microsoft powerpoint - endocrine system 2009
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The Endocrine System
Overview
Overview of endocrine systemMechanism of hormone actionRegulation of hormone secretionPituitary gland and hypothalamusThyroid glandAdrenal glandsPancreas
Genetic XY man with androgen insensitivity syndrome Testicular feminization. Testes, no uterus or oviducts.Target cells in these patients do
not respond to androgen even though its produced in the testes
Over-expression of the growth hormone (GH) gene generated this gigantic mouse
Endocrine v.s. Exocrine GlandsEndocrine glands
hormones, act on distant targettissues must possess receptorshormones travel in bloodendocrine organs are highly vascularized eg.- thyroid, pituitary, adrenals, gonads, parathyroids, pancreatic islets
Exocrine glandswater, mucous, enzymessecrete products into ducts ducts deliver products onto membrane surfaceeg., salivary glands, pancreatic acini, exocrine cells in GI tract, gonads (ova, sperm), liver
Hormone Replacement
Major classes of hormones
Proteins, polypeptides, peptidesTyrosine derivatives
CatecholaminesThyroid hormones
Steroids (cholesterol derivative)Prostaglandins (arachidonic acid derivative)
Peptide and protein hormones consist of assemblages of amino acids
Amine hormones are derived from amino acids
Steroid hormones are derived from cholesterol
Mechanism of Hormone Action
Hormone actions are mediated by high-affinity receptors on target cells
surface membrane receptorsintracellular receptors
Receptors are expressed at low concentrations in target cells
Hormone Action
In order to regulate effectively, blood hormone concentrations should not saturate receptorTherefore, there is amplification of the hormone signal after hormone interacts with receptor
Signal Transduction
Post-receptor signaling events are critical for biological action
SignalTransductionAnd AMPLIFICATION
•Specificity•Amplification•Second messengers•Transcription factors(proteins that affect gene expression)
Hormone(low amountin blood)
Receptor (low number)
SECOND MESSENGERS: Intracellular signaling agents that carry the hormone message into the cell:
•Cyclic AMP (cAMP)•Inositol trisphosphate (IP3)•calcium
Cyclic AMP is derived from dephosphorylation of ATP. The enzyme adenylate cyclase converts ATP to cyclic AMP.
IP3 and Diacylglycerol (DAG) are derived from membranephospholipids. Both are important in signaling, but IP3 is considered to be the second messenger because it is solubleand enters the cytoplasm.
Cyclic AMP/Protein kinase pathway
Cyclic AMP/Protein kinase A pathway
Stop here for test 1
Growth hormone scandal
-Creutzfeldt-Jakob disease2 French Doctors Face Charges for Hormone Use In France 25 children who took part in the hormone program in the 1980's have since developed Creutzfeldt-Jakob disease The treatment for dwarfism is human GH, which until the mid-1980's was obtained from the pituitary glandThe hormone used in the 1980's was collected from corpses in France and East Europe. About 1500 children were treated with GH between 1984 and 1986. Some pituitaries were collected in hospitals and homes for old people, sometimes from people who had died of Alzheimer's or other neurological diseases. In June 1985, after the risk of contamination with the agent causing Creutzfeldt-Jakob disease was fully recognised, the use of hormone extracted in this way was forbidden.
Mammalian nonopeptidesArginine VasopressinOxytocin
Hypothalamic releasing hormones
Creation of Adam," by Michelangelo Buonarroti, Sistine Chapel
From Toni R., The human hypothalamus: clinical anatomy of endocrine, autonomic and behavioral responses, J. Endocrinol. Invest 2003, in press
Drawings by Leonardo da Vinci (1508-1509)
Recent discoveries regarding the hypothalamus-pituitary axis
1894 Ramon Y Cajal discovers a connection between the hypothalamus and posterior pituitary lobe 1940- 1955 Harris and Green establish the basis for the neural control of the pituitary gland secretion and demonstrate its vascular link with the hypothalamus 1968 Guillemin and Schally isolate the first hypothalamic releasing factor
Source: http://www.endotext.org/neuroendo/neuroendo3b/neuroendo3b.htm
Blood supply
•Paraventricular nucleus•Supraoptic nucleus
PD= pars distalis
ME = median eminence
HPV = portal vessels
The hypothamus-pituitary portal system in a mammal
CRH
TRH
GnRH GHRH
SS
DA AVP
OXY
Thyroid
Adrenal
Gonads
TSH
ACTH
GtH
+
+
+
-GCs
TH
T, E-
BoneGrowth(Via IGFs)
Mammary Gland(Milk Production)
GH
PRL
+
+
PD
PN
ME
Kidney(H20Reabsorption)
Mammary Gland(Milk Release)
+
+
AVP
OXY
- IGF-I
Afferent Neuronal Control
PI
-
Regulation of thePituitary gland bythe Hypothalamus
Negative Feedback Control
Pancreas
Exocrine and Endocrine organEndocrine cells:
Islets of Langerhans (several cell types)Beta cells (70%)- insulinAlpha cells –glucagonDelta cells-somatostatin
History1869, Paul Langerhans, discovered islets1860s Miring and Minkowski
Removing pancreas causes diabetesTie off pancreatic duct in dogs, the exocrine pancreas digests itself, but the islets are left intact.These dogs did not develop diabetes
HistoryIslets were required for blood glucose regulation and that diabetes involved loss of the islets.Early 1920s. Fred Banting M.D. and Charles Best (Grad student) use dogs to develop first insulin preparation
The adrenal glandAdrenal Cortex
Outer glandderived from mesodermproduces steroid hormones
Adrenal MedullaInner region of glandproduces epinephrine and norepinephrinederived from neural crest
3 layers of adrenal cortex
Zona glomerulosa (outer zone)-produces aldosteroneZona fasciculata (middle zone)-produces cortisolZona reticularis (inner zone)- produces the weak androgen DHEA
Steroidogenic Pathway
•Steroids produced from cholesterol
•Synthesized upon demand
Cortisol
Increases blood glucose but spares liver glycogen stores.
Increases conversion of fats and amino acids into glucose.
Increases liver glycogen.
Aldosterone
Removing the adrenal gland (adrenalectomy) causes death in 2 weeks due to lack of aldosteroneAldosterone increases Na+ and water retention by kidneyWater and Na+ retention are required for normal blood pressureDecrease blood volume leads to decreased cardiac output, decreased blood pressure, and death.
Stress-Historical BackgroundClaude Bernard (1813-1878)
- maintaining a constant internal environment
Walter Cannon (1871-1945)“homeostasis” and the discovery of the role of adrenaline
Hans Selye (1907-1982)Introduced the term “stress”
Hans Selye
Canadian physician, studied the effects of ovarian extracts on ratsFound that many different treatments result in the same effects:
Enlargement of the adrenal glandReduction in thymus sizeDevelopment of GI ulcers
The “Pharmacology of Dirt”The early experiments of Hans Selye
Formalin, toxins
Stress
The triadcontrol stress
Larger Adrenals
Smaller Thymus
Smaller Lymph nodes
Peptic ulcers
From Selye, H. “The Stress of Life”
General Adaptation Syndrome
The Alarm PhaseElevated epinephrine and glucocorticoid secretion.Mobilization of stored glucose and elevated blood glucose.Mobilization of lipids.Increased heart rate, cardiac output, blood pressure and respiratory rate.
The Adaptation or Resistance PhaseElevated glucocorticoid secretion.Increased hepatic gluconeogenesis and conservation of stored glucose.Prevention of glucose uptake by muscle and adipose tissue.
The Exhaustion PhaseExhaustion of lipid reserves.Adrenal exhaustion; inability to synthesize corticosteroids.Leads to death if stressor not eliminated.
Coping with stress- metabolic effects of the HPA axis.
“Supra-Renal Capsules,”- the Altra-biliary Capsules of Caspar Bartholinus
Thomas Addison1855
ON THECONSTITUTIONAL AND LOCAL EFFECTS
OF
DISEASEOF THE
SUPRA-RENAL CAPSULES.
BYTHOMAS ADDISON, M.D.,
SENIOR PHYSICIAN TO GUY`S HOSPITAL
LONDON:SAMUEL HIGHLEY, 32 FLEET STREET.
1855.
“For a long period I had from time to time met with a very remarkable form of general anæmia, occurring without any discoverable cause whatever; cases in which there had been no previous loss of blood, no exhausting diarrhœa, no chlorosis, no purpura, no renal, splenic, miasmatic, glandular, strumous, or malignant disease. Accordingly, in speaking of this form of anæmia in clinical lecture, I, perhaps with little propriety, applied to it the term “idiopathic,” to distinguish it from cases in which there existed more or less evidence of some of the usual causes or concomitants of the anæmic state.
The disease presented in every instance the same general character, pursued a similar course, and, with scarcely a singleexception, was followed, after a variable period, by the same fatal result. It occurs in both sexes, generally, but not exclusively,beyond the middle period of life, and so far as I at present know, chiefly in persons of a somewhat large and bulky frame, and witha strongly-marked tendency to the formation of fat. It makes its approach in so slow and insidious a manner, that the patient canhardly fix a date to his earliest feeling of that languor, which is shortly to become so extreme. “
Epinephrine and norepinephrine
Increase blood glucosecauses liver glycogen to break down to glucose
Increase blood pressure by causing vasoconstrictionTwo adrenergic receptors
Beta adrenergic receptorsAlpha Adrenergic receptors
CatecholamineSynthesis-Synthesized from the amino acid tyrosine, which is taken up into medulla cells by active transport.
AdiposeMuscle Non-neural TissueGlycogen
NEFAsMG
Triglycerides
Lactate
Acetyl CoA
ATP
Glucose GlycogenBlood Glucose(to All Tissues)
ATP
GluconeogenesisKetones
Blood ketones(eg. Acetone, acetoacetic acid
normally low)
Liver
Glucocorticoids (GC):1. Promote protein catabolism.2. Inhibit glucose uptake by muscle.3. Promote gluconeogenesis in liver
via stimulation of PEPCK4. Permissive effect on E action
in adipose tissue.5. Elevate blood glucose.
ProteinGC (+)
AA
E (+)
Epinephrine (E):1. Promotes glycogenolysis.2. Promotes gluconeogenesis in liver.3. Promotes triglyceride breakdown
in adipose tissue.4. Elevates blood glucose.
GC (-)
E (+)
GC, E (+)
E (+)
The thyroid gland
Lays over the larynxAccumulates tyrosine and iodideHollow, soccer-ball shaped structures called follicles
Na+
Na+
I-
I-
I-
I-
Na+
K+
TG
I-
I-
Na+
Na+ TSH-R
TG iodination
TG-R ?I-
I-
I-
I-TG uptake
T4, T3
Blood
lysosomes
ClO4
ClO4:•blocks I- transport•blocks T4, T3 synthesis•causes enlarged thyroid
Thyroid hormones
Act on intracellular receptorsT3 is 10x more potent than T4Increase metabolic rate by increasing oxygen consumptionIncrease heat production by “uncoupling” oxidative phosphorylation, ie. Make less ATP, more heat
Adrenergic receptor agonists and antagonists
Diversity of Stressors“Systemic Stressor”(interoceptive or visceral stressors) Reflexive, visceral sensory pathwaysEtherHemorrhageFormalinCholecystokininSurgeryBacteria (LPS), “immune
stress”
“Neurogenic Stressor”Higher brain processing
RestraintConfinementNoveltyUnpredictabilitySocial statusGrief
Behavioral Responses
Endocrine Responses
Visceromotor Responses
Hypothalamus
Adrenal cortex
Pituitary gland
Increase Blood Glucose
Fat Muscle Liver
Spinal cord
Adrenal medulla
E
CRH
ACTH
Cort
NE Pupillary dilatation
Reduced GI function
Inc Heart rate
Promote sexual
orgasm
•Feeding behavior•Reproductive behavior•Locomotor activity•Learning and memory
STRESSOR
© Copyright 2007, Onion, Inc. All rights reserved
Posterior pituitary lobe
Claude Bernard“The constancy of the internal environment is the condition that life should be free and independent.... So far from the higher animal being indifferent to the external world, it is on the contrary in a precise and informed relation with it, in such a way that its equilibrium results from a continuous and delicate compensation, established as by the most sensitive of balances”
Walter CannonThe Wisdom of the Body, Walter B. Cannon, 1939. Second edition, W. W. Norton, New York. First use of the term “homeostasis”