mechanism hormone disease (lec 3).ppt
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Mechanisms of endocrine disease
Endocrine disorders result from hormonedeficiency, hormone excess or hormone
resistance
Almost without exception, hormonedeficiency causes disease
One notable exception is calcitonin
deficiency
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Cellular Mechanisms of Hormone Action
Target cellrecognize, bind and
initiate
Up regulation
Down regulation
Hormone effects
Direct stimulation Permissive facilitates maximum
response/function
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Deficiencyusually is due to destructiveprocess occurring at gland in which hormone
is producedinfection, infarction, physical
compression by tumor growth, autoimmune
attack
Mechanisms of endocrine disease
Type I Diabetes
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Deficiency can also arise from geneticdefects in hormone productiongene
deletion or mutation, failure to cleave
precursor, specific enzymatic defect (steroid
or thyroid hormones)
Mechanisms of endocrine disease
Congenital Adrenal Hyperplasia
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Inactivating mutations of receptors cancause hormone deficiency
Mechanisms of endocrine disease
Testicular Feminization Syndrome
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Hormone excess usually results in disease Hormone may be overproduced by gland
that normally secretes it, or by a tissue that
is not an endocrine organ. Endocrine gland tumors produce hormone in
an unregulated manner.
Mechanisms of endocrine disease
Cushings Syndrome
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Exogenous ingestionof hormone is thecause of hormoneexcessfor example,glucocorticoid excessor anabolic steroidabuse
Mechanisms of endocrine disease
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Activating mutations of cell surface receptorscause aberrant stimulation of hormoneproduction by endocrine gland.
McCune-Albright syndrome usually
caused by a mutation in a gene calledGNAS1 (Guanine Nucleotide bindingprotein, Alpha Stimulating activitypolypeptide 1).
Mechanisms of endocrine disease
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Malignant transformation of non-endocrine tissue causesdedifferentiation and ectopic productionof hormones
Anti-receptor antibodies stimulatereceptor instead of block it, as in thecase of the common form of
hyperthyrodism.
Mechanisms of endocrine disease
Graves Disease
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Alterations in receptor number and functionresult in endocrine disorders
Most commonly, an aberrant increase in the
level of a specific hormone will cause adecrease in available receptors
Mechanisms of endocrine disease
Type II diabetes
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Adrenal Gland
Adrenal glands are located on the top of both kidneys.
Each gland consists of a medulla, the center of the
gland, encased by a cortex.
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Adrenal Glands Adrenal cortex
80%of an adrenal glands total weight
Zona glomerulosaaldosterone 15%
Zona fasciculataglucocorticoids 78%
Zona reticularisandrogens and estrogens(others)
7%
Adrenal medulla
Innervation by SNS
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Adrenal Glands
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-Inner part medulla:
-Chromaffin cells-Source of catecholamines (Epi/NEpi),
-Innervated by pre-ganglionic sympathetic fibers; forms an
extension of the sympathetic nervous system (fight/flight).
-Outer part cortex:
-Source of steroid hormones
-Glucocorticoids, mineralocorticoids and sex steroids
Anatomy/Physiology of Adrenal Gland
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DHBR
NADP+NADPH
from phe, diet, or protein
breakdown
Tyrosine L-Dopa
H2OO2
Tyrosine hydroxylase(rate-determining step)
BH2BH4
1
Dopa
decarboxylase
CO2
Dopamine
pyridoxalphosphate
2
Dopamine hydroxylase
ascorbateH2O
Norepinephrine
O23
NMT
SAM SAH
Epinephrine
4
Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin;
DHBR, dihydrobiopterin reductase; NMT, N-CH3 transferase; SAH, S-
adenosyl-homocysteine; SAM, S-adenosylmethionine
Parkinsons disease: local
deficiency of dopamine
synthesis; L-dopa boostsproductionNMT specific to
adrenal medulla
SAM from
metabolism of
Met
DPN OHase in neuro-
scretory granules
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.....
...
acetylcholine
Adrenal Medulla
Chromaffin Cell
Neuron
Acute
regulation
Tyrosine
L-DopaDPN
DPN
NE
granuleinduction
Chronic
regulation
Stress
Hypothalamus
ACTH
Cortisolfrom adrenal
cortex via intra-
adrenal portal
system
EpinephrinePNMT
NE
neuro-
secretory
granules
E E E
NE E
Regulation of the release of
catecholamines and synthesis of
epinephrine in the adrenal medulla
chromaffin cell.
promotesexocytosis
................
EEE
ENEE
E E
NE
E
Ca2+
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Norepinephrine
Epinephrine COMT + MAO
Vanillylmandelic acid
Figure 3. Degradation of epinephrine, norepinephrine and dopamine via monoamine
oxidase (MAO) and catechol-O-methyl-transferase (COMT)
Neuronal re-uptake and degradation of catecholamines quickly
terminates hormonal or neurotransmitter activity.
Cocaine binds to dopamine receptor to block re-uptake of dopamine
Dopamine continues to stimulate receptors of the postsynaptic nerve.
Dopamine Homovanillic acid
COMT + MAO
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Classification of Adrenergic Hormone Receptors
Receptor Agonists SecondMessenger
G protein
alpha1 (1) E>NE IP3/Ca2+; DAG Gq
alpha2 (2) NE>E cyclic AMP Gi
beta1 (1) E=NE cyclic AMP Gsbeta2 (2) E>>NE cyclic AMP Gs
E = epinephrine; NE = norepinephrine
Synthetic agonists:
isoproterenol binds to beta receptorsphenylephrine binds to alpha receptors (nose spray action)
Synthetic antagonists:
propranolol binds to beta receptors
phentolamine binds to alpha receptors
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Metabolic and muscle contraction responses to catecholamine binding tovarious adrenergic receptors.
Process 1-receptor(IP3, DAG)
2-receptor
( cAMP)1-receptor
( cAMP)2-receptor( cAMP)
Carbohydrat
e
metabolism
liver
glycogenolysis
No effect No effect
liver/muscle
glycogenolysis;
liver gluconeogenesis; glycogenesis
Fat
metabolismNo effect lipolysis lipolysis No effect
Hormone
secretionNo effect
insulin,renine
secretion
No effect insulin, glucagon and
renin secretion
Muscle
contraction
Smooth
muscle - blood
vessels,
genitourinary
tractcontraction
Smooth
muscle -
some
vascular;
GI tractrelaxation
Myocardial
- rate,force
Smooth muscle
relaxation - bronchi,
blood vessels,
GI tract, genitourinary
tract
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1 or2receptor
ATPcyclic AMP
Gs
s
GTP
inactive
adenylylcyclase
GTP
ACTIVE
adenylyl
cyclase
inactive
adenylylcyclase
2 receptor
Mechanisms of1, 2, and 2 agonist effects on adenylyl cyclase activity
Gi
i
GTPs
GTP
i
X
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" FIGHT OR FLIGHT" RESPONSE
epinephrine/ norepinephrine major elements in the "fight or flight" response
acute, integrated adjustment of many complex processes in organs vital to the
response (e.g., brain, muscles, cardiopulmonary system, liver)
occurs at the expense of other organs less immediately involved (e.g., skin, GI).
epinephrine:rapidly mobilizes fatty acids as the primary fuel for muscle action
increases muscle glycogenolysis
mobilizes glucose for the brain by hepatic glycogenolysis/gluconeogenesis
preserves glucose for CNS by insulin release leading to reduced glucoseuptake by muscle/ adipose
increases cardiac output
norepinephrine elicits responses of the CV system - blood flow and insulinsecretion.
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ADRENAL CORTEX-DERIVED STEROIDS
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Adrenal Cortex
all hormones derived from cholesterol Stimulated by adrenocorticotropic hormone (ACTH)
Glucocorticoid hormones
Direct effect on carbohydrate metabolism
Anti-inflammatory and growth suppression effects Influences awareness and sleep habits
Inhibits bone matrix-protein matrix
Cortisol most potent naturally occurring
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Adrenal Cortex
Mineralocorticoid hormones
Aldosterone Na+ uptake in epithelial cells
distal nephrons
Na retention with loss of K+ and H+
Regulation by the renin-angiotensin
system
Na+ and H2O depletion K+ excreteion
blood volume
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Adrenal Cortex-derived Stero ids
Class Major Effects
Glucocorticoids Cortisol Glucose metabolism
control
Mineralocorticoids Aldosterone Na/K/H20 control
Sex steroids DHEA Androgen precursors
Androstendione
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SECRETION OF INDIVIDUAL
STEROID HORMONES IS
RESTRICTED TO SPECIFIC
REGIONS OF THE ADRENAL
CORTEX
CAPSULE
MEDULLARETICULARIS
MEDULLA
SYNTHESIS OF ADRENAL CORTEX HORMONES
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SYNTHESIS OF ADRENAL CORTEX HORMONES
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Hypothalamus
Anterior pituitary
Adrenal cortex
Corticotropin-releasingfactor (CRF)
Adrenocorticotropic hormone
(ACTH)
Glucocorticoids
(especially cortisol)
Hypoxia
Hypoglycemia
Hyperthermia
Exercise
Cortisol
insufficiency
Stress
Diurnal
rhythms
( - )
Somatostatin
Hypothalamic
lesions
( - )
(+)
(+)(+)
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minusside
chain
ALL STEROIDOGENIC TISSUES
CHOLESTEROL(C27)
+ 3-keto
+ 11-OH
PROGESTERONE
+3-keto
+ 21-OH
+ 3-keto
+ 11-OH
+ 21-OH
+ 17-OH
CORTISOL (C21)
CORTICOSTERONE
ALDOSTERONE(C21)
+ 20-keto
+ 17-OH
PREGNENOLONE(C21)
ANDROSTENEDIONE(C19)
+ 18-ALDEHYDE
TESTOSTERONE
ESTRADIOL (C19)
GONADS
ADRENAL CORTEX
ESTRONE
STEROID SYNTHESIS
DEHYDROEPIANDROSTERONE
DHEA
17-OH PROGESTERONE
DEHYDROEPIANDROSTERONESULFATE (C19 :DHEA-S)
+ 3-keto
aromatase
17-OH PREGNENOLONE
DIHYDROTESTOSTERONE (C19)
sulfotransferasedesmolase
desmolase
aromatase
Adrenals
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ENDOPLASMIC RETICULUM
OXIDATION OF STEROID NUCLEUS
BY SPECIFIC P-450 HYDROXYLASES
ALDOSTERONE
ANDROGENPRECURSORS
SYNTHESIS AND SECRETION OF STEROID HORMONES BY ADRENAL CORTEX
GONADS
Cholesterol in
Intracellular
Lipid droplets
2
1
3
KIDNEY
DIFFUSION OF STEROIDS
OUT OF CELLCORTISOL
CHOLESTEROL IS TAKEN UP INTO MITOCHONDRIA
EITHER DIRECTLY FROM PLASMA LDL/HDL OR FROM
INTRACELLULAR CHOLESTEROL ESTERS STORED
IN LIPID DROPLETS
UPTAKE OF CHOLESTEROL
ESTER FROM LDL AND HDL
IN PLASMA
StAR facilitates transfer of
cholesterol molecules between
inner and outer membranes
4
17-OH PROGESTERONEREMOVAL OFSIDE CHAIN
P450c11
11-HYDROXYLASE
h b l ff f l d
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The metabolic effects of glucocorticoids
They increase glucose production by:
1. Increasing the supply of amino acids to the liver2. Activating the expression of genes of gluconeogenic enzyme
Promote lipolysis in peripheral tissues by inducing enzyme synthesis
(Increase mobilization of peripheral fat)
When at very high levels can cause lipogenesis in face and trunk
When at a very high levels has catabolic effect on proteins in peripheral
tissues and anabolic effect in the liver
h b l ff f l d
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The metabolic effects of glucocorticoids
When at very high levels can cause lipogenesis in face and trunk
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Cortisol (hydrocortisone) and synthetic glucocorticoids(prednisone): Potent anti-inflammatory and
immunosuppressive agent [topical, oral, aerosolized, injection]
Therapeutic Effects of Glucocorticoids
-used to relieve symptoms of inflammation [swelling, heat,
redness, and pain];
-used in cases of insufficient synthesis (hormone replacement);
-used to treat certain forms of arthritis; skin, blood, kidney, eye,thyroid, and intestinal disorders (e.g., colitis); severe allergies; and
respiratory conditions such as asthma.
-used in the treatment of certain types of cancer.
How glucocorticoids suppress immune and inflammatory reactions
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A glucocorticoid interaction with its receptor results in increasing the transcription
of the protein IB, which binds and inhibits the activity of NF-B, a a transcriptionalactivator that stimulates transcription of genes for inflammatory cytokines. NF-B
is normally sequestered in an inactive state through association with IB proteins.(TNF is a proinflammatory cytokine.)
Glucocorticoid induction of
IB synthesis through GCbinding to its intracellular
receptor and stimulating trans-
cription of the gene.
IB binds toand inhibits the
nuclear translo-
cation of NF-B.
NF-B stimulates theultimate production of
inflammatory cytokinesTumor necrosis factor (TNF)binding to its receptor leads to
the ultimate degradation of IB
How glucocorticoids suppress immune and inflammatory reactions
mediated by cytokines
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Cortisol (the naturally-occurring glucocorticoid)
levels are regulated by a hypothalamus-
pituitary-adrenal hormone axis.
Corticotropin releasing hormone
(CRH) controls adrenocortioctropic hormone(ACTH) release from the pituitary.
ACTH is a trophic hormone that
stimulates:
-synthesis and secretion of cortisol and
-growth of the adrenal gland.
When cortisol levels increase, CRH and ACTH
secretion/release are reduced.
Adrenal Gland Steroids
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Mineralocort ic oids (e.g. aldosterone)-enhance renal tubular retention of Na+, HCO3- and water
and increase excretion of K+: this increases serum Na and
decreases serum K
-increased blood volume and pressure
Mineralocorticoids
Removal of the adrenal glands leads to death within just a few days due to:
-the concentration of potassium in extracelluar fluid becomes dramatically
elevated;
-urinary excretion of sodium is high and concentrations of sodium inextracellular fluid decreases significantly;
-volume of extracellular fluid and blood plummet;
-the heart begins to function poorly, cardiac output declines and shock ensues
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Control over aldosterone secretion is multifactorial:
-The two most significant regulators of aldosterone secretion are:
Concentrations of K+ in extracellular fluid: Small increases in blood
levels of potassium strongly stimulate aldosterone secretion.
Angiotensin II: Activation of the renin-angiotensin system as a result of
decreased renal blood flow (usually due to decreased vascular volume)
results in release of angiotensin II, which stimulates aldosterone secretion
Control of Aldosterone Secretion
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Adrenal Insufficiency (Addisons disease, 1:100,000)
Primary Adrenal Insufficiency:
-most common cause is autoimmune-mediated destruction of the adrenal
glands (>80%)
-secondary to tuberculosis, chronic fungal infections, infection by
cytomegalovirus (CMV), metastasis to the glands by cancer cells (~20%)
Secondary Adrenal Insufficiency:
-Addisons Disease caused by inadequate secretion of ACTH by the
pituitary gland;-may arise due to the prolonged or improper use of glucocorticoid
hormones( temporary);
Disorders of the Adrenal Gland
Di d f h Ad l Gl d
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Cushings Syndrome
-Cushing's Syndrome is EITHER a disease caused by anexcess of cortisol production, or a disorder resulting fromexcessive use of glucocorticoids
Disease-related excess production of cortisol (2 types):
1) Excess ACTH Production:
Ex. A pituitary tumorproducing too much ACTH
stimulates adrenal growth and increases cortisol(>70%); Also "ectopic" ACTH production (30%)
2) Adrenal cortex tumours: Tumours can be benign
(an adenoma), or malignant (a carcinoma). Usually
found on only one side.
Disorders of the Adrenal Gland
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Stress = any condition that threatens homeostasis
GAS (General Adaptation Syndrome) is our bodiesresponse to stress-causing factors
Three phases to GAS
Alarm phase (immediate, fight or flight, directed
by the sympathetic nervous system and
dominated by the catecholamines)
Resistance phase (dominated by
glucocorticoids) Exhaustion phase (breakdown of homeostatic
regulation and failure of one or more organ
systems)
Hormones and stress
The General Adaptation Syndrome
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The General Adaptation Syndrome
The General Adaptation Syndrome
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The General Adaptation Syndrome
Figure 18.21
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The General Adaptation Syndrome
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Retinoid Hormones
Isoprenoid hydrophobichormones.
The pro-hormone, retinol, ismade in the liver.
Retinol is converted to the
hormone, retinoic acid, bymany tissues.
Retinoic acid regulates cellgrowth and development inmost cells, but the principaltargets are the cornea, skin
and epithelia.
Excess Vitamin A can causebirth defects and liverdamage.
Severe acne is treated with
retinoid creams.
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THYROID HORMONES
G
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The Thyroid Gland
Figure 18.11b, c
Thyroglobulin is a protein rich in Tyr (100Tyr/1molecule)
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Synthesis of T3 and T4
The thyro id gland:Synthesizes and secretes triiodothyronine-T3 andthyroxine-T4
-the only body tissue that can accumulate iodide
Steps of thyroid hormone synthesis
-accumulat ion of iod idevia a specific iodide pump.
-iod inati t ion of tyros ineproduces monoiodotyrosine (MIT) and
diiodotyrosine (DIT)
- cou pl ing react ion:Synthesis of MIT/DIT:
-MIT +DIT produces T3 (3 iodine)-DIT+DIT, T4 (4 iodine).
-MIT/DIT are complexed with thyroglobulin.
-Thyroglobin pro teolys isliberates T3 and T4
- Released hormones are secreted: 5(T4) to
1(T3).
SYNTHESIS OF THYROID HORMONES STEP 1 IODINATION
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TYROSINE
IODINATION
TYROSINE
MONOIODOTYROSINE(MIT)
DIIODOTYROSINE (DIT)
I
I
NH2
TYROSINE
IODINATION
I
I
SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION
Approximately 10% of the tyrosine residues on the
550 amino acid residue Thyroglobulin molecule may
become iodinated by the enzyme - thyroid
peroxidase acting on the colloid at the luminal
surface of the thyroid follicle. These reactions only
occur in the thyroid at specific residues in
Hormonogenic sites located at the extreme ends of
the Thyroglobulin molecule.
Tyr
Tyr
THYROGLOBULIN
THYROGLOBULIN
THYROGLOBULIN-
SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES
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Thyroglobulin
CH2CHCOOH
Thyroglobulin
I
I
Tyr
3,5,35-tetraiodothyronine
SYNTHESIS OF THYROID HORMONES: STEP 2 COUPLING OF IODOTYROSINES
CH2CHCOOH
NH2+HO
II
I
Tyr
NH2
T4
Thyroglobulin
I
I
Tyr CH2CHCOOH
NH2
CH2CHCOOH
I
Tyr
NH2
Thyroglobulin
Tyr
II
I
Tyr O+
IT3
3,5,3-Triiodothyronine
Coupling of iodotyrosine moities results in the loss
of the peptide linkage to thyroglobulin allowing thyroid
hormones to diffuse across the cell membrane
II
Tyr
II
I
Tyr O
I
33
55
HO
HO
HO
HO
HO
3,5,35-tetraiodothyronine
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CH2CHCOOH
NH2
CH2CHCOOH
3,3,5-Triiodothyronine (reverse T3)
NH2
Tyr
II I
Tyr O
rT3
I
3,5,3-Triiodothyronine (T3)
II
Tyr
II
I
Tyr O
T4I
T3
Tyr
II I
Tyr O
I
5- deiodination5-deiodination
CH2CHCOOH
ACTIVATION PATHWAY
In peripheral tissuesDEACTIVATION PATHWAY
NH2
STEP 3DEIODINATION
SELENODEIODINASES
SECRETION OF THYROID HORMONE
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TG
IODINATIONOF THYROGLOBULIN
BY THYROID PEROXIDASE
DIFFUSION OF THYROXINE
THROUGH CELL MEMBRANE
DEGRADATION OF
THYROGLOBULIN
FUSION OF PHAGOSOME
WITH LYSOSOMES
ENDOCYTOSIS OF
COLLOID IN FOLLICLE BY
PSEUDOPOD
TG
TG
TG
T4
T4 T3>> >
I
IODIDE UPTAKE
BY Na/I
SYMPORTER
IODIDE IN
ECF~20nM
DEGRADATION
AND
RECYCLING
OF MIT/DIT
BY DEIODINASES FREE THYROXINE RELEASED FROM
PROTEIN INTO CYTOPLASM
TG
2
1
3
4
5
6
7
8
Additional metabolism??
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THYROID HORMONES
HORMONE
RELATIVE
POTENCYPRODUCTION
t(g/day)
4-8 (24)*
BOUND TO
PLASMAPROTEINS
(%)
-
99.95
(days)
80- 90 8
0.04 99.8 0.1
+ + + +
rT3
VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION
2-3 (27) *
1-3
6-7+T4
T3
*
(g/dL)
PLASMA
CONCENTRATION
0.3 99.7
R l d T3/T4 R l
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Regulated T3/T4 Release
T3/T4 synthesis/release is tightly regulated:
-reduced T3/T4 stimulates TRH release from the
hypothalamus (HPT) which then causes TSH
release from the pituitary (PIT).
TSH stimulates:1) T3/T4 synthesis and secretion
2) thyroid gland growth.
When T3/T4 levels increase, negative feedback
shuts off TRH and TSH secretion.
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Physiological Actions of T3/T4
Play a Central Role in Regulating :
-growth/development of most cells,
-basal metabolic rate and temperature (stimulate cellularrespiration)
-cardiac output by increasing rate/force of contraction,
-metabolism of cholesterol to bile acids,
-LDL receptor expression in hepatocytes,
-TSH secretion
THYROID HORMONES ARE ESSENTIAL TO LIFE!
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Symptoms include:fatigue/weakness, weight gain/difficultylosing weight, coarse/dry hair, dry/rough pale skin, cold intolerance,
muscle cramps/muscle aches, constipation, depression, irritability,
memory loss, abnormal menstrual cycles, decreased libido
-Myxedema coma:A medical emergency characterized byhypothermia, hypotension, hypoventilation and bradycardia
represents the extreme expression of severe hypothyroidism
Hypothyroidism (Myxedema)
Reduced circulating T3/T4 levels
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Problems with the Thyroid Gland
Hyperthyroidism:
high metabolic rate, hyperactivity, sensitivity to heat, protruding eyes Graves disease: when hyperthyroidism is due to an autoimmune problem
(TSH is mimicked by autoantibodies)
Hypothyroidism:
in the adult: myxedema- low metabolic rate, sensitivity to cold,sluggishness, weight gain/difficulty losing weight, coarse/dry hair, dry/roughpale skin, constipation, depression, irritability, memory loss, abnormalmenstrual cycles, decreased libido
in an infant: cretinism-- stunted growth, mental retardation, abnormal boneformation
Hashimotos disease: when hypothyroidism is due to an autoimmuneproblem (autoantibodies attack and destroy follicular cells)
goiterno T3 and T4 can be made because not enough iodides wereingested.
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Pr imary Hypothy ro id ism (Myxedema)
-When synthesis of T3/T4 is low, no feedbackinhibition of TSH occurs and TSH levels rise.
-TSH stimulation of the thyroid gland is
increased and lead to:
-the lack of T3/T4 synthesisin primary hypothyroidism leads to
TSH-mediated increases in size (goiter).
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When the pituitary can't make TSH
there is no signal to the thyroid gland
to make T3/T4. Thus secondary
hypothyroidism is (i.e. pituitary-
mediated) associated with decreasedT3/T4 AND TSH and thyroid atrophy.
Secondary Hypothyro id ism
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Primary hyperthyroidism: Thyroidsecretes T3/T4 in a TSH unregulated
fashion
Symptoms:
-heart palpitations, heat intolerance,
nervousness, insomnia, breathlessness,
increased bowel movements, light/absent
menstrual periods and fatigue
Primary Hyperthyroidism
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Loss of T3/T4-mediated negative
effects on TSH release by pituitary
-the thyroid is chronically stimulatedto synthesize and secrete T3/T4
and to grow. Thus ,goiter is also a
symptom of secondary
hyperthyroidism
Secondary Hyperthyroidism
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Relief of direct symptoms: Drugs that inhibit thyroid hormone
production/release (methimazole, propylthiouracil (PTU):
-Inhibit hrmone synthesis (iodine organification)
-Inhibit MIT coupling
Limitations: The symptoms associated with hyperthyroidism return
when the drugs are discontinued.
Hyperthyroidism-Treatments
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Radioactive Iodine:[135I]-most widely recommended permanent treatment of
hyperthyroidism
-treatment takes advantage of the fact that only thyroid cellscan incorporate iodine
-[135I] emits gamma () radiation: Directly kills thyroid cells
-There is no evidence that [135I] treatment for hyperthyroidism
causes cancer of the thyroid gland or of any other tissue
Hyperthyroidism-Treatments
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BUT IS CALCITONIN AN IMPORTANT PHYSIOLOGICAL SUBSTANCE?
The observation that calcitonin (CT) at supraphysiological doses is hypocalcemic, led to the mistaken
conclusion that it was important for calcium homeostasis and this idea has persisted to this day.
Despite these findings there is no apparent pathology due to CT excess or deficiency and there is no
evidence that circulating CT is of substantial benefit to any mammal.
Mammalian CT at physiological doses is not essential and very likely the CT gene has survived
because of the genes alternate mRNA pathway to produce calcitonin-gene-related peptide CGRP
found in neural tissues.
HIRSCH,PF and BARUCH H, ENDOCRINE 2003, 201-208
CALCITONIN IS SECRETED FROM THE THYROID PARAFOLLICULAR CELLS
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THE PARATHYROID HORMONE
Parathyroid Gland
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Parathyroid Gland
This gland only secretes
one hormone:
Parathyroid Hormone(or PTH)
PTH function (we began
learning this when we
studied bone):
increases bloodcalcium (Ca2+) levels
and decreases
blood phosphate
(PO42-) levels
PTH function (cont inued)
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PTH function (cont inued)
How does PTH work?
PTH causes Ca2+ & PO42- to be released from
bone into blood (by increasing osteoclast
activity)
PTH decreases the excretion of PO42- ionsthrough urine
PTH increases calcitriol production, so that more
Ca2+ is absorbed during digestion
PTH is regulated by blood calcium levels-- not by
other glands!
The Regulation of Calcium Ion Concentrations
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70Figure 18.15
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THE PANCREATIC HORMONES
The pancreatic islets
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Clusters of endocrine cells within the
pancreas called Islets of Langerhans or
pancreatic islets Alpha cells secrete glucagons
Beta cells secrete insulin
Delta cells secrete GH-IH F cells secrete pancreatic polypeptide
The pancreatic islets
The Endocrine Pancreas
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The Endocrine Pancreas
Figure 18.18a, b
BLOOD FLOWS RADIALLY FROM CENTER OF ISLET
ISLETS OF LANGERHANS
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BLOOD FLOWS RADIALLY FROM CENTER OF ISLETTO THE PERIPHERY FACILITATING PARACRINE
INHIBITION OF GLUCAGON SECRETION BY INSULIN
VENOUS BLOOD
MANTLE FORMED BY CELLSSECRETING GLUCAGON (20-25%)
CORE FORMED BY BETA CELLS
SECRETING INSULIN(60-70 % OF TOTAL)
1 MILLION ISLETS EACH
CONTAINING 2500 CELLS
ARTERIAL BLOOD
VENOUS BLOOD
CELL CELLSECRETORY
GRANULES
Canaliculus
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Endocrine Pancreas
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Endocrine Pancreas
Insulin
Synthesized from proinsulin
Secretion is promoted by blood
glucose
Facilitates the rate of glucose uptake
into the cells
Anabol ic hormone
Synthesis of proteins, lipids
and nucleic acids
E d i P
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Endocrine Pancreas
Glucagon
Secretion is promoted by decreased
blood glucose levels
Stimulates glycogenolysis,gluconeogenesis and lipolysis
Somatostatin (delta cells)
Regulation alpha and beta cellsecretions
PHYSIOLOGICAL ROLE OF INSULIN
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MAINTENANCE OF NORMAL PLASMA GLUCOSE LEVELS IN
SPITE OF LARGE CHANGES DUE TO FOOD INTAKE
PRESERVATION OF ENERGY STORES
STIMULATION OF GLUCOSE TRANSPORT
STIMULATION OF GLUCOSE UTILIZATION
RAPID UPTAKE OF DIETARY GLUCOSE
UTILIZATION OF DIETARY GLUCOSE
STIMULATION OF GLUCOSE OXIDATION
STIMULATION OF LIPID SYNTHESIS
STIMULATION OF GLYCOGEN SYNTHESIS
INHIBITION OF GLYCOGEN DEGRADATION
INHIBITION OF GLUCONEOGENESIS
INHIBITION OF LIPOLYSIS
INHIBITION OF PROTEOLYSIS
Endocrine Pancreas
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Endocrine Pancreas
Figure 18.19 The Regulation of Blood Glucose
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Figure 18.19 The Regulation of Blood Glucose
Concentrations
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THE PINEAL GLAND
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Pineal Gland
Secretes only one hormone: melatonin
- involved in your circadian rhythm (your recognition of day and
night times):
melatonin secretion decreases in the day
melatonin secretion increases at night
Melatonin is also involved in longer rhythms, like monthly and
seasonal
- inhibits reproductive function
- protects against damage by free radicals
- has anti-ageing, anti-cancer effects
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The Endocrine Functions of Other
Organs
The intestines
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Produce hormones important to the
coordination of digestive activities
The kidneys
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Produce calcitriol and erythropoietin (EPO) and theenzyme rennin
Calcitriol = stimulates calcium and phosphate ion
absorption along the digestive tract
EPO stimulates red blood cell production by bonemarrow
Renin converts angiotensinogen to angiotensin I
y
Angiotensin I converted to angiotensin II in
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Stimulates adrenal production of aldosterone
Stimulates pituitary gland release of ADH
Promotes thirst Elevates blood pressure
the lungs
Endocrine Functions of the Kidneys
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Endocrine Functions of the Kidneys
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LUNGS
The heart
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Specialized muscle cells produce natriuretic
peptides when blood pressure becomes excessive
Generally oppose actions of angiotensin II
The thymus
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Produces thymosins
help develop and maintain normal
immune defenses are involved in white blood cell production
y
Adipose tissues secrete
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Leptin, a feedback control for appetite
Resistin, which reduces insulin sensitivity
p
The gonads
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g
Interstitial cells of the testes
produce testosterone Most important sex hormone
in males
In females, oocytes develop in
follicles Follicle cells produce
estrogens
After ovulation, the follicle cells
form a corpus luteum thatreleases a mixture of estrogens
and progesterone
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I fought the law, but the law won..