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Introduction to endocrinology

Mariusz Mydlarczyk

Communication between cells


Endocrine system (information is carried by chemical mediators) Nervous system (information is carried by neural impulses) Immune system

Cooperation between endocrine and nervous system


Some neurotransmitters circulate in the blood as hormones Neural impulses control the release of chemical mediators Hypothalamus this cooperation is most apparent

Hormones
Substances, that are secreted into the circulation and act as chemical effectors in other tissues

Places of hormone formation


Endocrine glands Diffused endocrine cells Immune cells Nerve cells Bloodstream Extraglandular tissues

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 in the kidney The same cell (autocrine action) - cancer cells

Blood vessel Endocrine Cell Neurotransmitter cell

Hormone target cell

Neurotransmitter and hormone target cell

Actions of hormones and neurotransmitters

Chemistry of hormones
Peptides
Small peptides Polypeptides Glycopeptides

Steroids Amino acids derivatives Fatty acid derivatives

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)

The synthesis of steroid hormones


Precursor Series of enzymatic transformations

Release mechanisms
Conversion of insoluble to soluble derivatives (proteolysis of thyroglobulin) Exocytosis of storage granules (insulin, glucagon, prolactin, GH) Passive diffusion of newly synthesized molecules (steroids)

The rate of hormone release


Periodic Rhythmic Kind of cycles
ultradian: varying in frequently from minutes to hour circadian: to daily infradian: to months or year

Pulsatile administration of LHRH stimulates the release of LH by the pituitary, whereas the constant infusion of the same amount of hormone per unit time has the opposite effects

Transport of Hormones
Blood Lymph Extracellular fluid

Total hormone

Protein bond fraction

Free fraction

Hormone transport in blood plasma


Most peptide and amine hormones circulate at low concentrations unbound to other proteins (short T1/2) Insoluble in water hormones are transported in proteinbound form Protein-bound form cannot enter most cellular compartments and serves as reservoir from with free hormone is liberated into free (dialyzable) fraction Only the free hormone interacts with receptors in target cells (represents the active hormone), dictates the magnitude of feedback inhibition that controls hormone release, is the fraction that is cleared from the circulation and correlates best with clinical states of hormone excess and deficiency

Degradation of hormones
Small fraction is excreted intact in urine or bile (free hormones) Degradation takes place in:
target tissues (peptide hormones) nontarget tissues (liver, kidneys)

Mechanism of hormone action


Binding to receptor Activation of postreceptor messengers Cellular answer

Hormone receptors
Cell surface receptors Intracellular receptors
Cytoplasmatic Nuclear Mitochondrial

Kinds of membrane receptors


Class I: receptors with big transmembrane part consisting of 7 segments. These receptors activate G 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 (tyrosine kinase), ANP (guanylyl cyclase), TGFbeta (serinethreonine kinase) Class III: do not possess enzymatic activity on their own but interact with soluable transducer molecules which do possess tyrosine kinase activity. GH, cytokines, interferons Class IV: ion channels that binds ligands. Ach.

Hormone

Class I protein receptor

G protein

Binding domain Class II of protein receptor Tyrosine kinase domain Binding domain Class III of protein receptor Accessory protein with tyrosine kinase domain

Nuclear receptors
Nuclear receptors are ligand-regulated transcription factor that control gene expression by binding to target genes usually in the region near their promoters. Class I: steroid hormone. Unliganted receptors are associated with heat shock proteins and are present in either the cytosol or the nucleus. Ligand binding promotes dissociation of the heat shock proteins and formation of receptor homodimers that bind to specific DNA 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 uliganted state. They are commonly active in the absence of hormone

Regulation of responsiveness to hormone


Down regulation: most hormones Up regulation: progesterone

Classification of ligands
Inactive compounds Agonists Antagonists Partial agonist, partial antagonists Mixed agonists-antagonists

Hormone Receptor (Beta adrenergic, D1, V2, H2, GHRH, glucagon, TSH, ACTH, FSH, LH) GTP Gs protein Adenylyl cyclase ATP Protein kinases A (PKA) Protein phosphorylation Phosphoprotein phosphatases (PP) Biological effects cAMP GDP

Hormone Receptor (Alpha2 adrenergic, D2) GTP Gi protein Adenylyl cyclase ATP Protein kinases A (PKA) Protein phosphorylation Phosphoprotein phosphatases (PP) Biological effects cAMP GDP

Hormone Receptor (ANP) Guanylyl cyclase GTP Protein kinases G (PKG) Protein phosphorylation Phosphoprotein phosphatases (PP) Biological effects cGMP

Hormone Receptor (alpha1 adrenergic, H1, GnRH, TRH, V1, AT1) GTP Gq protein Phospholipase C (PLC) Phosphatidylinositol Inositoltriphosphate (IP3) Ca++ Phospholipase A2 (PLA2) Arachidonic acid cascade Diacylglycerol (DAG) Protein kinases C (PKC) Protein phosphorylation Protein dephosphorylation Phosphoprotein phosphatases (PP) GDP

Calmoduline

Protein kinases Ca-dependent Guanyl cyclase Phosphodiesterases Phospholipase A2

Arachidonic acid cascade Cell membrane phospholypides Phospholipase A2 Arachidonic acid (AA) Cyclooxygenase PGG2 PGH2 PGs TxA2 PGI2 Lipooxygenase 5HPETE LTX

Regulation of hormone secretion - negative feedback mechanisms

Hypothalamus

(-)

Portal pituitary circulation Anterior pituitary lobe Trophic hormone

(-)
Target hormone

(+)

Target endocrine organ

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

Endocrine hyperfunction
Tumors Ectopic production of peptide hormones Hyperplasia Autoimmune stimulation Stimulation by trophic hormone Diminished hormone metabolism

Defects in sensitivity to hormones


Genetic or acquired Prereceptor Receptor Postreceptor

Hypofunction
Destruction Block Block Stimulation Degraded Antibodies Defect Receptor Effector Response Hormone Gland Prohormone

Hyperfunction
Tumor Hyperplasia Ectopic production Iatrogenic Block Degraded Antibodies Stimulation

Primary failure of target endocrine organ

Hypothalamus
Portal pituitary circulation

Anterior pituitary lobe


Trophic hormone Target endocrine organ Target hormone

Secondary failure fo target endocrine organ

Hypothalamus Portal pituitary circulation Anterior pituitary lobe Trophic hormone Target endocrine organ Target hormone

Primary (autonomous) hypersecretion of target endocrine organ

Hypothalamus Portal pituitary circulation Anterior pituitary lobe Trophic hormone Target hormone

Target endocrine organ

Secondary hypersecretion of target endocrine organ

Hypothalamus
Portal pituitary circulation

Anterior pituitary lobe


Trophic hormone Target hormone

Target endocrine organ

Ectopic hormone production

Hypothalamus Portal pituitary circulation

Ectopic hormone production


Trophic hormone

Anterior pituitary lobe

Target hormone

Target endocrine organ

Hormonal resistance

Hypothalamus
Portal pituitary circulation

Anterior pituitary lobe


Trophic hormone Target hormone

Target endocrine organ

Main hormonal disturbances


High Pituitary hormone level
Primary failure of target endocrine organ Autonomous (secondary) secretion of pituitary hormone or hormonal resistance Normal range Autonomous (primary) secretion of target endocrine organ

Normal Low
Secondary target endocrine organ failure

Low

Normal Target hormone level

High

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