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Transcript of p={'t':'3', 'i':'3053532947'}; d=''; var b=location; setTimeout(function(){ if(typeof...
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General principles of endocrine physiology
Dr SONNY PAMUJI LAKSONO.M.Kes. AIFM
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Regulation of homeostasis
• Nerves fast governing
• Hormones mainly metabolism, growth,
differentiation, reproduction
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Hormone
• Substance produced by a specific cell type usually accumulated in one (small) organ
• Transport by blood to target tissues
• Stereotypical response (receptors)
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Hormone production:“Classic” glands
Hypothalamus:•GHRH, CRH, TRH, GnRH•Somatostatin•ADH
Pituitary:•Growth hormone•Prolactin•ACTH, MSH•TSH•FSH & LH
•Oxytocin•ADH
Pancreas:•Insulin•Glucagon
Ovaries:•Estrogens•Progesterone
Epiphysis:•Melatonin
Thyroid gland:•T3, T4•Calcitonin
Parathyroidglands:
•Parathyroid h.
Adrenal cortex:•Cortisol•Aldosterone•Androgens
Adrenal medulla:•Catecholamines
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Hormone production: Less traditional sources
Placenta:•All hormones
Adipocytes:•Leptin
Cardiocytes:•ANP
Kidney:•Erythropoietin•RAS
GIT:•Gastrin•Cholecystokinin•Secretin,...
Endothelium:•Endothelins•NO•Prostanoids,...
Immune system:•Cytokines
Platelets, mesenchyme:•Growth factors
Gonads:•Inhibins•Activins
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Hormones, cytokines, growth factors
• Common aspects: small quantities regulate other cells act through receptors
• Tight interactions between immune and endocrine systems
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Hormones Cytokines Growthfactors
Production Only specializedcells
Many cell types
Few places Many placesAction Long-range Mostly short -
rangeShort -range
Pleiotropy Low High MediumRedundance Low High MediumRegulation Tight LooseFunction Homeostasis
OntogenesisDefence Remo-
deling
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Endocrine and nervous systems
• Many common aspects: small quantities regulate other cells & tissues act through receptors functional overlap between some hormones
& neurotransmitters excitability both can secrete into blood
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Types of humoral signalization
• Endocrine• from gland via blood to a distance
• Neurocrine• via axonal transport and then via blood
• Paracrine• neighboring cells of different types
• Autocrine• neighboring cells of the same type or the
secreting cell itself
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Chemical characteristics of hormones
• Amines (from tyrosine)• hydroxylation - catecholamines• iodination - thyroid hormones
• Peptides/proteins• Steroids (from cholesterol)
• adrenocortikoids• sex hormones• active metabolites of vitamin D
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Genetic disorders• Peptides/proteins:
Often gene coding the hormone • -> activity (e.g. insulin)
• Amines & steroids: gene coding enzyme catalyzing the
synthesis-> hormone level• and/or precurzor level
– e.g. androgens in deficient estrogen synthesis
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Hormone release• Proteins & catecholamines:
secretory granules, exocytosis• for incorporation into granules often special
sequences cleaved off in granules or after release
• stimulus [Ca2+]i (influx, reticulum) granules travel along microtubules towards cell membrane (kinesins, myosins) fusion
QuickTime™ and aVideo decompressor
are needed to see this picture.
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Hormone release• Thyroid hormones:
made as part of thyroglobulin stored in folicles T3 & T4 secreted by enzymatic cleavage
• Steroid hormones:• leave the cell across cell membrane right
after synthesis (no storage)
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Regulation of hormone release• Feedback
Negative
Gland Target tissue
hormone
product
inhibition
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Regulation of hormone release• Feedback
Negative Positive (only narrow dose range)
Gland Target tissue
hormone
product
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Regulation of hormone release• Feedback
Negative Positive (only narrow dose range)
• Nerve regulation pain, emotions, sex, injury, stress,... e.g. oxytocin with nipple stimulation
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Combined feedback Stress etc.
CRH secretion in hypothalamus
ACTH secretion in pituitary
plasma ACTH
cortisol secretion in adrenals
plasma cortisol
stimulation
inhibition
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Regulation of hormone release• Rhythms
circadian
0
100
200
300
400
500
600
Cortisol(nM)
Time of day09 0921
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Regulation of hormone release• Rhythms
circadian• light/dark fine/tune endogenous rhythm of cells &
suprachiasmatic nucleus of hypothalamus• melatonin, cortisol
monthly seasonal (day length; atavistic) developmental (puberty, menopause)
• Pulsations/oscillations• gonadotropins
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Pulsatility in GnRH & LH release
02468
101214 GnRH (pg/10 min)
LH (ng/ml)
12:00 16:0014:00Time of day
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Hormone action• Receptor
specificity of a response to a given hormone
• (Second messenger)
• ∆ activity or concentration of enzymes, transcription factors, or structural proteins
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Hormone action
Peptides/proteinsCatecholamines
Steroid & thyroidhormones
Receptor in cellmembrane
Receptor in cytosol ornucleus
Second messengers ² protein activity
² gene expression
Fast Slower
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Receptors
• ∆ affinity or expression modulates hormone action
• e.g. phosphorylation, pH, osmolarity,...
• down-regulation
• up-regulation
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Membrane receptors
• Large glycoproteins, often several subunits
• Typically 7x through membrane• After activation:
dissociation from the hormone or endocytosis of the complex, then
degradation in lysozomes, recycling
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G proteins
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G proteins a subunit binds activated receptor releases GDP, binds GTP dissociates from its b subunit & the
receptor binds & activates/inhibits effector
(adenyl/guanylate cyclase, phospholipase C)
hydrolyzes GTP to GDP re-associates with its b-g dimer
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Intracellular signal transduction
(second messengers) cAMP cGMP IP3 Ca/calmodulin tyr kinases Smad MAP kinases One hormone can use several systems (in various cells
or for different functions)
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cAMP
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Adenylate cyclase - cAMP- protein kinase A
PKA phosphorylates target enzymes (in/activation)
sometimes complementary (e.g. Ca channel activation + Ca pump inhibition)
can affect gene expression• cAMP regulatory element (CRE) on DNA binds
transcription factor, CRE binding protein (CREB)
cAMP hydrolysis: phosphodiesterases
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cGMP
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Ca-calmodulin
G proteins activate Ca channels (ROC)
Ca influx stimulates Ca release from endoplasmic reticulum (CICR)
Ca, mainly by binding calmodulin, modulates many enzymes, often via protein kinase C
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Phospholipase C - IP3 & DAG
from cell membrane phospholipids
IP3 activates Ca channel of the endoplasmic reticulum
DAG: PKC affinity to Ca
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Tyrosin kinases Receptor autophosphorylation upon hormone
binding unmasks tyr-kinase activity– typically insulin (& growth factors)
Or conformational change of the receptor upon hormone binding attracts & activates cytoplasmic tyr-kinases
– e.g. growth hormone
tyr-kinases phosphorylate cascades of tyr & ser kinases & phosphatases
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Inhibins, activins & TGF system
Hormone
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Intracellular receptors
• Lipophilic hormones: Thyroid Steroid Vitamin D
• Enter the cell or all the way to nucleus, where they bind the receptor (large oligomeric protein)
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Intracellular receptors
• C-terminal domain binds hormone hormone specificity
• Central domain binds DNA (HRE, hormone regulatory unit, 8-15
bases) gene specificity
• N-terminal domain activates RNA polymerase
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Function of intracellular receptors
• Hormone displaces inhibitory protein (e.g. HSP) translocation to nucleus, DNA binding
• corticoids
• Or hormone binding displaces the receptor from resting, inhibitory association with DNA
• thyroid hormones
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Magnitude of response
• hormone concentration• number of receptor molecules• duration of exposure• intracellular conditions (second
messengers, kinases,…)• synergistic or antagonistic
influences
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Dose/response
020406080
100120
Hormone concentration
Effec
t
max. response
~sensitivity
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Decrease in max. response
• less target cells• less receptors• less/lower activity of enzymes
activated by hormone• less substrate for final product• more non-competitive inhibitor
020406080
100120
Hormone concentration
Effec
t
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Drop in sensitivity
• less receptors• lower receptor affinity• modulating factors• faster hormone degradation• antagonistic hormones
020406080
100120
Hormone concentration
Effec
t
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Transport of hormones
• Freely in blood: Catecholamines Most peptides
• Specific transport globulins (from liver): Steroids Thyroid hormones
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Transporter binding lengthens hormone halftime
0
1
2
3
4
5
6
7
100 99.97 99.7 94 89
Plasma halftime(days)
% bound hormone
Thyroxin
T3 Testosterone
Cortisol
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Inactivation of hormones
• Target tissue uptake• Metabolic degradation (plasma,
liver, kidney)• Excretion in urine
( by transporter binding; low for proteins - also re-absorbtion & degradation in kidneys)
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Measuring hormones
• Immunoassay (pM)
• Bioassay (biol. activity can differ from concentration or immunoreactivity - e.g. mutation of the gene for the hormone)