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

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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”