects on CN in cavernous sinus (III, IV, V, V2, VI). Test with CN exam, visual field exam and MRI.
2. Hyperfunction: see ++ 1 hormone. From most to least common: no hypofunction, increased prolactin,g GH, ACTH. 3. Hypofunction: pituitary hormone deficiencies. Usually losti in this order: GH, FSH/LH, TSH, ACTH Prolactin (Go Look For The Adenoma Please). |
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What do you attempt if hypo or hyperstimulation is detected to rule out other causes?
What test is performed to do this? |
If it is low, try and stimulate it, if it is high, try to suppress it.
Can perform a triple bolus test, giving IV insulin to stimulate cortisol and GH, TRH to stimulate TSH and prolactin, and CnRH to stimulate LH and FSH. |
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Outline the presentation features of a prolactinoma.
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-Galactorrhea
-Hypogonadism -Amenorrhea -Erectile dysfunction |
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Outline the presentation of symptoms of acromegaly.
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-Coarse features
-Enlarged jaw, nose, tongue -Cardiac and pulmonary dx -Spine deformity -Enlarged hands and feet -Diabetes meillitus |
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Outline the signs of excess ACTH
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-Signs of excess cortisol - catabolic effects, metabolic effects, fat distribution.
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Signs of hypofunction in GH, Gonadal, Thyroid, Adrenal and Prolactin hormonal axises?
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-GH: Short stature
-Gonadal axis - amenorrhea, infertility, erectile dysfunction, hypogonadism. -Thyroid axis: cold intolerance, weight gain, decreased concentration hormones, constipation, menorragia Adrenal Axis: weight loss, weakness, fatigue, low BP Prolactin: inability to lactate, may occur with stalk compression of pituitary, can also get increases due to lack of dopamine inhibition. |
