basic endocrinology and hypothalamus

8/3/2019 Basic Endocrinology and Hypothalamus

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University of Texas El Paso

April 7, 2005

Basic Endocrinology& the Hypothalamus

Kenneth L. Campbell

Professor of Biology

University of Massachusetts at Boston


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This presentation is made possible

by a grant entitledShortcourses in Endocrinology at

Minority Undergraduate Institutions

from theNational Institute of General Medical

Sciences (NIGMS)

toThe Minority Affairs Committee of the

Endocrine Society


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What is endocrinology?

Endocrinology =

Intercellular Chemical Communication

Endocrinology is about communication

systems & information transfer.


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What are endocrine systems for?

Endocrine Functions

Maintain Internal Homeostasis

Support Cell Growth

Coordinate Development

Coordinate Reproduction

Facilitate Responses to External Stimuli


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What are the elements of anendocrine system?

Sender= Sending Cell

Signal= Hormone

Nondestructive Medium= Serum & Hormone Binders

Selective Receiver= Receptor Protein

Transducer= Transducer Proteins & 2 Messengers

Amplifier= Transducer/Effector Enzymes

Effector= Effector Proteins

Response= Cellular Response (2 Hormones)


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What is a hormone?

A molecule that functions as a message within an organism;

its only function is to convey information.

Because of this function, physical descriptions of a chemicalthought to be a hormone are not adequate to indicate themolecule's physiological role. A molecule is a hormone only

when described in the context of its role in a biologicalcommunication system. Definition of a hormone requirestesting of that molecule in a biological response system,running a bioassay.

Ultimately, the existence of endocrinology is dependent onthe existence & use of bioassays. (This is also true for

pharmacology & toxicology.)


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What kinds of hormone are there?

Known Hormonal Classes

Proteins & peptides

Lipids (steroids, eicosanoids)

Amino acid derived(thyronines, neurotransmitters)

Gases (NO, CO)

chemcases.com/olestra/images/insulin.jpg

chem.pdx.edu/~wamserc/ChemWorkshops/ gifs/W25_1.gif

website.lineone.net/~dave.cushman/epinephrine.gif


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What is a hormone receptor?

Hormone Receptors are cellular proteinsthat bind with high affinity to hormones &

are altered in shape & function bybinding; they exist in limited numbers.

Binding to hormone is noncovalent &reversible.

Hormone binding will alter binding toother cellular proteins & may activate any

receptor protein enzyme actions.


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What are the main types of receptors?

Membrane Receptors

Imbedded in target cell membrane; integral proteins/glycoproteins; penetrate through membrane

For protein & charged hormones (peptides orneurotransmitters)

3 major groups: Serpentine = 7 transmembranedomains, Growth factor/cytokine = 1 transmembranedomain, Ion channels

Nuclear Receptors

Nuclear proteins that usually act in pairs & bind to

specific Hormone Recognition Elements (HREs) =sequences on the DNA in the promoter regions oftarget genes

For small, hydrophobic molecules (steroids, thyroidhormones)


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Serpentine, or G-

Protein Receptors

info.uibk.ac.at/c/c5/ c511/hcgr-2.gif

www.tau.ac.il/Research-Authority

/ trends/images/gnrh.gif

Cross your eyes, relax & see if you can seehow 2 molecules of steroid receptor, green &yellow, interact with a specific DNA sequence.

Each cytokine, growth factor, or tyrosine-kinasereceptor subunit crosses the cell membrane once.

Cytokine Receptor

www.abc.net.au/science/news/ img

/egfreceptor.jpg; CSIRO

What kinds of receptors exist?

soma.npa.uiuc.edu/courses/ bio303/Image100.jpg

Theacetylcholinereceptor is a

gated sodiumion channel.


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What are transducers?Transducers are proteins that convert the

information in hormonal signals into chemicalsignals understood by cellular machinery.

They change their shape & activity when theyinteract directly with protein-hormone complexes.

Usually enzymes or nucleotide binding proteins,they produce 2nd messengers, or change theactivity of other proteins by covalently modifyingthem (adding or removing phosphate, lipid groups,

acetate, or methyl groups), or they interact withother proteins that do these things.

They begin amplifying the energy content of the

original hormone signals.


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How many kinds oftransducers are there?


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What are effectors?

Effectors are the enzymes & otherproteins that convert the transduced

hormonal signal into biochemicalchanges that generate the cellular

response to hormone binding.

Usually amplify the signal further &

allow cellular work to be done: cellmotion, growth, division, altered

metabolism, secretion,

depolarization, etc.


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What are feedback systems?

Feedbacks Generate Control Loops

Negative

These maintain hormonal balance & are often linkedto homeostatic processes.

If the multiplicative effect of the several links in a

control loop is negative, the entire control loop isnegative.

Positive

These cause physiologic changes in the systeminvolved.

If the multiplicative effect of the several links in acontrol loop is positive, the entire control loop is

positive.

--+

++


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How dynamic are these systems?Hormone, receptor, transducer & effector levelsvary with time. Some change over short terms,

others over long terms.

Levels also vary with developmental stage,gender, & health status.

www.antiaging.com/images/ testosterone_decline.gif

After a248.e.akamai.net/.../pubs/mmanual_home/ illus/i232_1.gif


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Can single cells make or sensemore than one hormone at a time?Yes, cells can make multiple hormones, even ofdiffering chemical classes, & they can sensemultiple signals -- & integrate them -- all at once.Examples:

Ovarian granulosa cells make inhibin (protein),estradiol (steroid), & androstenedione (steroid)during the follicular phase of the ovarian cycle. Atthe same time they respond to FSH & growth factors(proteins), estradiol (steroid), & thyroxine (amino

acid derivative), along with other hormones.

Anterior pituitary gonadotropes respond to LHRH(peptide) & inhibin (protein), estradiol, testosterone,progesterone, & glucocorticoids (steroids) while

they make both FSH & LH (proteins).


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How do hormone levels vary?Hormone levels rise & fall due to synthesis ofhormone & due to degradation & clearance ofhormone. Target cell binding accounts for onlya small fraction of removal of hormone fromcirculation.

In addition to hormone levels changing, targetcell receptor, transducer, & effector levels canalso change with age, sex, & physiological ordevelopmental state. These also vary amongcell types giving rise to tissue differences inhormone sensitivity.


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What is the classicalendocrine system?

We now know

that nearlyevery tissuesecreteschemical

signals that actas hormones,heart, immunecells, stomach,

intestines, bonecells, liver, skin,glial cells, etc.

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


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a248.e.akamai.net/.../pubs/mmanual_home/ illus/i144_1.gifwww.cushings-help.com/ anterior-pituitary.gif

Structural Relationships:Hypothalamus & Pituitary

Modified from R. Guillemin & R. Burgus (1972)

The hormones of the hypothalamus, Sci Am 227:24-33.

Modified from R. Guillemin & R. Burgus (1972)The hormones of the hypothalamus, Sci Am 227:24-33.


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IntermediateLobe During development

a transitional zonebetween the neurallyderived posteriorlobe & the

epithelially derivedanterior lobe forms.It is lost in adults ofsome species like

humans but persistsin others. It makesmelanocortin (MSH).

Hormone A Hypop Hypothalamic Regulator(s) Hormonal Function(s)


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What are the regulatory productsof the hypothalamus?

Hormone Acronym

HypophysialCellType

Hypothalamic Regulator(s) Hormonal Function(s)

Corticotropin,Adrenocorticotropin

ACTH

Corticotrope

+Corticotropin Releasing Hormone,Corticoliberin (CRH); + Interleukin 1 ; -Glucocortical Steroids (via CRH); +Vasopressin; + PACAP

Stimulates glucocorticoid production byadrenal fasiculata & reticularis

Thyrotropin,ThyroidStimulatingHormone

TSH

Thyrotrope

-Thyroxine (T4); +Thyroid Releasing Hormone,Thyroliberin (TRH); -Somatostatin (SS)

Stimulates thyroxine production by thyroid

Prolactin,

Mammotropin, Luteotropin

P

RL

Lactot

rope;Mammotrope

-Dopamine; + TRH; - SS; + Estrogens; +

Oxytocin

Stimulates milk synthesis by secretory

epithelium of breast; supports corpus luteumfunction

Somatotropin, GrowthHormone

GH

Somatotrope

+ Growth Hormone Releasing Hormone,Somatoliberin (GHRH); - SS; + PACAP

Stimulates somatic growth, supportsintermediary metabolism

Follitropin,Follicle

StimulatingHormone

FS

H

Gonadotro

pe

+ Gonadotropin Releasing Hormone,Luteinizing Hormone Releasing Hormone,

Gonadoliberin (GnRH, LHRH); - Inhibin; - Sexsteroids (via LHRH)

Supports growth of ovarian follicles &estradiol production; Supports Sertoli cell

function & spermatogenesis

Lutropin,LuteinizingHormone

LH

Gonadotrope

+ GnRH (LHRH); - Sex steroids (via LHRH in &); + Estradiol in near midcycle

Supports late follicular development,ovulation, & corpus luteum function(especially progesterone synthesis); Supportstestosterone synthesis, Leydig cell

Melanotropin,MelanocyteStimulatingHormone

MSH

Melanotrope

+ CRH Supports dispersal & synthesis of pigment inmelanocytes; may alter adrenal response toACTH


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Where do these come from?


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How is the thyroid controlled?

Kenneth L. Campbell, 1997.All rights reserved.


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http://www.j3s.net/photolog/ghana/

t.20030909_goiter.jpg

Classic HighlandNew Guinea

goiter, a clearsign of endemic

iodine -

deficiencyhypothyroidism.


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How is the adrenal cortexcontrolled?

Kenneth L. Campbell, 1997. All rights reserved.

Hypo & Hyper


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http://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpg

Adrenal Anatomy

Weakness, fatigue

Unintended weight lossHyperpigmentationHypotensionSalt cravingHypoglycemiaNausea, emesis, diarrhea

IrritabilityDepression

From: Bramwell, 1892Atlas of Clinical Medicine

Addisons Disease

www.bmb.leeds.ac.uk/teaching/icu3/ lecture/21/Image82.gif

Cushings SyndromeHypo- & Hyper-Function of theAdrenal Cortex

H i th
http://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpghttp://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpghttp://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpghttp://www.bmb.leeds.ac.uk/teaching/icu3/lecture/21/Image82.gifhttp://www.bmb.leeds.ac.uk/teaching/icu3/lecture/21/Image82.gifhttp://www.bmb.leeds.ac.uk/teaching/icu3/lecture/21/Image82.gifhttp://www.bmb.leeds.ac.uk/teaching/icu3/lecture/21/Image82.gifhttp://www.bmb.leeds.ac.uk/teaching/icu3/lecture/21/Image82.gifhttp://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpghttp://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpghttp://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpghttp://www-medlib.med.utah.edu/WebPath/jpeg4/ENDO003.jpg


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How is growthhormone controlled?


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Acromegaly,Adult

Hypersomatotropism

Hypersomatotropic frombirth: Robert Wadlow,8'11.1", 490 #, died age 22;the Alton Giant.

Pituitary Dwarfism

The Wizard of Oz Munchkins

GHHypo-

&Hyper-

Secretion
http://www.sd-neurosurgeon.com/images/acromegaly%201.jpghttp://www.sd-neurosurgeon.com/images/acromegaly%201.jpghttp://www.sd-neurosurgeon.com/images/acromegaly%201.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.hoogle.org/wwoz/wiz_c013.jpghttp://www.hoogle.org/wwoz/wiz_c013.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.altonweb.com/history/wadlow/wadlow1.jpghttp://www.sd-neurosurgeon.com/images/acromegaly%201.jpghttp://www.sd-neurosurgeon.com/images/acromegaly%201.jpghttp://www.sd-neurosurgeon.com/images/acromegaly%201.jpg


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Body MassHomeostasis:

Our NewUnderstanding

www.garvan.org.au/library/ images/jpg/adipocytes.jpg


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The satiety axis


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A Little More About the CentralPlayers

H th d t ll d?


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How are the gonads controlled?LH


How are the gonads controlled?


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How are the gonads controlled?FSH



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Where werethe Gainj?

The Gainj are a natural fertility


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The Gainj are a natural fertilitypopulation with a low total fertility rate &

an intriguing reproductive history.

FSH in Gainj Men


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FSH in Gainj Men

LH i G i j M


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LH in Gainj Men

Many Gainj Men are Infertile


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Many Gainj Men are Infertile

H i l ti t ll d?


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How is prolactin controlled?



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Prolonged intensive nursingkeeps prolactin high &ovulation suppressed.

What questions remain open?


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Examples:

Molecular discovery Exploration of molecular interactions Definition of the genetics of endocrine

molecules & their interactions Description of dynamics & kinetics of

cellular interactions Impacts of environmental variables on

molecular or cellular interactions Impacts of toxicants on molecular or

cellular interactions Discovery & exploration of chemical

modifiers of the endocrine system

What questions remain open?

What speciali ations are in ol ed?


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Genomics, Proteomics,

Transgenics, Pharmacology,Toxicology, Clinical &

Veterinary Medicine, Nursing,Diagnostics, Forensics,Epidemiology, Statistics,

Biomedical Engineering,Informatics, Basic Endocrine

Research

What specializations are involved?


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Communication among cells & organisms &between organisms & their environment isabsolutely central to life & reproduction. Whilemany of the basics of endocrine communication areknown, we are continually surprised by newfindings that revise our existing knowledge. Many,of the details of endocrine molecular biology,genetics, cell biology, & development remain to bedefined. As one of the most dynamic & central of

the biomedical sciences for practitioners,paramedical professions, & basic scientists,endocrinology will continue to be a vital science formany years to come.

Conclusions:

Acknowledgements


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Support from: NSF, Umass/Boston, Sandia National Labs,Hybritech, Quidel, Monoclonal Antibodies Inc.

Acknowledgements

Gainj ProjectThe Gainj PeopleRees MidgleyAl HermalinLora MyersJim WoodPat JohnsonIla MaslarDiana LaiSam RefetoffPeter SmousePeter Heywood

Michael AlpersBrian DavisonYan RenLynne ShintoDiane DrinkwaterDarryl Holman

Related StudiesKathy OConnorCoralie MunroSusannah BarsomEllie BrindleCheryl Stroud

Kai OrtonJodiann ThompsonYefim ProshchitskiyYelena FilipovaMatt LoprestiOliver Schultheiss

Cheryl FrederickSteve MonfortMalcolm PottsDavid McClelland (dec)

Turkana ProjectAll Turkana SubjectsMike LittlePaul LeslieBen CampbellDhanesh DookhranKathy WhitemanAlexandra EvindarWilliam LukasSandra GrayJeanine QuigleyChristine Sekadde

-KigonduLeah Kirumbi

basic endocrinology and hypothalamus

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