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anat 322 > thyroid function > Flashcards

thyroid function Flashcards

1
Q

overview of HPT axis (5)

A
  1. TRH synthesized in parvo neurons of PVN and released in ant. pituitary
  2. TRH binds to receptors on thyrotrophs
  3. stimulation and release of TSH
  4. TSH stimulates thyroid gland to increase synthesis of T3 and T4
  5. T3 and T4 inhibit secretion of TRH and TSH by negative feedback
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2
Q

hypothalamic pituitary connections: where does arterial (1) and venous (1) blood go in the HP axis and through which vessels does it pass through

A

arterial blood: passes through hypothalamic artery directly to hypothalamus
venous blood: passes through superior hypophyseal artery to the pituitary

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3
Q

how is TRH synthesized (2)

A
  1. synthesized as a large pre-pro-TRH protein in hypothalamus and several tissues
  2. only parvo neurons in PVN project to ME
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4
Q

major driver of T4 synthesis

A

TRH

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5
Q

negative regulator of TRH gene expression

A

T3

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6
Q

T3 increases expression of…

A

TRH peptidase at the nerve ending

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7
Q

effects of TRH on TSH-producing cells (3)

A
  1. stimulates secretion of preformed TSH
  2. stimulates synthesis of new TSH
  3. critical for normal glycosylation of TSH at post-translational level
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8
Q

why does pituitary TSH have low biological activity

A

because it isn’t glycosylated

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9
Q

roles of TRH at genomic and non-genomic levels

A

genomic -> binds thyrotrophs and acts on TSH gene/TSH mRNA (positive regulator)
non-genomic -> glycosylation of TSH at the pituitary level (post-translational effect)

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10
Q

roles of T3 at genomic and non-genomic levels at (a) hypothalamic level and (b) pituitary level

A

(a) genomic -> negative regulation of TRH secretion
non-genomic -> increases TRH peptidase (inactivates TRH) (post-translational)
(b) genomic -> downregulates expression of TSH gene/TSH mRNA
non-genomic -> alters glycosylation of TSH (post-translational) to inactivate it

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11
Q

what is the active thyroid hormone and what is the prehormone

A

active -> T3
prehormone -> T4

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12
Q

what kind of cell are thyrotrophs

A

basophilic

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13
Q

what type of relationship do TSH and TH have

A

negative inverse relationship -> the more TSH, the less TH; the more TH, the less TSH

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14
Q

glycoproteins (4)

A
  1. FSH
  2. LH
  3. CG
  4. TSH
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15
Q

what structural aspect is common to all glycoproteins

A

alpha chain

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16
Q

what determines receptor specificity (glycoproteins)

A

beta chain

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17
Q

structurally, what inactivates TSH

A

separation of alpha and beta chains

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18
Q

structure of TSH

A

glycoprotein with 2 chains (alpha and beta) with a CHO moiety (glycosylation) that is essential for biological activity

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19
Q

peak of TSH

A

night

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20
Q

temporal aspects of TSH secretion (2)

A
  1. circadian
  2. pulsatile
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21
Q

relationship bw TH receptor occupancy and TSH

A
  1. the more TSH, the less TH receptor occupancy
  2. the less TSH, the more TH receptor occupancy (because more TH)
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22
Q

levels of (a) T3(T3); (b) T3(T4); (c) T4 in liver

A

(a) mostly T3(T3) bound to receptors
(b) small amounts of T3(T4)
(c) minimal amounts of T4

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23
Q

levels of (a) T3(T3); (b) T3(T4); (c) T4 in anterior pituitary

A

(a) same levels as other tissues
(b) much higher receptor occupancy of T3(T4)
(c) small amounts

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24
Q

why is the receptor occupancy rate in anterior pituitary > 90% for T3(T4)

A

anterior pituitary has mechanism to convert T4 into T3 within the thyrotrophs

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25
Q

where does D2 convert T4 to T3

A

in the pituitary

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26
Q

relationship between TSH suppression and T3

A

linear relationship (more T3, more suppression)

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27
Q

what is needed to keep TSH levels normal

A

high level of receptor occupancy

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28
Q

what contributes to a large fraction of nuclear T3 in thyrotrophs

A

T4

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29
Q

anatomy of thyroid gland (4)

A
  1. thyroid cells organized in follicles
  2. follicles contain colloid, which contain thyroglobulin
  3. TH is synthesized and stored in thyroglobulin (until stimulated by TSH)
  4. C cells are found between follicles and produce calcitonin
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30
Q

structural difference bw T3 and T4

A

T4 has an extra iodine atom

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31
Q

synthesis and storage of thyroglobulin

A

produced in thyrocytes and stored in follicles in thyroid gland

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32
Q

why don’t all tyrosine residues participate in hormonogenesis

A

depends on their location; if they are too far apart, even with 3D modifications, are unable to react together and form dimers/oligomers

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33
Q

broad steps of TH synthesis (4)

A
  1. uptake of iodide
  2. incorporation - organification of iodide into tyrosine (iodination)
  3. coupling of iodinated tyrosines to form TH
  4. diffusion of TH into blood
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34
Q

rate limiting enzyme in thyroid gland

A

thyroperioxidase (TPO)

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35
Q

steps of iodination (2)

A
  1. inorganic iodide anion is oxidized to diatomic (molecular) iodine
  2. iodine covalently linked to tyrosyl residues
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36
Q

coupling of iodinated tyrosines to form TH

A

T3 -> DIT + MIT
T4 -> DIT + DIT

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37
Q

MIT and DIT: which is biologically active

A

DIT

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38
Q

mechanism/pathway of TH synthesis in thyrotroph (6)

A
  1. iodide passively follows Na+ into the thyrotroph (via NIS transporter) because [iodide] is ~200x higher inside thyrotroph than outside thyrotroph
  2. pendrin transports iodide from cytoplasm of thyrotroph into the colloid
  3. iodide taken up by thyroglobulin where TH are synthesized
  4. thyroglobulin with TH is endocytosed into thyrotroph
  5. endosomes fuse with lysosomes: degradation of thyroglobulin + release of TH in thyrotroph
  6. TH diffuse into blood
39
Q

TSH effects on thyroid gland (2)

A
  1. release of preformed hormone
  2. stimulation of all steps in TH synthesis
39
Q

events that happen when TH is released (2)

A
  1. thyroglobulin endocytosis
  2. digestion and release of hormones
40
Q

TH synthesis steps that TSH stimulates (4)

A
  1. NIS level and activity
  2. iodide oxidation and organification
  3. coupling of iodotyrosines
  4. thyroglobulin synthesis and processing
41
Q

where is T3 mostly synthesized and why

A

most is made outside of the thyroid (peripherally); because most organs can convert T4 to T3

42
Q

where is T4 synthesized

A

only in thyroid gland

43
Q

what is the real thyroid hormone

A

T4

44
Q

iodothyronine deodination reactions (3)

A
  1. D2 converts T4 to T3
  2. D3 converts T4 to reverse T3
  3. D1 converts T4 to either T3 or reverse T3
45
Q

what decides if D1 will convert T4 to T3 or reverse T3

A

depends on levels of circulating T4 (availability): if high T4, D1 converts to reverse T3, if low T4, D1 converts to T3

46
Q

action of (a) D1; (b) D2; (c) D3

A

(a) converts T4 to either T3 or reverse T3
(b) converts T4 to T3
(c) converts T4 to reverse T3

47
Q

levels of T3 and T4 at nuclear receptor level

A

T3 ~10x more abundant than T4 at nuclear receptor level

48
Q

which TH is more potent and why

A

T3 ~10x more potent than T4 because has a higher affinity for the receptor

49
Q

which TH responsible for most of activity of thyroid secretions

A

T3

50
Q

levels of T3, T4 and TSH in hypothyroidism

A

T3 -> almost constant levels; not until severe hypothyroidism that levels decrease
T4 -> decreased
TSH -> increased only in severe hypothyroidism

51
Q

which hormone is looked at to diagnose hypothyroidism

A

T4 (or TSH)

52
Q

why does T3 stay elevated in hypothyroidism

A

decrease in T4 -> increase in TSH -> TSH increases levels of D2 in thyroid -> thyroid becomes main source of T3

53
Q

source of T3 in hypothyroidism

A

mainly from the thyroid, no more synthesis in the periphery

54
Q

levels of D3 mRNA in hippocampus (a) hypothyroidism (b) hyperthyroidism and why

A

(a) decreased expression because want to make less reverse T3 (because not a lot of T3, so want to limit reverse T3 production)
(b) increased expression because want to decrease T3 levels so make more reverse T3

55
Q

2-cell model of tissue modulation of TH levels - cerebral T3 autoregulation (5)

A
  1. serum T4 transported (OATP) into astrocyte
  2. T4 converted into T3 by D2
  3. T3 acts on nuclear receptors in astrocyte
  4. T3 transported into neuron (MCT8)
  5. T3 acts on nuclear receptor in neuron OR converted into reverse T3 by D3 (inactivated)
56
Q

“therapies” for hypothyroidism (3)

A
  1. increase D2
  2. decrease D3
  3. upregulate transporters
57
Q

biological roles of thyroid hormones (4)

A
  1. growth and development
  2. specific functions
  3. energy balance/maintenance of weight
  4. thermogenesis (homeothermic species)
58
Q

types of thermogenesis (2)

A
  1. basal thermogenesis -> heat produced every day to sustain vital functions (using up ATP)
  2. facultative/adaptive thermogenesis -> heat produced on demand (energy lost as heat from uncoupling of respiration chain)
59
Q

best substrate for oxidation

A

FFA

60
Q

action of sympathetic system (NA) on TH

A

activates D2 locally (in cell) -> increased levels of T3 -> can upregulate UCP1

61
Q

what does ucp1 do

A

uncouples the respiratory chain, allowing fast substrate oxidation with low ATP -> increases heat production

62
Q

symptoms of hyperthyroidism (2)

A
  1. weight loss in spite of increases appetite
  2. profuse sweating and heat intolerance (want to dissipate heat from upregulated ucp1)
63
Q

levels of (a) basal thermogenesis; (b) muscle mass; (c) fat mass before and after anti-thyroid medication

A

(a) before -> high basal thermogenesis; after -> normal
(b) before -> decreased muscle mass; after -> reestablish muscle mass
(c) before -> decreased fat; after -> gain

64
Q

TRH neurons in PVN receive input from (2) in ARC

A
  1. AgRP/NPY-synthesizing neurons
  2. aMSH/CART-synthesizing neurons
65
Q

effect of aMSH on TRH expression

A

increases TRH expression in PVN neurons expressing MCR-4

66
Q

levels of T4 when (a) fed; (b) fasted; (c) fasted + leptin

A

(a) high
(b) low
(c) mid

67
Q

action of leptin on HPT axis

A

leptin upregulates HPT axis (distant modulator)

68
Q

action of leptin on HPA axis

A

leptin acutely inhibits release of CRH, blunting stress-induced activation of HPA axis

69
Q

why does leptin upregulate HPT axis

A

goal of leptin is to burn fat; increased HPT means increased oxidation and FFA catabolism

70
Q

action of AgRP/NPY on TRH expression

A

decreases TRH expression

71
Q

action of DA on TRH

A

DA stimulates TRH (receptor level)

72
Q

action of DA on TSH

A

inhibits TSH (genomic level)

73
Q

action of SST on HPT axis

A

inhibits HPT axis

74
Q

positive modulators of TSH (4) and their effect for a given T4 level

A
  1. TRH
  2. increased leptin
  3. cold (NE to activate thermogenesis)
  4. CART (psychosis)
    * for a given T4, higher TSH
75
Q

negative modulators of TSH (6) and their effect for a given T4 level

A
  1. GCs
  2. reduced leptin
  3. DA
  4. SST
  5. cytokines (TNF-a)
  6. NFkB-induced D2 expression
    * for a given T4, lower TSH
76
Q

symptoms of hypothyroidism (2)

A
  1. sensitive to cold
  2. weight gain despite decreased appetite
77
Q

effects of hypothyroidism on TSH pulse frequency and regularity and what does it insinuate

A

mostly unchanged; suggests that TRH pulse generator is not affected by [TH]

78
Q

effects on (a) CR; (b) pulsatility; (c) basal levels of TSH in mild and severe hypothyroidism

A

(a) CR mostly preserved; almost lost in severe hypothyroidism
(b) pulsatility mostly preserved; decrease in amplitude in severe hypothyroidism
(c) decreased basal levels of TSH in both

79
Q

where metabolically unhealthy obesity and where metabolically healthy obesity

A

unhealthy -> android (area of waist)
healthy -> gynoid (area of hips/thighs)

80
Q

levels of TSH, T3 and T4 in (a) underweight; (b) obesity

A

(a) low levels of T3 and TSH
(b) high levels of T3 and TSH

81
Q

effects of administration of DA agonist on TSH secretion in obese subjects (3) and what does it insinuate

A
  1. decreases baseline levels of TSH
  2. slight loss of CR
  3. decreased amplitude of TSH secretion when should peak during night
    * suggests that reduced DA signaling might be involved in perturbation of TSH hormonal axis in obese premenopausal women (because DA is a negative regulator, so lack of central DA input would lead to increased TSH levels)
82
Q

what is cushing’s syndrome and what is a characteristic symptom

A

excess cortisol secretion; catabolic state with central fat redistribution

83
Q

effects of cushing’s syndrome on TSH secretion (3) and what does it insinuate

A
  1. low baseline levels of TSH
  2. almost loss of CR
  3. low amplitude of TSH secretion
    * diminished TSH secretory regularity in active disease suggests GC-induced dysregulation of TRH
84
Q

why would GCs be involved in dysregulation of TRH

A

PVN is site of CRH secretion and subject to negative cortisol feedback; PVN is site of TRH secretion

85
Q

what is acromegaly and what is a characteristic symptom

A

excess GH, but fused bones; anabolic state with fat depletion

86
Q

effects of acromegaly on TSH secretion (3)

A
  1. basal TSH secretion decreasd
  2. pulsatility/amplitude decreased
  3. CR mostly preserved
87
Q

why is TSH decreased in acromegaly

A

to compensate for the increase in GH, there is secretion of SST; SST is a negative modulator for TSH so levels decrease

88
Q

non-specific response of HPT axis to stress (3)

A
  1. reduced plasma T3
  2. increased/normal/reduced plasma T4
  3. normal or low TSH
89
Q

mechanisms of non-specific response of HPT axis to stress (4)

A
  1. preserved TH synthesis (not fault of the thyroid)
  2. heightened TH metabolism and/or excretion
  3. intracellular TH retention (maintain neutrality)
  4. down-resetting of hypothalamus
90
Q

mediators of non-specific response of HPT axis to stress (4) and why

A
  1. cytokines (pathology)
  2. GCs (fight or flee)
  3. reduced leptin (forced fasted state)
  4. other unknown factors (via SST, DA) that shift curve left
91
Q

what neurons regulate TRH neurons (2)

A

NPY/AgRP and POMC neurons in ARC

92
Q

characteristics of TH receptors (2)

A
  1. nuclear
  2. heterodimers with RXR
93
Q

molecular changes in hypothyroidism (2)

A
  1. changes in TH
  2. changes in deiodinases

anat 322 (7 decks)

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