Endocrine 7

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Thyroid hormone -->

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two compounds - name refers to the mols of iodine found per mol of compound T3 is more potent than T4

T4 (3,5,3',5'-tetraiodothyronine)

T3 (3,5,3'-triiodothyronine)

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T3, T4

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synthesized in thyroid gland
T4--> T3 in thyroid gland and periphery

- synthesis req iodide: thryroid gland extracts 80-120ug /day normal intake 400-500ug rest excreted in kideny

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The gland stores 100 fold excess of iodide protecting against daily variation of iodide intake

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- Also sotres amt of iodinate tyrosine bound to thyrogloulin sufficient to synthesize nearly 100 day supply of thyroid hormone in abs of any iodine intake

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Thyroglobulin

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iodination of tyrosines linked to a large protein
- iodination is accomplished by oxidation of iodide to iodine by enzyme thyroid peroxidase

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1. thyroid peroxidase
2. Hydrogen peroxide
3. Iodinated thyroglobulin
4. Lysosomal proteases

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1. iodination is accomplished by oxidation of iodide to iodine
2. electron acceptor in rxn
3. sotred and term a colloid
4. release thyroid hormones from colloid

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1. 5'- deiodinase converts
2. 5- deiodinase converts

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1. T4 --> T3
2. T4 --> RT3
in both thyroid gland and periphery

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triodothyronines are further deiodinated in periphery to

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di and monoiodothyronines

Complete deiodination --> thyronine --> can be convereted to inactive thyroacetic acid derivatives

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Thyroid Circulation

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only free form is active >99% is bound to serum binding proteins

>60% to a low volume, high affinity reservoir protein termed throxine binding protein TBG

rest bound to albumin or pre albumin form a high volume reservoir to lower affinity

T4--> 2ng/dl half life 6-7 days
T3--> 0.3ng/dl half life 1 day

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Effects:

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 1.    After  entering  cells,  T4  is  deiodinated  to  T3   or  RT3.    T3  is  the  active  form,  RT3  is  essentially   inactive  and  may  even  inhibit  the  conversion  of  T4   to  T3.  
 2.    T3  acts  by  binding  to  a  nuclear  receptor,  
altering  gene  transcription.    3.    Increases  metabolic  rate,  heat  production,  and   activity  of  NaK-­ATPase.    
4.    Increases  the  effectiveness  of  catecholamines.    
5.    Increases  ventilation  and  cardiac  output.    
6.    Increases  food  intake  and  mobilization  of   endogenous  energy  reserves.    
7.    Increases  rate  of  absorption  of  glucose  from   gut,  can  cause  transient  hyperglycemia.    
8.    Decreases  body  weight,  muscle  and  adipose   tissue  mass.

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Regulation of secretion

1. TSH- thyroid stimulating hormone, thyrotropin

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acts on the thyroid gland to promote syn and release of thyroid hormones

- formation of iodine from iodide is promoted, iodination reaction itself is non enzymatic and not regulated

-synthesized in anterior pituitary

-T3 suppresses release of TSH
- T4 suppresses release after conversion to T2 within the pituitary

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Regulation of secretion

2. TRH- thyrotropin releasing hormone

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-promotes release of TSH

- TRH --> tripeptide syn in hypothalamus

reaches pituitary via median eminence and long portal veins

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Regulation of secretion

3. Somatostatin

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decreases TSH secretion

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Regulation of secretion

4. Exposure to cold

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stimulates production of thyroid hormone in animals

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Regulation of T4 Effectiveness

Change sin the activity of intracellular T4 5'- deiodinase regulate the effectiveness of T4

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both drugs and the environment can alter this conversion in a tissue specific manner

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Regulation of T4 effectiveness

Ex. cold exposure

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activates 5' deiodinase in brown adipose tissue producing a thermogenic response without an inc in circulating T3 or T4

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Inc in T3

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lead to inc in response regardless of activity of 5' deiodinase

T4 --> permissive
T3--> acitve

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Prazosin

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alpha 1 adrenergic blocker, blocsk the cold induced inc in the activity of the 5' deiodinase

- used to treat HTN

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Glucocorticoids, propylthiouracil, and propranolol

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inhbit conversion of T4 to T3 in the liver but not the pituitary

hepatic T3 falls without inc TSH or T4

other drugs dec conversion peripherally and in the pituitary --> inc TSH and T4

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Hypothyroidism (1-4)

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  1.   If  present  at  birth,  and  uncorrected,  leads  to  permanent  mental  retardation  and  dwarfism.    Termed  cretinism.     2.   In  adults,  mentation  becomes  slow,  voice  becomes  husky,  cold  is  poorly  tolerated.     3.   Hypothyroidism  can  be  provoked  by  insufficient  iodine  intake  (<100ug/day).    In  this  case,  TSH  rises,  and  a   goiter  (thyroid  gland  hyperplasia)  appears.    In  addition,  pharmacologic  doses  of  iodine  (>6mg/day)  also  inhibit   thyroid  hormone  release  perhaps  by  inhibiting  proteolytic  release.    Anions  such  as  perchlorate,  thiocyanate,  and   pertechnate  block  iodide  uptake  through  competitive  inhibition  of  the  iodide  transporter.     4.   Hypothyroidism  can  be  provoked  by  goitrogens  from  foods  such  as  cabbage  and  turnips.    The  compounds  are   found  in  these  foods  as  a  progoitrin  which  is  converted  in  the  gut  to  the  active  form  termed  goitrin.    Usual  diets  do  not   contain  enough  goitrogens  to  be  a  problem,  but  in  some  unusual  diets  the  amounts  increase  and  lead  to  goiters.

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Hypothyroidism (5-7)

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5.   Autoimmune  destruction  of  the  thyroid  gland,  termed  Hashimoto's  thyroiditis,  ultimately  leads  to   hypothyrodism.    In  some  cases,  the  early  phases  of  the  disease  may  be  characterized  by  hyperthyrodism.     6.   TSH  deficiency.     7.   Treatment:    First,  determine  if  iodine  intake  is  sufficient,  the  treatment  of  hypothyroidism  inspired  the  original   sales  of  iodized  salt.    Second,  determine  if  an  environmental  input  (goitrogens  in  diet)  is  causing  syndrome.    If  thyroid   gland  cannot  produce  hormone,  treat  by  giving  a  hormone  preparation.

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Hyperthyroidism, thyrotoxicosis

symptoms

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1. Weight loss despite inc in food intake
2. discomfort in warm environments--> leading to fever
3. rapid heart rate
4. Tremor, nervousness

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Hyperthyroidism, thyrotoxicosis

causes

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1. Excess TSH
2. Thryoid cancer
3. Graves' disease --> cause antibodies (usually IgG) which bind to and activate the TSH receptor

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Graves disease

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some antibodies block TSH action without stimulating gland but some bind and mimic the effects of TSH

high levels of T3 and T4 --> reduce TSH
persistent stimulation of the gland cause hyperplasia and enlarged gland is termed a goiter

exophthalmos- eyes bulge forward

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Hyperthyroidism, thyrotoxicosis

Treatments

1. Block iodide trapping

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use anions that are competitive inhbitors at the level of the transporter

onset of action: slow due to reservoir of iodinated tyrosine T4 and T3 coupled to thyroglobulin

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Hyperthyroidism, thyrotoxicosis

Treatments

2. Block conversion of iodide to iodine

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thiocarbamides (propylthiouracil, methimazole) inhit the thyroid peroxidase catalyzed reaction. Compounds block the coupling rxn

Onset of action: slow

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Hyperthyroidism, thyrotoxicosis

Treatments

3. Inhibits release

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iodide in excess inhbits release of T3 and T4 by blocking proteolysis of colloid

-pts with excess stimulation of the gland iodide trapping is inc potentiating the inhbiting effect

colloid accumulates and the vascularity of tissue dec : beneficial repsonse in prep for surgical removal of galnd

onset of action fast bc effect does not depend on depletion of a reservoir

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Hyperthyroidism, thyrotoxicosis

Treatments

4. Radiotherapy using I-131

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concentration I-131 tyroid tissue the radioactivity can kill the cells