Dr.erfan - Endocrinology, Kuliah Fk 2011

7/31/2019 Dr.erfan - Endocrinology, Kuliah Fk 2011

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Introduction to endocrinology

Mariusz Mydlarczyk


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Communication between cells

Endocrine system (information is carried bychemical mediators)

Nervous system (information is carried by

neural impulses)

Immune system


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Cooperation between endocrineand nervous system

Some neurotransmitters circulate in theblood as hormones

Neural impulses control the release of

chemical mediators

Hypothalamus this cooperation is most

apparent


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Hormones

Substances, that are secreted into thecirculation and act as chemical

effectors in other tissues


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Places of hormone formation

Endocrine glands Diffused endocrine cells

Immune cells Nerve cells

Bloodstream

Extraglandular tissues


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Places of hormone action

Target cells through the circulation(endocrine action) most hormones

The same tissue without entering the

circulation (paracrine and juxtacrine action) sex steroids in the ovary, angiotensin II inthe kidney

The same cell (autocrine action)- cancer cells


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Endocrine

Cell

Neurotransmitter

and hormone

target cell

Hormone

target cell

Neurotransmitter

cell

Actions of hormones and neurotransmitters

Blood vessel


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Chemistry of hormones

Peptides Small peptides

Polypeptides

Glycopeptides

Steroids

Amino acids derivatives Fatty acid derivatives


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The synthesis of peptide hormones Translation mRNA into protein precursor

Posttranslational:

cleavage (pre-pro-hormone, prohormone, hormone)

processing (thyroglobulin, thyroid hormones)

Submits:

derived from single precursor

derived from separate precursors

The same peptide cam be formed from different

prohormone encoded by distinct genes (TSH) Individual prohormone can be metabolized into

different hormones (POMC)


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The synthesis of steroid hormones

Precursor

Series of enzymatic transformations


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Release mechanisms

Conversion of insoluble to solublederivatives (proteolysis of thyroglobulin)

Exocytosis of storage granules (insulin,

glucagon, prolactin, GH)

Passive diffusion of newly synthesized

molecules (steroids)


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The rate of hormone release

Periodic Rhythmic

Kind of cycles

ultradian: varying in frequently from minutes tohour

circadian: to daily

infradian: to months or year


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Pulsatile administration of LHRH

stimulates the release of LH by thepituitary, whereas the constant infusion

of the same amount of hormone per unittime has the opposite effects


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Transport of Hormones

Blood Lymph

Extracellular fluid


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Total hormone

Protein bond

fractionFree fraction


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Hormone transport in blood plasma

Most peptide and amine hormones circulate at lowconcentrations unbound to other proteins (short T1/2)

Insoluble in water hormones are transported in protein-bound form

Protein-bound form cannot enter most cellularcompartments and serves as reservoir from with freehormone is liberated into free (dialyzable) fraction

Only the free hormone interacts with receptors in targetcells (represents the active hormone), dictates the

magnitude of feedback inhibition that controls hormonerelease, is the fraction that is cleared from the circulationand correlates best with clinical states of hormone

excess and deficiency


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Degradation of hormones

Small fraction is excreted intact in urine orbile (free hormones)

Degradation takes place in:

target tissues (peptide hormones)

nontarget tissues (liver, kidneys)


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Mechanism of hormone action

Binding to receptor

Activation of postreceptor messengers Cellular answer


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Hormone receptors

Cell surface receptors Intracellular receptors

Cytoplasmatic

Nuclear

Mitochondrial


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Kinds of membrane receptors Class I: receptors with big transmembrane part

consisting of 7 segments. These receptors activateG proteins. Receptors for ACTH, LH, FSH, hCG,

TSH, glucagon, katecholamines, muscarine,serotonine, dopamine, histamine

Class II: mobile, with own enzymatic properties.

Receptors for insulin, growth factors (tyrosinekinase), ANP (guanylyl cyclase), TGFbeta (serine-threonine kinase)

Class III: do not possess enzymatic activity ontheir own but interact with soluable transducermolecules which do possess tyrosine kinaseactivity. GH, cytokines, interferons

Class IV: ion channels that binds ligands. Ach.


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Hormone

G proteinClass I protein receptor


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Binding domain

Binding domain

Tyrosine kinasedomain

Accessory protein

with tyrosine kinase

domain

Class II of

protein

receptor

Class III of

protein

receptor


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Nuclear receptors

Nuclear receptors are ligand-regulated transcriptionfactor that control gene expression by binding to targetgenes usually in the region near their promoters.

Class I: steroid hormone. Unliganted receptors areassociated with heat shock proteins and are present ineither the cytosol or the nucleus. Ligand binding

promotes dissociation of the heat shock proteins andformation of receptor homodimers that bind to specificDNA elements (HREs hormone response elements)

Class II: thyroid hormone, retinoid, vitamin D,peroxisimal proliferator-activated receptors (PPR).Receptors already present in the nucleus in the uligantedstate. They are commonly active in the absence ofhormone


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Regulation of responsiveness tohormone

Down regulation: most hormones

Up regulation: progesterone


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Classification of ligands

Inactive compounds Agonists

Antagonists

Partial agonist, partial antagonists

Mixed agonists-antagonists


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GTP

ATP

Biological effects

Protein phosphorylation

Protein kinases A(PKA)

Phosphoproteinphosphatases (PP)

cAMP

Adenylyl cyclase

Gs protein GDP

Receptor

(Beta adrenergic, D1, V2, H2, GHRH, glucagon, TSH, ACTH, FSH, LH)

Hormone


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GTP

ATP

Biological effects


Protein kinases A

(PKA)

Phosphoprotein

phosphatases (PP)

cAMP

Adenylyl cyclase

Gi protein GDP

Receptor

(Alpha2 adrenergic, D2)

Hormone


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GTP

Biological effects


Protein kinases G

(PKG)

Phosphoprotein

phosphatases (PP)

cGMP

Guanylyl cyclase

Receptor

(ANP)

Hormone


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GTP

Protein kinases Ca-dependent

Guanyl cyclase

Phosphodiesterases

Phospholipase A2

Calmoduline

Ca++

Inositoltriphosphate

(IP3)

Arachidonic acid

cascade

Phospholipase A2

(PLA2)

Phosphoprotein

phosphatases (PP)


Protein dephosphorylation

Protein kinases C

(PKC)

Diacylglycerol

(DAG)

Phosphatidylinositol

Phospholipase C(PLC)

Gq protein GDP

Receptor

(alpha1 adrenergic, H1, GnRH, TRH, V1, AT1)

Hormone


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Arachidonic acid cascade

PGs

TxA2

PGI2

PGH2

PGG2

Cyclooxygenase

LTX

5HPETE

Lipooxygenase

Arachidonic acid

(AA)

Phospholipase A2

Cell membrane phospholypides


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Regulation of hormone secretion - negative feedback mechanisms

Trophic hormone

Target endocrine organ

Target hormone

Anterior pituitary lobe

Portal pituitary circulation

Hypothalamus

(-)

(-)

(+)


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Endocrine hypofunction

Destruction of gland: autoimmune disease,neoplasm, infection, hemorrhage, injury

The absence of stimulation by trophic hormone

Defects in hormone synthesis Defects in sensitivity to hormones

Damage to tissues that produce active forms of

hormones

Increased hormone metabolism


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Endocrine hyperfunction

Tumors Ectopic production of peptide hormones

Hyperplasia

Autoimmune stimulation

Stimulation by trophic hormone

Diminished hormone metabolism


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Defects in sensitivity to hormones

Genetic or acquired Prereceptor

Receptor

Postreceptor


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Hypofunction Hyperfunction

Destruction Gland Tumor

Block Hyperplasia

Prohormone

Ectopic production

Iatrogenic

Hormone

Degraded Degraded

Receptor

Effector

Response

BlockStimulation

Block

StimulationDefect

AntibodiesAntibodies


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Primary failure of target endocrine organ

Trophic hormone


Target hormone



Hypothalamus


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Secondary failure fo target endocrine organ

Trophic hormone


Target hormone



Hypothalamus


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Primary (autonomous) hypersecretion of target endocrine organ

Trophic hormone


Target hormone



Hypothalamus


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Secondary hypersecretion of target endocrine organ

Trophic hormone


Target hormone



Hypothalamus


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Ectopic hormone production

Ectopic hormone

production

Trophic hormone


Target hormone



Hypothalamus


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Hormonal resistance

Trophic hormone


Target hormone



Hypothalamus


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Main hormonal disturbances

Target hormone level

HighNormalLow

Autonomous

(primary) secretion

of target endocrine

organ

Secondary targetendocrine organ

failureLow

Normal rangeNormal

Autonomous

(secondary)

secretion of

pituitary hormone

or hormonal

resistance

Primary failure of

target endocrine

organHigh

Pituitary

hormone

level

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Dr.erfan - Endocrinology, Kuliah Fk 2011