CLINICAL ENDOCRINOLOGY - PowerPoint Presentation

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CLINICAL ENDOCRINOLOGY

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OBJECTIVES:Explain why the endocrine system is so closely related to the nervous system.

Distinguish between an endocrine gland and an exocrine gland.

Define the term

hormone and explain its general characteristics.

Distinguish between a steroidal and non-steroidal hormone, in terms of composition and action.

For each of the glands, name the hormone(s) they secrete, identify the target organ of each hormone, and the effect of each hormone.

Define the term

gonadotropin

, name of hormones secreted by the pituitary ,

thyroid,adrenal

glands,pancreatic

gonadal

gland ….

Distinguish between dwarfism,

giantism

, and

acromegaly

Describe how calcium levels are maintained in the blood.

The hormones that work together to regulate water and electrolyte levels in the blood and therefore regulate blood pressure.

Describe how glucose levels are maintained in the blood.

Compare and contrast cretinism,

myxedema

, Grave’s Disease, and goiter.

Define the blood ,stimulatory tests, and other diagnostic procedures to define the disease.

To describe secondary sexual characteristics ,differentiate between virilism and hirsutism, get information about PCOS and

ovulatory

cycle.

Describe the adipose tissue -derived hormones (

leptin,adiponectin,resistin

) and their role in adiposity

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Learning outcomes

List the cells and state the hormones secreted by anterior and posterior

pituitary,thyroid

gland,adrenal,pancreas

, gonads

Explain the role of hypothalamus in controlling anterior & posterior pituitary

Describe the regulation of secretion & actions of different hormones

Explain the neural control of hormone release.

Describe specific hormonal disorders

Describe the role of adipose tissue in regulation of body metabolism

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Nervous and Endocrine Systems Act

together to coordinate functions of all body systems

Nervous system

Nerve impulses/ Neurotransmitters

Faster responses, briefer effects, acts on specific target

Endocrine

system

Composed of

endocrine glands

that produce, store, and secrete

hormones

.

HORMONE

= a very powerful chemical substance secreted by an endocrine gland into the bloodstream, that affects the function of another cell or "target cell

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Types of GlandsExocrine Glands

are those which release their cellular

secretions through a duct which empties to the outside or into the lumen (empty internal space) of an organ. These include certain sweat glands, salivary and pancreatic glands, and mammary glands. They are not considered a part of the endocrine system.

Endocrine Glands

are those glands which have no duct and release their secretions directly into the intercellular fluid or into the blood. The collection of endocrine glands makes up the endocrine

system.The

main endocrine glands are :

pituitary (anterior and posterior lobes)

thyroid, parathyroid - `

Adrenal (cortex and medulla)

pancreas and gonads

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Hormone typesCirculating – circulate in blood throughout bodyLocal hormones – act locally

PARACRINE

– act on neighboring cells

AUTOCRINE

– act on the same cell that secreted them

Slide7

General characteristic of hormones

needed in very small amounts (potent);

produce long-lasting effects in the cells they target;

regulate metabolic processes (maintain homeostasis)

may be steroid (produced from cholesterol = fat-soluble) or non-steroid (water-soluble).

they have specific rates

and patterns of secretion (diurnal,

pulsatile

, cyclic patterns, pattern that depends on

the

level of circulating substrates)

they operate within feedback systems, either positive

(rare)

or negative, to maintain an optimal internal environment

they affect only cells with appropriate receptors



specific

cell function

(s)

is initiated

they are excreted by the kidney, deactivated by the liver or by other mechanisms

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Some general effects of hormones

Hormones regulate the transport of ions, substrates and

metabolit

e

s

across

the cell membrane

:

they stimulate

transport of glucose

and amino acidsthey influence of ionic transport across the cell membranethey influence of epithelial transporting mechanismsthey stimulate or inhibit of cellular enzymesthey influence the cells genetic information

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Control of Hormone Secretion Control of secretion is in the form of neural, hormonal, or humoral

stimuli.

1. Neural:

Signals from nervous system

The adrenal medulla is directly stimulated by the sympathetic nervous system. Epinephrine and NE reinforce the actions of the sympathetic nervous system.

2

. Hormonal

Occurs when hormones from one endocrine gland stimulate the secretion of

hormones from another endocrine gland.

E.g. TRH,TSH, TH

E.g. CRH,

ACTH,Cortisol These routes of secretion are usually controlled in a negative feedback manner.3. Humoral : Chemical changes in the blood Occurs when substances other than hormones control the secretion of endocrine glands. E.g. Insulin secretion by the pancreas is determined by several factors. Rise in glucose after a meal triggers insulin secretion. Rise in amino acids after a meal triggers insulin secretion. In addition hormonal and neural stimuli also play a role in insulin secretion. or change in osmolarity (ADH release)

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Chemical classes of hormones1. Amino acid-derived

: Hormones that are modified amino acids (

catecholamines

, thyroid hormones, prostaglandins,

leucotrienes

, dopamine,

serotonine

, GABA,

melatonin)

2.

Polypeptide and proteins

: Hormones that are chains of amino acids of less than or more than about 100 amino acids, respectively. Some protein hormones are actually glycoproteins, containing glucose or other carbohydrate groups. (insulin, GH, Leptin...)3. Steroids: Hormones that are lipids synthesized from cholesterol. Steroids are characterized by four interlocking carbohydrate rings.(a) Corticoids (cortisol, aldosterone,, b) sex hormones(androgen,estrogen, progesterone),c) Nitric oxide (NO)4. Eicosanoids: Are lipids synthesized from the fatty acid chains of phospholipids found in plasma membrane.Hormones circulating in the blood diffuse into the interstitial fluids surrounding the cell. Cells with specific receptors for a hormone respond with an action that is appropriate for the cell. Because of the specificity of hormone and targetcell, the effects produced by a single hormone may vary among different kinds of target cells.

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Another groups of

hormones

A.

gastrointestinal hormones

(

more than

26 GI polypeptides)

B.

opioid

peptides

(endogenic

opioids

)

C.

tissue growth factors

(epidermal growth factor, nerve growth factor,

PDGF,

insuline

-like growth factor ...)

D.

atrial natriuretic hormone (ANF)

E. transforming growth factors and hematopoietic and other growth factors (FGF....)

F. endothelial factors (endothelins, EDRF...)

G.

c

ytokines

(interleukiny, interferón, TNF....)

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Hormones activate target cells by one of two methods, depending upon the chemical nature of the hormone.

•

Lipid-soluble hormones

(steroid hormones and hormones of the thyroid gland) diffuse through the cell

membranes of target cells. The lipid-soluble hormone then binds to a receptor protein that, in turn, activates a

DNA segment that turns on specific genes. The proteins produced as result of the transcription of the genes and

subsequent translation of mRNA act as enzymes that regulate specific physiological cell activity.

•Lipid-soluble hormones are bound to plasma proteins and are less easily metabolized and excreted from the body.

E.g. TH has a half-life of several days.

E.g.

Cortisol

has a half-life of about 90 minutes

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1

Lipid-soluble

hormone

diffuses into cell

Blood capillary

Target cell

Transport

protein

Free hormone

1

Lipid-soluble

hormone

diffuses into cell

Blood capillary

Activated

receptor-hormone

complex alters

gene expression

Nucleus

Receptor

mRNA

DNA

Cytosol

Target cell

Transport

protein

Free hormone

2

1

Lipid-soluble

hormone

diffuses into cell

Blood capillary

Activated

receptor-hormone

complex alters

gene expression

Nucleus

Receptor

mRNA

Newly formed

mRNA directs

synthesis of

specific proteins

on ribosomes

DNA

Cytosol

Target cell

Transport

protein

Ribosome

2

3

1

Lipid-soluble

hormone

diffuses into cell

Activated

receptor-hormone

complex alters

gene expression

Nucleus

Receptor

mRNA

Newly formed

mRNA directs

synthesis of

specific proteins

on ribosomes

DNA

Cytosol

New proteins alter

cell's activity

Transport

protein

Ribosome

New

protein

2

3

4

Lipid-soluble

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- Water-soluble hormones are easily degraded by enzymes in the blood stream and are also excreted very quickly from the kidneys. E.g. insulin has a half-life of about 10 minutes in the body.

E.g. Epinephrine has a half-life of about 10 seconds in the body.

Water-soluble hormones

(polypeptide, protein, and most amino acid hormones) bind to

a receptor

protein on the plasma membrane of the cell. The receptor protein, in turn, stimulates the production of one of chemical messengers.

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Water-soluble

hormone

Receptor

G protein

Blood capillary

Binding of hormone (first messenger)

to its receptor activates G protein,

which activates adenylate cyclase

Adenylate cyclase

Target cell

1

Water-soluble

hormone

Receptor

G protein

cAMP

Second messenger

Activated adenylate

cyclase converts

ATP to cAMP

Blood capillary

Binding of hormone (first messenger)

to its receptor activates G protein,

which activates adenylate cyclase

Adenylate cyclase

Target cell

ATP

1

2

Water-soluble

hormone

Receptor

cAMP serves as a

second messenger

to activate protein

kinases

G protein

Protein kinases

cAMP

Second messenger

Activated adenylate

cyclase converts

ATP to cAMP

Blood capillary

Binding of hormone (first messenger)

to its receptor activates G protein,

which activates adenylate cyclase

Adenylate cyclase

Target cell

ATP

1

2

3

Activated

protein

kinases

Water-soluble

hormone

Receptor

cAMP serves as a

second messenger

to activate protein

kinases

G protein

Protein kinases

cAMP

Activated

protein

kinases

Second messenger

Activated adenylate

cyclase converts

ATP to cAMP

Activated protein

kinases

phosphorylate

cellular proteins

Blood capillary

Binding of hormone (first messenger)

to its receptor activates G protein,

which activates adenylate cyclase

Adenylate cyclase

Target cell

ATP

1

2

4

3

Protein—

P

ADP

Protein

ATP

Water-soluble

hormone

Receptor

cAMP serves as a

second messenger

to activate protein

kinases

G protein

Protein kinases

cAMP

Activated

protein

kinases

Protein—

Second messenger

Activated adenylate

cyclase converts

ATP to cAMP

Activated protein

kinases

phosphorylate

cellular proteins

Millions of phosphorylated

proteins cause reactions that

produce physiological responses

Binding of hormone (first messenger)

to its receptor activates G protein,

which activates adenylate cyclase

Adenylate cyclase

Target cell

P

ADP

Protein

ATP

ATP

1

2

4

3

5

Water-soluble

hormone

Receptor

cAMP serves as a

second messenger

to activate protein

kinases

G protein

Protein kinases

cAMP

Activated

protein

kinases

Protein—

Second messenger

Phosphodiesterase

inactivates cAMP

Activated adenylate

cyclase converts

ATP to cAMP

Activated protein

kinases

phosphorylate

cellular proteins

Millions of phosphorylated

proteins cause reactions that

produce physiological responses

Blood capillary

Binding of hormone (first messenger)

to its receptor activates G protein,

which activates adenylate cyclase

Adenylate cyclase

P

ADP

Protein

ATP

ATP

1

2

6

4

3

5

Water-soluble Hormones

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second messengers: The small molecule generated inside cells in response to binding of hormone or other mediator to cell surface receptors

Calcium (Ca

2+

)

Target: calmodulin

Calmodulin

 protein kinases

Cyclic nucleotides

cAMP & cGMP

Target: protein kinases

Diacylglycerol (DAG) & IP3Phosphoipase C act on the PIP2 From membrane lipidsDAG  Protein Kinase C (membrane)IP3  Ca2+ (triggers the release of Ca2+from the endoplasmic reticulum, which then activates enzymes that generate cellular changes.)

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RECEPTORS: General Characteristics of Receptors

Receptors bind hormones, resulting in a biological response

All receptors exhibit

general characteristics

:

Specific Binding (structural and

steric

specificity)

High Affinity (at physiological concentrations)

Saturation (limited, finite # of binding sites)

Signal Transduction (early

chem event must occur)Cell Specificity (in accordance with target organ specificity).

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All receptors have two functional domains:

Recognition domain

: it binds the hormone

Coupling domain:

it generates a signal that couples the hormone recognition to some intracellular function.

Coupling means signal transduction.

Receptors are proteins.

They are present in

cell membranes

Intracellular receptors:

cytoplasmic receptors nuclear receptors

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Cell Surface (membrane)Receptors

There are three types of cell surface receptors:

Ion channel receptors :

Ionotropic

Transmembrane receptors: G-protein-coupled

receptors,

Metabotropic

Receptors that are kinases or bind kinases

: Protein kinases

 phosphorylation

Neurotrophins

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Cell surface receptors: G- protein receptors

Basic G-protein Receptor

ligand binds

to receptor (outer surface of cell).

receptor

changes shape

(inner surface of cell). shape change allows receptor

to bind inactive G-protein

inactive G-protein binds

to receptor receptor activates G-protein

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G-alpha drops GDP, picks up GTP when G-alpha binds GTP --> G-beta and G-gamma are released

G-alpha + GTP is released from receptor into cytoplasm

G-alpha + GTP = active G-protein

.

activated G-protein binds to target protein target protein's activity is altered - might be stimulated or might be inhibited .

G-alpha + GTP is released from receptor into cytoplasm

G-alpha + GTP = active G-protein

.

The G protein activates

adenylate

cyclase, the enzyme that catalyzes the production of cAMP from

ATP.Cyclic AMP then triggers an enzyme that generates specific cellular changes - might be stimulated or might be inhibited .

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Intracellular Receptors

Some receptor proteins are

intracellular

, found in the

cytosol

or nucleus of target cells

Small or hydrophobic

chemical messengers (1

st

messenger,I,e

hormone) can readily cross the membrane and activate receptorsExamples of hydrophobic messengers are the steroid and thyroid hormones of animalsAn activated hormone-receptor complex can act as a transcription factor, turning on specific genes

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The action of nuclear receptors is slow, as it takes some hours for the whole process to occur. The effect is long-lasting (or even permanent) and changes the properties of the cell. This type of process is important in development, differentiation and maturation of cells, e.g. gametes (eggs and sperm cells).

Transcriptional activator proteins

DNA

 RNA  Proteins

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Steroid Hormones

Steroid hormones are lipid soluble.

Steroids can diffuse through the membrane

Diffuse through the membrane

2. Binds & activates intracellular receptor.

3. Steroid-Receptor complex then enters the nucleus and binds to a particular sequence on the DNA which is called hormone response element (HRE).

4. Activates a gene.

5. Gene  transcribed into messenger RNA.

6. mRNA goes to the ribosomes

7.  Translate mRNA into protein

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Thyroid and Retinoids

go directly into the nucleus.

Their receptor is already bound to HRE, but along with a co –repressor protein which fails to activate transcription.

The association of the ligand with the receptor results in the dissociation of the co repressor.

Now this receptor- ligand complex can bind other co activator proteins and transcription begins.

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Negative Feedback in the

Hypothalamus

.

Most hormonal regulation by negative feedback

Few examples of positive feedback

hypothalamus maintains fairly constant levels of hormones because it operates The a

negative feedback system.

E.g

:

Hypothalamus

Thyroid Stimulating Hormone-Releasing Hormone

Anterior pituitaryThyroid gland

Thyroid Stimulating Hormone

Thyroid hormones

excitatory

inhibitory

Slide31

positive feedback. In such a system, hormones cause a condition to intensify, rather than decrease. As the condition intensifies, hormone production increases. Such positive feedback is uncommon, but does occur during childbirth, where hormone levels build with increasingly intense labor contractions. Also in lactation, hormone levels increase in response to nursing, which causes an increase in milk production. The hormone produced by the hypothalamus causing the milk let down and uterine contraction is

oxytocin

.

Slide32

A classic example is the production of estrogen in response to

gonadotropins

. The consequences (or the outcome ) of increased estrogen production are the further production of

gonadotropins

, thus promoting more estrogen production.

Slide33

Mechanisms of hormonal alterations

A. elevated hormones level

B. depressed hormones level

may be caused by

:

1. failure of feedback systems

2. dysfunction of endocrine gland or endocrine function of cells:

a) secretory cells are

unable to produce

or

do not

obtain

an adequate quantity of required

hormone precursors

b) secretory cells are

unable to convert the precursors

to the

appropriate active form of hormon

c) secretory cells may synthesize and

release excessive amounts

of hormone

Slide34

3. degradation of hormones at an altered rate or they may be

inactiv

at

ed

by antibodies before reaching

the target cell

4. ectopic

sources

of hormones

C. failure of the target cells to respond to hormone

M

ay be caused by:

receptor-associated disorders:

decrease in the number

of receptor

s



 hormone - receptor bindingimpaired receptor function

 sensitivity to the hormoneantibodies against specific receptorsunusual expression

of receptor function2. intracellular disorders:- a)

inadequate

synthesis of the

second messenger

s

b)

number of intracellular receptors

may be

decreased

or they may

have

altered

af

f

inity

for hormones

c)

alterations

in

generation of new messenger RNA

or absence of

substrates for new protein synthesis

Slide35

Primary & secondary endocrine diseases

Based on site of hormone defect (either increase or decreased secretion), Endocrine disorders are classified as:

A) Primary Disease:

If defect is in the target gland from which hormone has originated

B) Secondary Disease:

If defect is in the Anterior Pituitary or Hypothalamus

E.g.,

Primary hypothyroidism means decreased secretion of thyroid hormone from the Thyroid gland

Secondary hypothyroidism means deficiency of Anterior pituitary/ Hypothalamic hormone which stimulates production of thyroid hormone from the thyroid gland (

defect not in the thyroid gland

)

Slide36

Investigations for

Endocine

Disorders

Basal

hormonal concentrations

1. Basal plasma levels (one-time examination)

2. Diurnal dynamics of hormone concentrations (e.g.

cortisol,growth

H)

3. Other hormonal cycles (e.g. menstrual phase

dynamics: cyclic changes of LH, FSH, estrogens and progesteron) 4. Urinary output: 24 hr Is alternative method for hormones with diurnal dynamics (cortisol, aldosterone) or pulsate secretion (catecholamines), 5. Hormonal metabolites - plasma, urine (e.g. C-peptide), 5- HIAA (hydroxyindole acetic acid),Serotonin metabolite Urinary excretion measurement in patients with suspicious carcinoid.

6. Indirect evaluation - measurement of a metabolic response (ADH ...

diuresis

, insulin ...

glycaemia

etc.)

Slide37

II. Functional

tests

Functional tests:-

1. Inhibitory tests

2. Stimulatory tests

Basal

hormonal concentration very often doesn´t allow to establish a diagnosis of hypo- or

hyperfunction

.

Suspect

hypofunction  Stimulatory tests = quantification of functional reserve of endocrine gland, Insulin hypoglycemia test, Arginin infusion test,TRH test GnRH test,CRH test

Suspect

hyperfunction



Inhibitory tests

= quantification of responsibility of endocrine gland to inhibitory

factors, e.g.

Dexamethazone test

, Dopaminergic drugs testPrinciples:negative feedback inhibition / stimulationdirect stimulation / inhibition

Slide38

Thyroglobulin

(

Tg

)

,

anti-

Tg

antibodies

Markers of

non-medullar thyroid c

arcinoma

.CEA (carcinoembryonic antigen)Marker of non-medullar thyroid carcinoma (and ather malignancy – e.g. colorectal ca)Diagnostic usage in combination with Tg and anti-Tg AbCalcitonin, procalcitoninHormonal product and diagnostic marker of medullar thyroid carcinoma (lower sensitivity that Tg for non-medullar thyroid ca)

Tumor markers in endocrinology

newborn screening

:

1. Congenital hypothyroidism - incidence 1 : 5000

screening based on elevation of TSH

2. Congenital adrenal hyperplasia (CAH) - incidence 1 : 10-14000

screening based on elevation of 17-OH-progesterone

3.

Phenylketonuria

Slide39

Imaging methods

Indications:

Localization of endocrine active tumors, hyperplasia, ectopic hormonal production

Evaluation of systemic complications

Native X-ray exams

Ultrasonography

CT / MRI

Scintigraphy

Angiography

Biopsy

Thyroid gland - unclear solitary nodule, tumors2. Adrenal glands - rarelyThyroid gland - Fine needle aspiration biopsy (FNAB)