1
Q
overview of HPT axis (5)
A
- TRH synthesized in parvo neurons of PVN and released in ant. pituitary
- TRH binds to receptors on thyrotrophs
- stimulation and release of TSH
- TSH stimulates thyroid gland to increase synthesis of T3 and T4
- T3 and T4 inhibit secretion of TRH and TSH by negative feedback
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
3
Q
how is TRH synthesized (2)
A
- synthesized as a large pre-pro-TRH protein in hypothalamus and several tissues
- only parvo neurons in PVN project to ME
4
Q
major driver of T4 synthesis
A
TRH
5
Q
negative regulator of TRH gene expression
A
T3
6
Q
T3 increases expression of…
A
TRH peptidase at the nerve ending
7
Q
effects of TRH on TSH-producing cells (3)
A
- stimulates secretion of preformed TSH
- stimulates synthesis of new TSH
- critical for normal glycosylation of TSH at post-translational level
8
Q
why does pituitary TSH have low biological activity
A
because it isn’t glycosylated
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)
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
11
Q
what is the active thyroid hormone and what is the prehormone
A
active -> T3
prehormone -> T4
12
Q
what kind of cell are thyrotrophs
A
basophilic
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
14
Q
glycoproteins (4)
A
- FSH
- LH
- CG
- TSH
15
Q
what structural aspect is common to all glycoproteins
A
alpha chain
16
Q
what determines receptor specificity (glycoproteins)
A
beta chain
17
Q
structurally, what inactivates TSH
A
separation of alpha and beta chains
18
Q
structure of TSH
A
glycoprotein with 2 chains (alpha and beta) with a CHO moiety (glycosylation) that is essential for biological activity
19
Q
peak of TSH
A
night
20
Q
temporal aspects of TSH secretion (2)
A
- circadian
- pulsatile
21
Q
relationship bw TH receptor occupancy and TSH
A
- the more TSH, the less TH receptor occupancy
- the less TSH, the more TH receptor occupancy (because more TH)
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
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
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
25
where does D2 convert T4 to T3
in the pituitary
26
relationship between TSH suppression and T3
linear relationship (more T3, more suppression)
27
what is needed to keep TSH levels normal
high level of receptor occupancy
28
what contributes to a large fraction of nuclear T3 in thyrotrophs
T4
29
anatomy of thyroid gland (4)
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
30
structural difference bw T3 and T4
T4 has an extra iodine atom
31
synthesis and storage of thyroglobulin
produced in thyrocytes and stored in follicles in thyroid gland
32
why don't all tyrosine residues participate in hormonogenesis
depends on their location; if they are too far apart, even with 3D modifications, are unable to react together and form dimers/oligomers
33
broad steps of TH synthesis (4)
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
34
rate limiting enzyme in thyroid gland
thyroperioxidase (TPO)
35
steps of iodination (2)
1. inorganic iodide anion is oxidized to diatomic (molecular) iodine
2. iodine covalently linked to tyrosyl residues
36
coupling of iodinated tyrosines to form TH
T3 -> DIT + MIT
T4 -> DIT + DIT
37
MIT and DIT: which is biologically active
DIT
38
mechanism/pathway of TH synthesis in thyrotroph (6)
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
TSH effects on thyroid gland (2)
1. release of preformed hormone
2. stimulation of all steps in TH synthesis
39
events that happen when TH is released (2)
1. thyroglobulin endocytosis
2. digestion and release of hormones
40
TH synthesis steps that TSH stimulates (4)
1. NIS level and activity
2. iodide oxidation and organification
3. coupling of iodotyrosines
4. thyroglobulin synthesis and processing
41
where is T3 mostly synthesized and why
most is made outside of the thyroid (peripherally); because most organs can convert T4 to T3
42
where is T4 synthesized
only in thyroid gland
43
what is the real thyroid hormone
T4
44
iodothyronine deodination reactions (3)
1. D2 converts T4 to T3
2. D3 converts T4 to reverse T3
3. D1 converts T4 to either T3 or reverse T3
45
what decides if D1 will convert T4 to T3 or reverse T3
depends on levels of circulating T4 (availability): if high T4, D1 converts to reverse T3, if low T4, D1 converts to T3
46
action of (a) D1; (b) D2; (c) D3
(a) converts T4 to either T3 or reverse T3
(b) converts T4 to T3
(c) converts T4 to reverse T3
47
levels of T3 and T4 at nuclear receptor level
T3 ~10x more abundant than T4 at nuclear receptor level
48
which TH is more potent and why
T3 ~10x more potent than T4 because has a higher affinity for the receptor
49
which TH responsible for most of activity of thyroid secretions
T3
50
levels of T3, T4 and TSH in hypothyroidism
T3 -> almost constant levels; not until severe hypothyroidism that levels decrease
T4 -> decreased
TSH -> increased only in severe hypothyroidism
51
which hormone is looked at to diagnose hypothyroidism
T4 (or TSH)
52
why does T3 stay elevated in hypothyroidism
decrease in T4 -> increase in TSH -> TSH increases levels of D2 in thyroid -> thyroid becomes main source of T3
53
source of T3 in hypothyroidism
mainly from the thyroid, no more synthesis in the periphery
54
levels of D3 mRNA in hippocampus (a) hypothyroidism (b) hyperthyroidism and why
(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
2-cell model of tissue modulation of TH levels - cerebral T3 autoregulation (5)
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
"therapies" for hypothyroidism (3)
1. increase D2
2. decrease D3
3. upregulate transporters
57
biological roles of thyroid hormones (4)
1. growth and development
2. specific functions
3. energy balance/maintenance of weight
4. thermogenesis (homeothermic species)
58
types of thermogenesis (2)
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
best substrate for oxidation
FFA
60
action of sympathetic system (NA) on TH
activates D2 locally (in cell) -> increased levels of T3 -> can upregulate UCP1
61
what does ucp1 do
uncouples the respiratory chain, allowing fast substrate oxidation with low ATP -> increases heat production
62
symptoms of hyperthyroidism (2)
1. weight loss in spite of increases appetite
2. profuse sweating and heat intolerance (want to dissipate heat from upregulated ucp1)
63
levels of (a) basal thermogenesis; (b) muscle mass; (c) fat mass before and after anti-thyroid medication
(a) before -> high basal thermogenesis; after -> normal
(b) before -> decreased muscle mass; after -> reestablish muscle mass
(c) before -> decreased fat; after -> gain
64
TRH neurons in PVN receive input from (2) in ARC
1. AgRP/NPY-synthesizing neurons
2. aMSH/CART-synthesizing neurons
65
effect of aMSH on TRH expression
increases TRH expression in PVN neurons expressing MCR-4
66
levels of T4 when (a) fed; (b) fasted; (c) fasted + leptin
(a) high
(b) low
(c) mid
67
action of leptin on HPT axis
leptin upregulates HPT axis (distant modulator)
68
action of leptin on HPA axis
leptin acutely inhibits release of CRH, blunting stress-induced activation of HPA axis
69
why does leptin upregulate HPT axis
goal of leptin is to burn fat; increased HPT means increased oxidation and FFA catabolism
70
action of AgRP/NPY on TRH expression
decreases TRH expression
71
action of DA on TRH
DA stimulates TRH (receptor level)
72
action of DA on TSH
inhibits TSH (genomic level)
73
action of SST on HPT axis
inhibits HPT axis
74
positive modulators of TSH (4) and their effect for a given T4 level
1. TRH
2. increased leptin
3. cold (NE to activate thermogenesis)
4. CART (psychosis)
* for a given T4, higher TSH
75
negative modulators of TSH (6) and their effect for a given T4 level
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
symptoms of hypothyroidism (2)
1. sensitive to cold
2. weight gain despite decreased appetite
77
effects of hypothyroidism on TSH pulse frequency and regularity and what does it insinuate
mostly unchanged; suggests that TRH pulse generator is not affected by [TH]
78
effects on (a) CR; (b) pulsatility; (c) basal levels of TSH in mild and severe hypothyroidism
(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
where metabolically unhealthy obesity and where metabolically healthy obesity
unhealthy -> android (area of waist)
healthy -> gynoid (area of hips/thighs)
80
levels of TSH, T3 and T4 in (a) underweight; (b) obesity
(a) low levels of T3 and TSH
(b) high levels of T3 and TSH
81
effects of administration of DA agonist on TSH secretion in obese subjects (3) and what does it insinuate
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
what is cushing's syndrome and what is a characteristic symptom
excess cortisol secretion; catabolic state with central fat redistribution
83
effects of cushing's syndrome on TSH secretion (3) and what does it insinuate
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
why would GCs be involved in dysregulation of TRH
PVN is site of CRH secretion and subject to negative cortisol feedback; PVN is site of TRH secretion
85
what is acromegaly and what is a characteristic symptom
excess GH, but fused bones; anabolic state with fat depletion
86
effects of acromegaly on TSH secretion (3)
1. basal TSH secretion decreasd
2. pulsatility/amplitude decreased
3. CR mostly preserved
87
why is TSH decreased in acromegaly
to compensate for the increase in GH, there is secretion of SST; SST is a negative modulator for TSH so levels decrease
88
non-specific response of HPT axis to stress (3)
1. reduced plasma T3
2. increased/normal/reduced plasma T4
3. normal or low TSH
89
mechanisms of non-specific response of HPT axis to stress (4)
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
mediators of non-specific response of HPT axis to stress (4) and why
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
what neurons regulate TRH neurons (2)
NPY/AgRP and POMC neurons in ARC
92
characteristics of TH receptors (2)
1. nuclear
2. heterodimers with RXR
93
molecular changes in hypothyroidism (2)
1. changes in TH
2. changes in deiodinases
