2013-02-05 Physio Thyroid Hormones; Hormonal Reg. of Intermed. Metab.

Question 1

What is the structure of the thyroid hormones?

Answer 1

thyroid hormones are iodothyronines—compounds formed by coupling two iodinated tyrosine molecules via an ether linkage

Question 2

What are the main forms of thyroid hormone?

Which is most active?

Answer 2

tetraiodothyronine (T₄)—90% of hormon secreted by gland; less active

triiodothyronine (T₃)—9% of hormone secreted by gland; most active

reverse-triiodothyronine (rT₃)—1% of hormone secreted by gland; thought to be inactive

Question 3

What causes a goiter? Is this a sign of hypothyroidism or hyperthyroidism?

Answer 3

excessive TSH stimulates hypertrophy and increased vascularization of the thyroid tissue

Not a specific s: can still be euthyroid

occurs:

• iodine deficiency (body increases size of thyroid to be able to “trap” more iodine)
• Graves’ dz, TSAb’s (thyroid-stimulating antibodies) binds TSHRs

Question 4

What are sx of hypothyroidism?

Answer 4

In order of prevalance:

• weakeness
• dry skin
• coarse skin
• lethargy
• slow speech
• edema of eyelids
• sensation of coldness
• reduced sweating
• cold skin
• thick tongue
• facial edema
• coarse hair
• pallor
• memory probs
• constipation
• wt. gain
• allopecia
• hoarsesness
• deafness

Question 5

What is the sex ratio in severe hypothyroidism incidence?

Answer 5

9 females : 1 male

Question 6

What are sx of thyrotoxicosis?

Answer 6

In order of prevalence:

• nervousness
• hyperhydrosis
• heat intolerance
• palpitations
• fatigue
• wt loss
• tachy
• dyspnea
• weakness
• incr appetite
• eye complaints—exopthalmos
• hyper-defecation

Question 7

How is TH made?

Answer 7

1. I^- is taken into thyroid follicular cells via active transport w/ NIS (sodium-iodide symporter)
2. I^- is there perioxidated to: I² or I⁺
3. Iodinate tyrosine residues in thyroglobulin (TG) to for MIT and DIT (mono- and di-iodotyrosine)
4. couple these to form T₄ or T₃; each TG contains ~3 T₄ or T₃ residues so this coupling happens both intra- and inter-molecularly
5. stored as “colloid” in lumen of follicle
6. TG phagocytosed and cleaved releasing T4, T3, rT3, DIT and MIT
   
   • T4, T3, and rT3—>bloodstream when signalled
   • DIT and MIT = inactive; deiodinated to save I

Question 8

What controls synth and secretion of TH?

Answer 8

1. autoregulation—independent of TSH; high intake of I^- (e.g. seaweed) leads to decr T4/T3 secretion and NIS activity—>decr uptake
   
   • temporary, will be overcome w/in 48-72 hrs
2. extrathyroid reg—TSH (thyrotropin)—>membrane receptor—>cAMP
   
   • enhancement of hormone biosynthesis
   • thyroidal intermediary metabolism
   • phospholipid and RNA synthesis
   • growth and vascularity of the gland.
3. Negative feedback—T3 (and T4 broken down into T3 intracellulary) inhibited synthesis of α- and ß-subunits of TSH
4. Pathologic—abnormal antibodies can either block or stimulate TSHR
5. Pregnancy—hCG mimics TSH

Question 9

What controls TSH?

Answer 9

1. Thyrotropin-releasing hormone (TRH) from the hypothal —hypophysial portal sys—>ant. pit.,—>binds to cell membrane receptors—>enhances both the release of TSH and its synthesis
2. Negative feedback:
   
   • hypothal—T3 (and T4—intracell—>T3) inhibits TRH release
   • ant. pit—T3—>binds to TH receptor on TRE—>suppressed transcription of both α- and ß-TSH genes

Question 10

How are T4 and T3 transported in the blood?

Answer 10

>99% of both are bound to proteins

• T4: stays bound ~9 days
  
  • 60% binds thyroxine-binding globulin (TBG), [which in contrast to the TRs has a higher affinity for T4 than for T3]
  • 30% to thyroxine-binding prealbumin (TBPA)
  • and 10% to albumin
• T3: stays bound ~ 1 day
  
  • only TBG and albumin

Question 11

How is TH distributed and metabolized in the periphery?

Answer 11

Most TH is T4. metab’d via different deiodinases that are expressed differently throughout the body; this allows for differential action of TH even though there is uniform blood concentration

• D1: found primarily in liver, kidney and thyroid
  
  • responsible for the production (T4—>T3) of T3 circulating in plasma
• D2: found primarily in the pituitary, CNS and brown fat
  
  • resp. for T4—>T3 in these tissues
• D3: high levels in placenta and preg. uterus; lower levels in several tissues, in particular develpoing brain
  
  • T₄ and T₃—>rT₃

Question 12

Describe liver metab of TH.

Answer 12

Significant % of circulating T4, T3 and other iodothyronines are conjugated with glucuronic acid and to a lesser extent sulfates.

conjugated forms excreted into the bile.

In intestines, conjugates are hydrolyzed releasing the original hormones, some of which can be reabsorbed into the bloodstream.

unabsorbed iodothyronines pass through the GI tract and are excreted in feces.

Question 13

What metabolic effects does TH regulate?

Answer 13

• BMR and heat production
• water and ion transport
• calcium and phosphorus metabolism
• cholesterol and fat metabolism
• nitrogen metabolism
• carbohydrate metabolism

Question 14

What are TH’s effects on growth and development?

Answer 14

• growth of many vertebrate tissues;
• amphibian metamorphosis;
• maturation of CNS.

Question 15

Describe the importance of adequate TH on fetal and neonatal development.

Answer 15

CNS development requires adequate TH

• babies are tested at birth for hypothyroidism at birth and treated right-away right after birth (i.e. once they’ve stopped getting TH from mother); will be on synthroid for life
• WORSE = maternal iodine deficiency during pregnancy
  
  • if not caught early, irreversible CNS development problems—MR
  • child will be euthyroid once born however

Question 16

describe the effects of iodine deficiency and excess on thyroidal iodine accumulation, TH biosynthesis and secretion.

Answer 16

excess iodine—>temporarily suppresses release of T4 and T3

iodine deficiency—>goiter? increased TSH? preferrential synthesis of T3 > T4

Question 17

discuss the structure and properties of TH receptors, their prefered ligand and their role as modulators of transcription of specific genes.

Answer 17

• T3 and T4 enter cell (probably via cell membrane transporters)
  
  • T4—5’-monodeiodinase
• high-affinity, low-capacity Intracellular nuclear receptors bind TH (prefer T3)
• T3-TR complexes bind thyroid-responsive elements (TREs) on direct response genes
  
  • examples include genes for: TSH, myelin, myosin

Question 18

Aside from TH’s effects on metabolism and growth/development, what other organ systems does TH regulate?

Answer 18

• the cardiovascular system
• respiration
• GI tract
• muscle function

Question 19

What is Hashimoto’s thyroiditis?

Answer 19

autoimmune destruction of thyroid

Question 20

Which form of TH can cross the placenta? Why is this relevant?

Answer 20

Only T4 crosses. In iodine deficiency mothers ∆ to make only T3 b/c it’s more efficient (high efficacy w/ less I)

leads to “neurological cretinism” in