CLINICAL ENDOCRINOLOGY. OBJECTIVES: 1.Explain why the endocrine system is so closely related to the...

CLINICAL ENDOCRINOLOGY

OBJECTIVES:1. Explain why the endocrine system is so closely related to the nervous system.2. Distinguish between an endocrine gland and an exocrine gland.3. Define the term hormone and explain its general characteristics.4. Distinguish between a steroidal and non-steroidal hormone, in terms of

composition and action.5. For each of the glands, name the hormone(s) they secrete, identify the

target organ of each hormone, and the effect of each hormone.6. Define the term gonadotropin, name of hormones secreted by the

pituitary ,thyroid,adrenal glands,pancreatic gonadal gland ….7. Distinguish between dwarfism, giantism, and acromegaly8. Describe how calcium levels are maintained in the blood.9. The hormones that work together to regulate water and electrolyte levels in

the blood and therefore regulate blood pressure.10. Describe how glucose levels are maintained in the blood.11. Compare and contrast cretinism, myxedema, Grave’s Disease, and goiter.12. Define the blood ,stimulatory tests, and other diagnostic procedures to

define the disease.13. To describe secondary sexual characteristics ,differentiate between virilism

and hirsutism, get information about PCOS and ovulatory cycle.14. Describe the adipose tissue -derived hormones ( leptin,adiponectin,resistin)

and their role in adiposity

Learning outcomes1. List the cells and state the hormones secreted by

anterior and posterior pituitary,thyroid gland,adrenal,pancreas, gonads

2. Explain the role of hypothalamus in controlling anterior & posterior pituitary

3. Describe the regulation of secretion & actions of different hormones

4. Explain the neural control of hormone release.

5. Describe specific hormonal disorders

6. Describe the role of adipose tissue in regulation of body metabolism

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

Types of GlandsExocrine Glands are those which release their cellularsecretions 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

• Hormone types– Circulating –

circulate in blood throughout body

– Local hormones – act locally

• PARACRINE – act on neighboring cells

• AUTOCRINE – act on the same cell that secreted them

General characteristic of hormones1. needed in very small amounts (potent);2. produce long-lasting effects in the cells they target;3. regulate metabolic processes (maintain homeostasis) 4. may be steroid (produced from cholesterol = fat-soluble) or

non-steroid (water-soluble).5. they have specific rates and patterns of secretion (diurnal,

pulsatile, cyclic patterns, pattern that depends on the level of circulating substrates)

6. they operate within feedback systems, either positive(rare) or negative, to maintain an optimal internal environment

7. they affect only cells with appropriate receptors specific cell function(s) is initiated

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

Some general effects of hormones

Hormones regulate the transport of ions, substrates and metabolites across the cell membrane:1. they stimulate transport of glucose and amino acids2. they influence of ionic transport across

the cell membrane3. they influence of epithelial transporting

mechanisms4. they stimulate or inhibit of cellular

enzymes5. they influence the cells genetic

information

Control of Hormone Secretion Control of secretion is in the form of neural, hormonal, or humoral stimuli.1. Neural: Signals from nervous systemThe 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 ofhormones 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)

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.

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. cytokines (interleukiny, interferón, TNF....)

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 cellmembranes of target cells. The lipid-soluble hormone then binds to a receptor protein that, in turn, activates aDNA segment that turns on specific genes. The proteins produced as result of the transcription of the genes andsubsequent 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

1 Lipid-solublehormonediffuses into cell

Blood capillary

Target cell

Transportprotein

Free hormone


Blood capillary

Activatedreceptor-hormonecomplex altersgene expression

NucleusReceptor

mRNA

DNACytosol

Target cell

Transportprotein

Free hormone

2


Blood capillary


NucleusReceptor

mRNANewly formedmRNA directssynthesis ofspecific proteinson ribosomes

DNACytosol

Target cell

Transportprotein

Ribosome

2

3



NucleusReceptor

mRNANewly formedmRNA directssynthesis ofspecific proteinson ribosomes

DNACytosol

New proteins altercell's activity

Transportprotein

Ribosome

Newprotein

2

3

4

Lipid-soluble

- 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.

Water-solublehormone

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


Receptor

G protein

cAMP

Second messenger

Activated adenylatecyclase convertsATP to cAMP

Blood capillary


Adenylate cyclase

Target cell

ATP

1

2


Receptor

cAMP serves as asecond messengerto activate proteinkinases

G protein

Protein kinases

cAMP

Second messenger


Blood capillary


Adenylate cyclase

Target cell

ATP

1

2

3 Activatedproteinkinases


Receptor


G protein

Protein kinases

cAMP

Activatedproteinkinases

Second messenger


Activated proteinkinasesphosphorylatecellular proteins

Blood capillary


Adenylate cyclase

Target cell

ATP

1

2

4

3

Protein— P

ADP

Protein

ATP


Receptor


G protein

Protein kinases

cAMP


Protein—

Second messenger



Millions of phosphorylatedproteins cause reactions thatproduce physiological responses


Adenylate cyclase

Target cell

P

ADP

Protein

ATP

ATP

1

2

4

3

5


Receptor


G protein

Protein kinases

cAMP


Protein—

Second messenger

Phosphodiesteraseinactivates cAMP



Millions of phosphorylatedproteins cause reactions thatproduce physiological responses

Blood capillary


Adenylate cyclase

P

ADP

Protein

ATP

ATP

1

2

6

4

3

5

Water-soluble Hormones

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

• Calcium (Ca2+)– Target: calmodulin– Calmodulin protein kinases

• Cyclic nucleotides– cAMP & cGMP– Target: protein kinases

• Diacylglycerol (DAG) & IP3

– Phosphoipase C act on the PIP2 From membrane lipids– DAG Protein Kinase C (membrane)– IP3 Ca2+ (triggers the release of Ca2+from the

endoplasmic reticulum, which then activates enzymes that generate cellular changes.)

RECEPTORS: General Characteristics of Receptors

• Receptors bind hormones, resulting in a biological response

• All receptors exhibit general characteristics:

1. Specific Binding (structural and steric specificity)

2. High Affinity (at physiological concentrations)

3. Saturation (limited, finite # of binding sites)

4. Signal Transduction (early chem event must occur)

5. Cell Specificity (in accordance with target organ specificity).

All receptors have two functional domains:

1. Recognition domain: it binds the hormone

2. 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

Cell Surface (membrane)ReceptorsThere are three types of cell surface

receptors: 1. Ion channel receptors :Ionotropic

1. Transmembrane receptors: G-protein-coupled receptors,Metabotropic

Receptors that are kinases or bind kinases: Protein kinases phosphorylation

Neurotrophins

Cell surface receptors: G- protein receptors

A. Basic G-protein Receptor a. ligand binds to receptor (outer surface

of cell). b. receptor changes shape (inner surface

of cell). shape change allows receptor to bind inactive G-protein

c. inactive G-protein binds to receptor d. receptor activates G-protein

a. G-alpha drops GDP, picks up GTP b. when G-alpha binds GTP --> G-beta and G-

gamma are releasedc. G-alpha + GTP is released from receptor into

cytoplasm d. G-alpha + GTP = active G-protein.e. activated G-protein binds to target protein

target protein's activity is altered - might be stimulated or might be inhibited .

f. G-alpha + GTP is released from receptor into cytoplasm

g. G-alpha + GTP = active G-protein.h. 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 .

http://photos1.blogger.com/blogger/3716/526/1600/G-receptor.jpg

Intracellular Receptors

• Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells

• Small or hydrophobic chemical messengers (1st messenger,I,e hormone) can readily cross the membrane and activate receptors

• Examples of hydrophobic messengers are the steroid and thyroid hormones of animals

• An activated hormone-receptor complex can act as a transcription factor, turning on specific genes

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 proteinsDNA RNA Proteins

Steroid Hormones

Steroid hormones are lipid soluble.Steroids can diffuse through the

membrane1. Diffuse through the membrane2. 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 ribosomes7. Translate mRNA into protein

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.

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 pituitary

Thyroid gland

Thyroid Stimulating Hormone

Thyroid hormones

excitatory

inhibitory

• 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.

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.

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

H orm on e excess H orm on e d e fic ien c y H orm on e res is tan c e

E n d oc rin e d is eases

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

inactivated by antibodies before reaching the target cell

4. ectopic sources of hormones

C. failure of the target cells to respond to hormone

May be caused by:

1. receptor-associated disorders:

a. decrease in the number of receptors hormone - receptor bindingb. impaired receptor function sensitivity to the hormonec. antibodies against specific receptorsd. unusual expression of receptor function2. intracellular disorders:-

a) inadequate synthesis of the second messengersb) number of intracellular receptors may be decreased or they may

have altered affinity for hormonesc) alterations in generation of new messenger RNA or absence of

substrates for new protein synthesis

Primary & secondary endocrine diseasesBased 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)

Investigations for Endocine DisordersI. 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.)

II. Functional testsFunctional tests:-

1. Inhibitory tests2. 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 test

Principles:• negative feedback inhibition / stimulation• direct stimulation / inhibition

Thyroglobulin (Tg), anti-Tg antibodiesMarkers of non-medullar thyroid carcinoma.

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 Ab

Calcitonin, 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 : 5000screening based on elevation of TSH

2. Congenital adrenal hyperplasia (CAH) - incidence 1 : 10-14000screening based on elevation of 17-OH-progesterone

3. Phenylketonuria

Imaging methods

Indications:

A. Localization of endocrine active tumors, hyperplasia, ectopic

hormonal production

B. Evaluation of systemic complications

1. Native X-ray exams

2. Ultrasonography

3. CT / MRI

4. Scintigraphy

5. Angiography

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

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