Intro to Endo Physio

8/3/2019 Intro to Endo Physio

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Endocrine PhysiologyAn Introduction

Victor L. Mendoza, M.D.


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Regulation of the Functions

of the Body

Nervous system

Endocrine (Hormonal) systemEndocrine (Hormonal) system

Major Control Systems:


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Endocrine vs Nervous Control

both share a role for control and coordination

throughout the body

should not be considered as separate entities

some endocrine glands respond to

nervous stimuli

endocrine system maintains nervous system

both systems involve reflexes


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Wh

at is endocrinologyEndocrinology =

Intercellular Chemical Communication

Endocrinology is about communication systems & information

transfer.


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ENDOCRINE SYSTEM

Uses chemical signals for cell to cell communication

Coordinates the function of cells

Response to an endocrine signal occurs within

minutes toh

ours


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Wh

at is endocrinologyEndocrine Functions

Maintain Internal Homeostasis

Support Cell Growth

Coordinate Development

Coordinate Reproduction

Facilitate Responses to External Stimuli


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Homeostasis & Controls

Successful compensation

Homeostasis reestablished

Failure to compensate Pathophysiology

Illness

Death

Figure: Homeostasis


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Amolecule that functions as a message within an

organism; its only function is to convey information.

Because of this function, physical descriptions of a

chemical thought to be a hormone are not adequate to

indicate the molecule's physiological role. A moleculeis a hormone only when described in the context of its

role in a biological communication system. Definition

of a hormone requires testing of that molecule in a

biological response system, running a bioassay.

Ultimately, the existence of endocrinology is dependenton the existence & use of bioassays. (This is also true

for pharmacology & toxicology.)

What is a hormone?What is a hormone?


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HORMONESH o r m a e i nH o r m a e i n excite; stir up

Endocrine System

chemical substances acting as messengers, produced by

ductless glands, that are transported in the circulation to targetcells

discrete chemical substances which transfer information from

one set of cells to another

chemical substances secreted into body fluids by one cell or achemical substances secreted into body fluids by one cell or agroup of cells and that exert a physiological control effect ongroup of cells and that exert a physiological control effect on

other cells of the bodyother cells of the body


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HormonesHormones

hormones are specialized chemical substances

effective only at specific target cells

hormones are classified according to t

he cells t

heyact upon


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Hormone ClassificationHormone Classification

Endocrines: hormones that are released into the

blood stream and interact with distant target

cells

Paracrines: local hormones that act on nearby

cells

Autocrines: local hormones that act on the cell

that released them


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Signal Chemicals

Made in endocrine cells

Transported via blood

Receptors on target

cells

Long Distance Communication: Hormones

Figure: Long distance cell-to-cell communication


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Figure: Long distance cell-to-cell communication


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Paracrines and Autocrines

Local communication

Signal chemicals diffuse

to target Example: Cytokines

Autocrinereceptor onsame cell

Paracrineneighboring cells

Figure: Direct and local cell-to-cell communication


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What kinds of hormone are there?What kinds of hormone are there?

Known Hormonal Classes

Proteins & peptides

Lipids (steroids, eicosanoids)

Amino acid derived

(thyronines, neurotransmitters)


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PEPTIDEHORMONES

Consist of specific amino acids (at least 3 amino acids)

Synthesized as large precursor proteins

Stored in membrane-enclosed compartments

Hydrophillic

Most abundant


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Protein and Polypeptide Hormones:

Synthesis and Release

Figure : Peptide hormone synthesis, packaging, and release

water soluble, stored in vesicles, secreted by exocytosis triggered

by an increase in cytosolic calcium, fast acting, short half-life


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Steroid Hormones

made from cholesterol

lipophilic (secreted as they are synthesized,

not stored)

specific protein carrier molecules

slow acting - genomic actions


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Endocrine System

HORMONES (peptides vs steroids)

* steroids are small hydrophobic molecules which are protein

bound in plasma while peptides are larger hydrophilic moleculesthat are usually free in plasma

* steroids have longer plasma half-lives than

peptides

* steroids have cytosol or intranuclear receptors while

peptides have membrane receptors


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Endocrine System

HORMONES (peptides vs steroids)

* steroids act directly through a nuclear mechanism, peptides

through a second messenger

* a longer time is required before the effects of steroids are

initiated or terminated because they have to be synthesized

and destroyed

* steroid hormones are synthesized in the smooth ER and are

released without being stored in granules; peptide hormones

are synthesized in the rough ER and are stored in granules


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Amine Hormones

derivatives of single amino acid residues,

primarily TYROSINE (tryptophan)

can behave either like peptides (catecholamines)

or steroids (thyroid hormones)

key characteristics: surface (catecholamines) or intracellular

(thyroid hormones) receptors

fast or slowacting


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Signal Pathways

Signal molecule (ligand)

Receptor

Intracellular signal

Target protein

Response

Figure: Signal pathways


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Hormones

Only target cells will respond to a specific hormone

(but some cells are targets for more than one hormone)

Only target cells possess specific receptors for the

hormone.


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Hormones

Receptor:

The molecular entity (usually a protein or

glycoprotein) either outside or within a cellthat recognizes and binds a particular hormone

When a hormone binds to its receptor, biologic

effects characteristic of that hormone isinitiated


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Endocrine System

RECEPTORS

Receptor proteins have two principal domains:

* hormone binding site

in majority of instances, has high specificity and

affinity

* activity site

couples the HR complex directly or indirectly

to enzyme systems and biological responses

distinguishes receptor from other proteins which

bind hormones but with no known biological activity


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Endocrine System

(conformational change; altered activity)

causes a series of biochemical changes *which produces the physiological responses

* regulation of enzyme

activity

* regulation of biosynthesis and degradationof nucleic acids and proteins

* regulation of the ability of the targets cells to

grow and replicate

R HRH +


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Endocrine System

(conformational change; altered activity)

causes a series of biochemical changes *which produces the physiological responses

R HRH +

Hormones signal cells to start or stop secreting,

contracting, dividing, or differentiating. They may also

accelerate or slow the rates of these processes, or theymay modify responses to other hormones. Function ofhormoneis to modify the physiological activity of a target cell or tissue

The specific response elicited in a given cell is determined by the cell

rather than the hormone; different cell types may respond to the same

stimulus in different ways.


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Can single cells make or sense more thanCan single cells make or sense more thanone hormone at a time?one hormone at a time?

Yes, cellsYes, cells can make multiple hormonescan make multiple hormones, even of differing, even of differingchemical classes, & theychemical classes, & they can sense multiple signalscan sense multiple signals ---- &&integrate themintegrate them ---- all at once.all at once.

Examples:

OvarianOvarian granulosa cellsgranulosa cells makemake inhibininhibin (protein),(protein), estradiolestradiol (steroid),(steroid),&& androstenedioneandrostenedione (steroid) during the follicular phase of the(steroid) during the follicular phase of theovarian cycle. At the same time they respond toovarian cycle. At the same time they respond to FSHFSH && growthgrowthfactorsfactors (proteins),(proteins), estradiolestradiol (steroid), &(steroid), & thyroxinethyroxine (amino acid(amino acidderivative), along with other hormones.derivative), along with other hormones.

Anterior pituitaryAnterior pituitary gonadotropesgonadotropes respond torespond to LHRHLHRH (peptide) &(peptide) &inhibininhibin (protein),(protein), estradiolestradiol,, testosteronetestosterone,, progesteroneprogesterone, &, &glucocorticoidsglucocorticoids (steroids) while they make both(steroids) while they make both FSHFSH && LHLH(proteins).(proteins).


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Receptor locations

Cytosolic orNuclear Lipophilic ligand enters

cell

Often activates gene

Slower response

Cell membrane

Lipophobic ligand can'tenter cell

Outer surface receptor

Fast response

Figure: Target cell receptors


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Membrane associated

enzymes

External reactions

Internal reactions

Receptors bind specific

ligand

Example: Hormones

Cell recognition

molecules

Figure : Cell membrane receptor


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2nd Messenger2nd Messenger

water soluble hormones are denied entrance to the

cell by the lipid bilayer of the plasma membrane

protein receptors embedded into th

e plasmamembrane are able to respond to specific hormones

first messengersin the blood


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Protein hormones bind to specific receptor sites on

the target cells

hormone-protein receptor complex stimulates GG

proteinprotein


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G proteinG protein links the receptors on the outer surface of

the cell to an enzyme (adenylyl clyclase) embedded

on the inner surface of the plasma membrane

adenylyl cyclase converts ATP into cyclic AMP

(cAMP) 2ndmessenger


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cAMPactivatesprotein kinases that trigger a

cascade of enzymatic reactions in the cell

enzymatic reactions cause the cell to carry out its specific

physiological function

a single molecule ofhormone may cause the

production of thousands of molecules ofcAMP


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Cyclic AMPCyclic AMP

cAMP amplifies the signal that causes the cell to

perform its specific function

energy production in liver cells

hormone production in thyroid cells

increased contraction of cardiac muscle


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RECEPTORSPeptide Hormone Receptors

located in the cell membrane with the hormone

binding site expressed on the exterior cell surface

HR complex

alters the activity of membrane bound enzymesand transport processes

acts directly on target siteschange cellular concentration of

regulating molecules which then

function as second messengers(calcium ion, cAMP, DAG, etc)

alteration of enzyme activity

directly modifying

existing enzyme moleculesaltering the synthesis and

concentration of enzyme molecules


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Plasma MembranePlasma Membrane

ReceptorG-protein coupling Signal generator

Second messengers

Ca++, cAMP,cGMP,

phosphoinositides,prostaglandins, etc.

Enzyme activity

Enzyme concentration and other

cell proteins

DNA transcription

mRNAs

Substrates

Hormones

Secreted proteins

etc

Metabolic

pathways

Intrinsic kinase

activity

1A

1

23

Peptide +

Catecholamine

hormones


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Steroid Hormones: Action

Figure 7-7: Steroid hormone action


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Plasma MembranePlasma Membrane

ReceptorG-protein coupling Signal generator

Second messengers

Ca++, cAMP,cGMP,

phosphoinositides,prostaglandis, etc.

Enzyme activity

Enzyme concentration and other

cell proteins

DNA transcription

mRNAs

Substrates

Hormones

Secreted proteins

etc

Metabolic

pathways

Intrinsic kinase

activity

1A

1

23

Peptide +

Catecholamine

hormones

Receptor

Steroid Thyroid

Vitamin D Hormones


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HormonesHormones

hormones help regulate the rate of biochemical

reactions

like enzymes, hormones are not changed by the reactions

they regulate

secretion rates ofhormones vary from one gland to

another depending on physiological conditions (may

be episodic, pulsatile, or follow a daily rh

yth

m)


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HormonesHormones

ex: epinephrine (adrenaline) is secreted by the adrenal

glands in response to an emergency that calls for an

immediate increase of blood flow to the muscles

ex: ovarian hormones are secreted cyclically overextended periods of time to regulate the menstrual cycle


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Hormones

Modulation of Responding Systems Concentration ofhormones

Timing of secretion ofhormones

Receptivity of target tissues Sensitivity

Concentration ofhormones

Number of receptors

Capacity to respond Number of competent or differentiated cells Level of development of enzymatic machinery within cells


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Control of Hormone Release

SUBSTRATECONTROL

NERVOUSCONTROL

TROPHICHORMONES

- glucose regulating insulin release

- pituitary hormones

- released by the anterior pituitary


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Regulation of the Endocrine System

The endocrine cell, in addition to synthesizing and

secreting its own hormone products, has the ability to

sense the biologic consequences of secretion of that

hormone. This enables the endocrine cell to adjust itsrate of hormone secretion to produce the desired level

of effect, thereby ensuring maintenance of homeostasis.


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Feedback Loops

Figure: Negative and positive feedback


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Negative Feedback Controls:

Long & Short Loop Reflexes

Figure: Negative feedback

loops in the

hypothalamicanterior pituitary

pathway


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Summary of the Endocrine System

Figure: ANATOMY SUMMARY: Hormones


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HYPOTHALAMUS

Integrates functions that maintain chemical and

temperature homeostasis

Functions with the limbic system

Controls the release ofhormones from the anterior

and posterior pituitary


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Figure: Autonomic control centers in the brain


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HYPOTHALAMUS

Synthesizes & releases hypophysiotropic hormones:

Thyrotropin-releasing hormone (TRH)

Corticotropin-releasing hormone (CRH)

Gonadotropin-releasing hormone (GnRH) Growthhormone-releasing hormone (GHRH)

Growthhormone-inhibiting hormone (GHIH)

Prolactin-releasing factor (PRF)

Prolactin-inhibitn hormone (PIH)


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HYPOTHALAMUS

Synthesizes hypophysiotropic hormones in cell

bodies of neurons located in the hypothalamus

Transports hormones down the axon and stored in

the nerve endings

Secretion ofhormones is in pulses


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HYPOTHALAMUS: Secretion ofHypophysiotropic

Hormones

Is influenced by emotions

Can be influenced by the metabolic state of the

individual

Delivered to the anterior pituitary via the

hypothalamic-hypophyseal portal system

Usually initiates a three-hormone sequence


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Endocrine Control: Three Levels of Integration

Figure: Hormones of the hypothalamic-anterior pituitary pathway


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Sella turcica of the sphenoid bone

Location of the Pituitary


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Structure of the Pituitary Gland


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Structure of the Pituitary Gland

Two distinct lobes:

anterior pituitary

(adenohypophysis; pars distalis)

posterior pituitary

(neurohypophysis; pars nervosa)

- true endocrine tissue

- secretes classic hormones

- neural tissue

- secretes neurohormones


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Anterior PituitaryAnterior Pituitary

adenohypophysis contains many glandular epithelial

cells

larger of the two lobes (75%)

connected to the hypothalamus by a vascular link


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Posterior PituitaryPosterior Pituitary

neurohypophysis composed of nervous tissue

connected by neuronal tracts to th

eh

ypoth

alamus

neural link of nerve cells and blood vessels called the

infundibulum


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Pituitary and HypothalamusPituitary and Hypothalamus

Hormones secreted by the posterior pituitary are

synthesized and regulated by neuronal centers in the

hypothalamus

nerve impulses link the hypothalamus with the posterior

pituitary


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Hormones of the NeurohypophysisHormones of the Neurohypophysis

posterior pituitary does not actually manufacture

hormones

hormones synthesized in the hypothalamus are

transported through the nerve fibers as secretory

vesicles to the posterior pituitary

hormones are stored until nerve impulses from the

hypothalamus stimulate their secretion


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Hormones of the NeurohypophysisHormones of the Neurohypophysis

Two hormones are secreted in this manner from the

hypothalamus:

antidiuretic hormone (ADH)

oxytocin


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ANTERIOR PITUITARY HORMONES


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Anterior pituitary produces seven (7) separate hormones

All but two are considered tropic hormones whose primary

target is another endocrine gland

ANTERIOR PITUITARY NON-TROPIC HORMONES


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ANTERIOR PITUITARY NON-TROPIC HORMONES

Growthhormone (GH)

Prolactin

ANTERIOR PITUITARY TROPIC HORMONES


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ANTERIOR PITUITARY TROPIC HORMONES

Gonadotropins:

- Luteinizing hormone (LH)

- Follicle stimulating hormone (FSH)

Adrenocorticotropic hormone (ACTH)

Thyroid stimulating hormone (TSH)

Melanocyte stimulating hormone (MSH)

The Hypothalamic-Hypophyseal Portal System


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The Hypothalamic-Hypophyseal Portal System

2 capillary beds directly joined by blood vessels


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ANTERIOR PITUITARYANTERIOR PITUITARY



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Growth Hormone (GH, Somatotropin): primary hormone

responsible for regulating body growth, and is important in

metabolism

Thyroid-stimulating Hormone (TSH): stimulates secretion ofthyroid hormone & growth of thyroid gland

Adrenocorticotropic Hormone (ACTH): stimulates cortisol

secretion by the adrenal cortex & promotes growth of adrenalcortex

ANTERIOR PITUITARY


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ANTERIOR PITUITARY

Follicle-stimulating Hormone (FSH): Females: stimulatesgrowth & development of ovarian follicles, promotes secretion of

estrogen by ovaries. Males: required for sperm

production

Luteinizing Hormone (LH): Females: responsible for ovulation,formation of corpus luteum in the ovary, and regulation of ovarian

secretion of female sexhormones. Males: stimulates cell in the

testes to secrete testosterone

Prolactin: Females: stimulates breast development and milkproduction. Males: involved in testicular function


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ANTERIOR PITUITARY

Synthesis of different anterior pituitary hormone is

by different cell populations.Corticotropes - ACTH

Lactortropes - Prolactin

Somatotropes - GH

Thyrotropes - Thyrotropin

Gonadotropes - FSH, LH


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ANTERIOR PITUITARY

SECRETES TROPIC HORMONES IN PULSATILE FASHION


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What is the classicalWhat is the classical

endocrine system?endocrine system?

We now know that

nearly every tissue

secretes chemical

signals that act as

hormones, heart,

immune cells,

stomach, intestines,bone cells, liver,

skin, glial cells, etc.

www.cushings-help.com/ images/endocrine.jpg


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How do hormone levels vary?How do hormone levels vary?

Hormone levels rise & fall due toHormone levels rise & fall due to synthesissynthesis of hormone &of hormone &due todue to degradationdegradation & clearance of hormone. Target cell& clearance of hormone. Target cellbinding accounts for only a small fraction of removal ofbinding accounts for only a small fraction of removal ofhormone from circulation.hormone from circulation.

In addition to hormone levels changing,In addition to hormone levels changing, target celltarget cellreceptor, transducer, & effector levels can also changereceptor, transducer, & effector levels can also change

with age, sex, & physiological or developmental state.with age, sex, & physiological or developmental state.These also vary among cell types giving rise to tissueThese also vary among cell types giving rise to tissuedifferences in hormone sensitivity.differences in hormone sensitivity.


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Hypothalamic stimulationfrom CNS

Pituitary stimulationfrom hypothalamic trophic Hs Endocrine gland stimulationfrom pituitary trophic Hs

Endocrine Control: Three Levels of Integration


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Pathologies: Over orUnder Production

Figure : Negative feedback by exogenous cortisol


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Pathologies: Due to Receptors

Figure : Primary and secondary hypersecretion of cortisol


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Hormones

Hormone Interactions Synergistic

Ex.: FSH & LH stimulate different stages of spermatogenesis at puberty

Ex.: Estrogen, Cortisol, Prolactin and Oxytocin complimentary action in regards

milk production Ex.: Epinephrine and norepinephrine increase heart rate

Permissive Ex.: Uterus exposed to estrogen induces formation progesterone

Ex.: Glucocorticoids permissive on catecholamines

Ex.: PTHhas a permissive effect on actions of vitamin D3


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Hormone Interactions Antagonistic

Ex.: Estrogen during pregnancy inhibits prolactin

Ex.: Insulin and glucagon

Hormones


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Growthhormone

Prolactin

Gonadotropins:

Luteinizing hormone (LH)

Follicle stimulating hormone (FSH)

Adrenocortocotropic hormone (ACTH)

Thyroid stimulating hormone (TSH)

Melanocyte stimulating hormone (MSH)

Anterior Pituitary Hormones


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peptide hormone

both a hormone and a trophic factor

- stimulates release of insulin-like growth

factors (IGFs; somatemedins)

chemical structure different between species

GROWTHHORMONE


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also called somatotropin

affects all parts of the body associated with growth

rather than targeting specific organs

increases tissue mass by stimulating cell division

GROWTHHORMONE

GROWTH HORMONE


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GH is only one necessary factor for normal

development

thyroid hormone

androgens

estrogens

insulin

IGFs

GROWTHHORMONEEffect on Growth

GROWTH HORMONE


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GH stimulates long bone growth

- increases length prior to epiphyseal closure

- increases width after epiphyseal closure

IGFs stimulate both bone and cartilage growth

GROWTHHORMONEBone Development

GROWTH HORMONE


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GH stimulates growth by increasing formation of RNA

- increased RNA causes increased protein synthesis

G

Hdecreases t

he breakdown of protein

GH causes a shift from the use of carbohydrates for energy to use of

fats

overall effect --> a change in the body's composition to increased

muscle mass and decreased fat deposition

GROWTHHORMONEAction

GROWTH HORMONE


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GH stimulates growth by increasing formation of RNA

- increased RNA causes increased protein synthesis

GH decreases the breakdown of protein

GH

causes a sh

ift from th

e use of carboh

ydrates for energy to use of fats

blood glucose levels rise resulting in hyperglycemia

*ifhyperglycemia is prolonged, it may lead to excessive

stimulation and early "burnout" of the beta cells, eventuallyleading to diabetes mellitus

GROWTHHORMONEAction

GROWTH HORMONE


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released in a pulsatile fashion in response to GHRH release

from the hypothalamus; inhibited by GHIH

also released by:

- hypoglycemia and fasting

- sleep

- stress

- exercise- increased amino acids in plasma

GROWTHHORMONERegulation of Secretion

GROWTH HORMONE


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Release of GH is controlled by 2hormones produced by the

hypothalamus:

- Growth-hormone releasing hormone (GHRH)

- stimulates GH release- Growth-hormone inhibiting hormone (GHIH)

- "somatostatin"

- inhibits release of GH


GROWTH HORMONE


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in childhood, results in pituitary dwarfism

- complete deficiency

- partial deficiency

both respond to GH therapies

GROWTHHORMONEDeficiency

GROWTH HORMONE


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direct effect of GH is to maintain the epiphyseal disks of long bones

dwarfism is the result of deficient GH and

premature closure of the epiphyseal plates

cretinism (also dwarf) is caused by the

deficiency of thyroid hormone, not

pituitary hormone

gigantism is the result of continued release of GH

at the end of adolescence



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