Hypothalamus Hypothalamus -- pituitary pituitary -- adrenal glandsadrenal glands

Magdalena Gibas MD, PhDDept. of Physiology

University of Medical SciencesPoznań, Poland

The hypothalamus is the general director of the hormone system. At every moment, the hypothalamus analyses messages coming from: the brain and different regions of the body.

Afterwards, it performs a number of functions, such as maintaining a stable body temperature, controlling blood pressure, ensuring a fluid balance, and even proper sleep patterns.

Cell bodies of neurons that produce releasing/inhibiting hormones Hypothalamus

Primary capillaries in median eminence

Arterial flow

Releasinghormones

Anteriorpituitaryhormone

LongPortalveins

Releasing/inhibiting hormones

ANTERIORPITUITARY

Secretory cells that produce anterior pituitary hormones

Anterior pituitary hormonesVenous outflow

Gonadotropic Thyroid-Proactin hormones stimulating ACTH Growth

(FSH and LH) hormone hormone

HypothalamusHypothalamusreleases hormones at median eminence and sends to anterior pituitary via portal veinportal vein.

ControlControl ofof pituitarypituitary hormonehormonesecretionsecretion by by hypothalamushypothalamus

• Secretion by the anterior pituitaryanterior pituitary is controlled by hormones called hypothalamic releasing hormonesand inhibitory hormones secreted within the hypothalamus itself and then conducted to the anterior pituitary through hypothalamic hypothalamic --hypophysialhypophysial portal vesselsportal vessels ..

•• PPosterior pituitaryosterior pituitary secrets two hormones, which are synthesized within cell bodies of supraopticand paraventricular nuclei of the hypothalamus and transmitted through axonsthrough axons of these neurons.

FunctionFunction ofof thethe releasingreleasing andandinhibitoryinhibitory hypothalamic hormoneshypothalamic hormones

• Thyrotropin- releasing hormone (TRH)(TRH)- causes release of thyroid - stimulating hormone (TSH)

• Corticotropin - releasing hormone (CRH)(CRH)– causes release of ACTH

• Growth hormone releasing hormone (GHRH)(GHRH)- causes release of growth hormone, and

• Growth hormone inhibitory hormone (GHIH)(GHIH),,which is the same as the hormone somatostatinsomatostatinand which inhibits the release of growth hormone.

Function of the releasing andFunction of the releasing andinhibitoryinhibitory hypothalamic hormoneshypothalamic hormones

• Gonadotropin - releasing hormone ((GnRHGnRH))– causes release of the two gonadotropic hormones, LH and FSH

• Prolactin inhibitory hormone (PIH)(PIH),,- belived to be dopamine - causes inhibition ofprolactin release.

• PRL-releasing factor (PRF)(PRF)..- belived to be TRH – increases prolactin release

TheThe locationlocation ofof pituitarypituitary((hypophysishypophysis)) relativerelative to to brainbrain andand

hypohalamushypohalamus

Hypothalamus

Pituitary stalk

Posterior lobe

Intermediatelobe

Pituitary gland

Anteriorlobe

Optic chiasm

HypothalamicHypothalamic--Pituitary SystemsPituitary Systems

The pituitary is controlled largely by the hypothalamus and regulates numerous processes.

Anterior = endocrine, 6 hormones

Intermediate = minor, 1

Posterior = neuroendocrine, 2

SixSix veryvery importantimportant hormoneshormones arearesecretedsecreted byby anterioranterior pituitarypituitary :

• Secreted by lactotropes prolactin (PRL)(PRL)

• Secreted by thyrotropes thyroid stimulating hormone(TSH)(TSH)

• Secreted by gonadotropes follicle - stimulating hormoneFSHFSH, and luteinizing hormone LHLH

• Secreted by corticotropes adrenocorticotropin (ACTH)(ACTH)

• Secreted by somatotropesgrowth hormone (GH; (GH; somatotropinsomatotropin))

HypopituitarismHypopituitarism• deficiency of one or more anterior pituitary

hormones, which results in insufficient stimulation and therefore insufficient hormonal output of the respective target glands

• Tumors• Pituitary irradiation• Pituitary apoplexy• Postpartum pituitary necrosis (Sheehan’s

syndrome due to postpartum hemorrhage andhypovolemia)

How can pituitary tumors cause hypopituitarism?e.g. what is the effect of prolactinoma

on fertility in both sexes?

To venous circulation

Arterial blood supply

Posterior pituitary

Supraopticnucleus

Paraventricularnucleus

Hypothalamus

Posterior Posterior pituitarypituitaryreceives axons from the supraoptic(ADH) and paraventricularnuclei(oxytocin).

(ADH)

(oxytocin)

Two hormones are secreted by posteriorposterior pituitarypituitary::

•• Antidiuretic hormoneAntidiuretic hormone(ADH; (ADH; vasopressinvasopressin))

•• OxytocinOxytocin

•• IntermediateIntermediate -- lobelobecells secretes:

•• POMCPOMC(proopiomelanocortin), which is precursor ofalpha-MSH (melanotropin )

Growth hormoneGrowth hormone((somatotropinsomatotropin))

Somatomedins

Liver

Growth hormone

Somatotrophs ofAnterior pituitary

Somatostatin( - )

GHRH (+)

Portalvein

Hypothalamus

Sleep centerIn the brain

Chemicalstimuli

Stress centersIn the brain

• GHRH, somatostatin(GHIH) and ghrelincontrol GH release

• pancreatic somatostatinhas other functions(inhibits hormone secretion by and cells)

Ghrelin from stomach (+)

(-)

(+)

StimuliStimuli thatthat increaseincrease secretion secretion ofof GH:GH:

• GHRH; Ghrelin(brain-gut peptide)

• Deficiency of energysubstrate:- Hypoglycemia- Exercise - Fasting

• Increase in circulatinglevels of certain amino acids

• Glucagon

• Stressful stimuli

• NREM stage of sleep

Sleep

6 AMMidnight6 PMNoon

Time of day

Plasma GHconcentration(relative units)

GH is released in pulses, with a major GH is released in pulses, with a major peak during deep sleep before REpeak during deep sleep before REMM

GhrelinGhrelin• Produced mainly by stomach

(released into blood)• Other sources: intestines;

hypothalamus• Receptors located in

pituitary (GH), hypothalamus (food intake), heart, blood vessels (BP)

Ghrelin causesGhrelin causes ::

• GH release• food intake (appetite-stimulatory

peptide) via NPY neurones in hypothalamus• fat utilization

(GH-inependent mechanism)

• glucose utilization

StimuliStimuli thatthat decreasedecrease secretionsecretionofof GH:GH:

• REM sleep

• High blood glucoseconcentration ( of ghrelin release)

• Cortisol

• FFA ( of ghrelin release)

• Growth hormone

• Somatomedins

Physiology of growthPhysiology of growth

GH GH stimulatesstimulates cartilagecartilage andand bonebonegrowth growth by:by:

• increased depositiondeposition ofof proteinprotein by thechondrocytic and osteogenic cells that cause bonegrowth

• increased rate of reproductionreproduction of these cells

• the specific effect of converting chondrocytesconverting chondrocytesinto osteogenicinto osteogenic cellscells, thus causing specific deposition of new bone.

Direct and indirect effects of Direct and indirect effects of GHGH

• Direct effects are the result of growth hormone binding its receptor ontarget cells

• Indirect effects are mediated primarily by aninsulininsulin--like growth factorlike growth factor--1 1 andand 2 2 (IGF(IGF--11; IGF; IGF--22),),hormones that are secreted from the liver and other tissues in response to GH

SomatomedinsSomatomedins -- thethe polypeptidepolypeptidegrowthgrowth factorsfactors secretedsecreted by by thethe

liverliver (IGF(IGF--I, IGFI, IGF--II)II)•• IGFIGF--II (insulin-like growth factor) stimulates

skeletal growth by increasing collagen and protein synthesis in chondrocytes. IGF-I may be also produced locally

•• IGFIGF--IIII stimulates tissue growth and increasesorgan size especially during fetal development (by increasing the rate of: protein synthesis, RNA synthesis, DNA synthesis)

Distinguish betweenDistinguish between::

• Somatotropin - GH• Somatostatin - GHIH• Somatomedin – polypeptide growth factor

PhysiologyPhysiology ofof growthgrowth

GrowthGrowth isis affectedaffected by:by:• thyroid hormones• androgens • estrogens • glucocorticoids • insulin• genetic factors • adequate nutrition

sex hormones

PhysiologyPhysiology ofof growthgrowth –– growthgrowth periodsperiods::• In humans, there are 2 periods of rapid growth, the

first in infancy and the second in late puberty just before growth stops

• The first period is a continuation of the fetal growth period

• The second growth spurt is due to an interaction between sex steroids, GH, and IGFsex steroids, GH, and IGF--11sex sex hormoneshormones amplitude of the spikes of amplitude of the spikes of GH GH secretionsecretion IGFIGF--1 1 growthgrowth

Although androgens and estrogens initially stimulate growth, they finally terminate growthby causing the epiphysesto fuse to the long bones.

Two growth Two growth periodsperiods

1. Why pituitary dwarfs treated with testosterone first grow few inches and then stop?

2. Why people who were castrated before puberty tend to be tall?

PhysiologyPhysiology ofof growthgrowth –– role role ofofthyroidthyroid hormoneshormones:• Thyroid hormones have a permissive permissive

action to GHaction to GH, possibly via potentiationof the actions of somatomedins. They also appear to be necessary for a completely normal rate of GH secretion

• Thyroid hormones have a widespread effects on the ossification of cartilage, the growth of teeth, the contorous of the face, and the proportions of the body

Long bones continue to grow and elongate (lengthen) through adolescence.

This process is called ossification

Developing heart that appears as a red nodule

While still in the embryonic stage, a baby's heart develops under the supervision of the growth growth hormone hormone

Adult heart

Metabolic effects of Metabolic effects of GHGH

GH GH playsplays role role inin promotingpromotingprotein protein depositiondeposition

• GH directly enhances transport of most amino acidsthrough the cell membranes to the cytoplasm

• GH stimulates the transcription of DNA in the nucleus, causing formation of increased quantities of RNA. This in turn promotes more protein to besythesized

• GH also increases rate of RNA translation, causingprotein to be sythesized

• GH decreases protein and amino acides catabolism, thus acting as a “protein “protein sparersparer””

GH GH increasesincreases fatfat utilization utilization for for energyenergy::

• It causes release of fatty acids from adiposetissue (increases the concentration of FFA in thebody fluids)

• It also causes increased convertion of FFA to acetylcoenzyme A (acetyl-CoA) with subsequentutilization of this for energy (ATP)

• Excessive amounts of GH may produce excessivemobilization of fat from the adipose tissue, causingketosis

GH GH hashas 4 major 4 major effectseffects on on carbohydratecarbohydrate metabolismmetabolism::

• It decreases use of glucose for energy

• It stimulates gluconeogenesis

• It produces decreased uptake of glucose by the cellsand increased blood glucose concentration

• The increase of blood glucose concentration causedby GH stimulates the beta cells of the pancreas to secrete extra insulin

GROWTH HOMONE

MUSCLE LIVER ADIPOSE

Insulin-likeeffects of GH

Anti-insulineffects of GH

Amino aciduptake

Proteinsynthesis

Glucoseuptake

Lipolysis

Decreased adiposity

RNAsynthesis

Gluconeogenesis

Somatomedinproduction

Proteinsynthesis

Glucoseuptake

Increasedmuscle mass

InsulinInsulin--like GH effectslike GH effects: liver and muscle protein synthesis; AAntinti--insulininsulin: glucose uptake, lipolysis

SOMATOMEDINS

CHONDROCYTES OF BONE MANY ORGANS AND TISSUES

Increased lineargrowth

Increased tissue growthIncreased organ size

Collagen synthesis

Protein synthesis

Cell proliferation

Protein synthesis

RNA synthesis

DNA synthesis

Cell size and number

IGF-IIIGF-I

IGFIGF--II stimulates bone growth by stimulating chondrocytes, which make cartilage.

SOMATOMEDINS

CHONDROCYTES OF BONE MANY ORGANS AND TISSUES

Increased lineargrowth

Increased tissue growthIncreased organ size

Collagen synthesis

Protein synthesis

Cell proliferation

Protein synthesis

RNA synthesis

DNA synthesis

Cell size and number

IGF-IIIGF-I

IGFIGF--IIII stimulates tissue growth and repair by stimulating RNA and protein synthesis

GH GH --summarysummary

AbnormalitiesAbnormalities ofof GH GH secretionsecretion

• Panhypopituitarism• Dwarfism (in 30% -

isolated GH)• Laron dwarfism• Gigantism• Acromegaly

GIGANTISMGIGANTISM

• excessive production of GH before adolescence

ACROMEGALYACROMEGALY – excessive productionof GH after adolescence

Intradental separation and prognathism in a patient with acromegaly.

AcromegalyAcromegaly

The The somatopausesomatopause is directly related to the decline of growth

hormone produced by the body during aging

•• Clinical Signs of Clinical Signs of the the SomatopauseSomatopause::

• Weight gain • Energy Loss• Skin wrinkling• Decreasing muscle mass• Loss of bone density• Increasing body fat

(especially around the waist)

AgeAge--related lowering of GHrelated lowering of GH ((somatopausesomatopause)) ::

• decrease in muscle mass and muscle strength• impairment of psychical efficiency (GH contribute to

the function of the hipocampushipocampus, a brain structure important for the learning and memory)

• osteoporosis• cardiac failure• altered immune function (GH slows atrophy of thymus

and controlls differentiation and activity of some cells in the immune system eg. neutrophils) and many others.

• increased rate of oxidative stress• increased risk of cardiac mortality (cholesterol, free

radicals etc.)

GH - youth hormone?

• GH may reverse biological effects of aging

• GH is not recommended for common use in adults

• GH supplementation:- GHD- AIDS wasting syndrome- short bowel syndrome

OtherOther hormoneshormones ofof anterioranterior pituitarypituitary: : ACTH, TSH, FSH, LHACTH, TSH, FSH, LH, PRL, PRL

ACTHACTH -- adrenocorticotropinadrenocorticotropinregulatesregulates adrenocorticaladrenocortical functionfunction

• It strongly stimulates cortisol production of adrenal cortex

• it also stimulates the production of other adrenocortical hormones

• ACTH also exhibits some extraadrenal effects - it has a pigmenting action (MSH activity)

• CRH, ACTHACTH and cortisol secretion exhibit circadian rhythm (high in the early morning, low in the late evening)

TSHTSH stimulatesstimulates thethe thyroidthyroid glandglandfoliclesfolicles::

• it increases the rate of thyroglobulinthyroglobulin synthesissynthesis

• it increases the uptake of iodide ionsuptake of iodide ions from the blood by thyroid cells

• it activates all of the chemical processes that cause T4 T4 production and releaseproduction and release by the thyroid gland

• the rate of TSH secretion by anterior pituitary is controlled mainly by the negative feedback effect of T4

With the sounding of the alarm, the hypothalamushypothalamus secretes the special GnRHGnRH hormone.This hormone sends a command to the pituitary glandpituitary gland to secrete two hormones, the Follicle Stimulating Hormone (FSHFSH) and the Luteinizing Hormone (LHLH).

Because of the "hidden" clock, the brain's hypothalamus area "understands" when a person's adolescence has started

Pituitary Pituitary gonadotropinsgonadotropins

FSHFSH functionsfunctions::

•• FSHFSH stimulates early growth of the ovarian follicle

•• FSHFSH stimulates spermatogenesis

LHLH functionsfunctions::

•• LHLH stimulates ovulation and luteinization

•• LHLH stimulates testosterone secretion

ProlactinProlactin

HypothalamusHypothalamus

Prolactin Oxytocin

Anteriorpituitary

Posteriorpituitary

Alveolus

Ductalsystem

Milk synthesisMilk synthesisin alveoliin alveoli

Milk secretion from alveoliMilk secretion from alveoliinto into ductal ductal systemsystem

ProlactinProlactin ↑milk synthesis andsecretion into alveoli

Birth ↓ Prolactin, ↑ neural

control (breast mechanorec.)

SucklingSuckling Hypothal. ↑Prolactin 1 hr ↑Milk production

Effect weakens over months

ADHADH and oxytocinand oxytocin-- pposterior pituitary hormonesosterior pituitary hormones

HormonesHormones ofof tthe posterior he posterior pituitary glandpituitary gland

•• OxytocicOxytocic hormonehormone::- it causes contraction especially of the uterus

and to a lesser degree other smooth muscles of the body

- it stimulates myoepitelialmyoepitelial cellscells in the breastcausing milk ejection

- it also participates in the process of sperm ejection

HypothalamusHypothalamus

Prolactin Oxytocin

Anteriorpituitary

Posteriorpituitary

Alveolus

Ductalsystem

Milk synthesisMilk synthesisin alveoliin alveoli

Milk secretion from alveoliMilk secretion from alveoliinto into ductal ductal systemsystem

Suckling, baby sounds

hypothal ↑oxytocin(paraventricular nucleus)↑myoepithel.

contract milk let-down

RegulationRegulation ofof oxytocinoxytocin secretionsecretion((paraventricularparaventricular nucleusnucleus):):

• suckling via stimulation of touch receptors in breast

• distension of female genital tract (duringlabour)

• pain

• psychological stimuli (baby’s cry, orgasm)

HormonesHormones ofof tthe posterior he posterior pituitary glandpituitary gland

•• AntidiureticAntidiuretic hormonehormone (ADH(ADH; ; vasopressinvasopressin))::- increases the permeability of the kidney

collecting ducts and tubules to water

- it allows the water to be reabsorbed, thereby conserving water in the body

- it has also vasoconstrictor and pressoreffects (higher concentrations of ADH cause an increase in arterial blood pressure by vasoconstriction)

There are special sensors in the hypothalamus area of the brain called osmoreceptorsosmoreceptors.. These sensors measure the amount of fluid in your blood at every moment you are alive. If they determine that the amount of fluid in the blood has fallen, they immediately react and stimulate supraoptic nucleussupraoptic nucleus.

RegulationRegulation ofof ADHADH productionproduction::

OOsmoticsmotic regulationregulation

- when the ECF becomes too concentrated, fluid is pulled by osmosis out of the osmoreceptors, decreasing their size and initiating signals in the hypothalamus to cause additional ADH secretion

Regulation ofRegulation of ADHADH productionproduction::

•• HemodynamicHemodynamic regulationregulation: changes in blood volume and blood pressure affect vasopressin secretion via baroreceptors. However,stimulation of ADH release requires more than10% blood volume decrease.

•• Other stimulatorsOther stimulators for ADH secretion include:angiotensin II, nicotine, pain, increased temperature, and some emotions

•• AlcoholAlcohol strongly inhibitsinhibits ADH release

Regulation of Regulation of ADH ADH secretionsecretion

Adrenal glandsAdrenal glands

Adrenalgland

Capsule

Medulla

Zona glomerulosa

Zonafasciculata

Zonareticularis

Cortex

Location of adrenal glandsadrenal glands

• the outer cortex cortex (80%) releases steroidssteroids;

• the inner medulla medulla (20%) releases catecholaminescatecholamines

TheThe adrenaladrenal cortexcortex –– three zonesthree zones

AdrenalAdrenal gland secretiongland secretion•• AdrenalAdrenal cortexcortex secretssecrets::- corticosterone (all 3 cortical zones)- cortisol ( z. fasciculata) - aldosterone (z. glomerulosa)- sex hormones ( z. reticularis)

•• AdrenalAdrenal medullamedulla secretssecrets::- catecholamines (epinephrine, norepinephrine,

dopamine)

hormone (CRH)

(z. fasciculata)

Brain

NE and E

Blood Variouseffectororgans

NE

Heart

Spinal cord

Adrenalglands Medulla

PreganglionicSympathetic neurons

Sympatheticganglia

Postganglionic sympatheticneuron

The anatomical analogy between cells of The anatomical analogy between cells of adrenal medulla and sympathetic adrenal medulla and sympathetic

postganglionic neuronspostganglionic neurons• Postganglionic fiber has effectson one specific effector organ,such as the heart.•• The cells of The cells of adrenal medullaadrenal medullamay influence the activity of various organs in the body (they secrete hormones to the circulation)

Adrenal catecholaminesAdrenal catecholamines

The release of AK is carried out by direct connection of nerve fibers from

hypothalamus to intermediolateral cells(IML), and then to adrenal medulla

Tyrosine

DOPA

Dopamine

Norepinephrine

PNMT

Epinephrine

Tyrosinehydroxylase

Chromaffin cells secrete epinephrine into the blood, instead of NE at a synapse.

Tyrosine DOPA DA NENE (hydroxylation and decarboxylation of Tyrosine)PNMTPNMT (cortisol elevates) EPI EPI (methylation of norepinephrine)

TheThe effecteffect ofof catecholaminescatecholamines ononheartheart andand circulationcirculation::

•• NOREPINEPHRINENOREPINEPHRINE• via receptors -

vasoconstriction,• causes increase in

systolic and diastolic blood pressure, reflex bradycardia and decrease in cardiac output per minute

•• EPINEPHRINEEPINEPHRINE• via receptors -

vasoconstriction,• via receptors -

vasodilation• widening of the pulse

pressure, and increase of HR and cardiac output perminute;

Circulatory effects of catecholaminescatecholamines

TheThe metabolicmetabolic effectseffects ofofcatecholaminescatecholamines:

• increase in glycogenolysis• increase in gluconeogenesis• increase in secretion of glucagon• inhibition of insulin secretion (via receptors)• increase in lipolysis• increase in metabolic rate and calorigenic effect

blood blood glucoseglucose

The effects of catecholamines on smoothsmooth musclesmuscles andand sphincterssphincters:

•• EpinephrineEpinephrine::• causes dilation of

the airway, gasrtointestinaltract and urinary bladder

•• EpinephrineEpinephrine::• provokes

constriction of gastric and urinary bladder sphincters

FunctionFunction ofof dopaminedopamine::

• vasodilation in the mesentery and kidneys• vasoconstriction (by releasing norepinephrine?)

elsewhere• positively inotropic effect on the heart (by 1 r-ors)• increase in systolic pressure and no change in no change in

diastolic pressurediastolic pressure

Regulation of adrenal Regulation of adrenal medullarymedullarysecretionsecretion

• The major stimulus for catecholamine release from adrenal medulla is sympathetic nervous sympathetic nervous system activationsystem activation

• Stress, change in posture, low blood sugar or sodium levels are the factors that activate the sympathetic nervous system

• hemorrhagehemorrhageepinephrineepinephrine

•• exerciseexercisenorepinephrinenorepinephrine

The Fight or Flight System

Adrenergic responsesAdrenergic responses of selected tissues

Increased inotropyIncreased chronotropyVasoconstrictionVasodilationIncreased renin releaseDecreased motilityIncreased sphincter toneDecreased insulin releaseIncreased glucagon releaseIncreased insulin and glucagon releaseIncreased glycogenolysisIncreased lipolysisIncreased sweatingBronchodilationContraction, relaxation

Beta-1

AlphaBeta-2BetaAlpha, beta

Alpha

Beta

Alpha, betaBetaAlphaBeta-2Alpha, beta

Heart

Blood vessels

KidneyGut

Pancreas

LiverAdipose tissueSkinBronchiolesUterus

EffectReceptorOrgan

Liver

Lactate

Glycogenolysis

Muscle

Blood

Lactate

Glycogenolysis

Glucose

Glycerol

Lipolysis

Adiposetissue

Glucose

Fatty acids

EPIEPI raises glycogenolysis in liver/muscle and lipolysis in adipose; elevates blood glucose

Effects of epinephrine

PPheochromocytomaheochromocytoma • High blood pressure• Other paroxysmal

symptoms are usually nonexistent, unless the person experiences pressure from the tumor, emotional stress, changes in posture, or is taking beta-blocker drugs for a heart disorder

- rapid pulse, palpitations - headache- nausea, vomiting- clammy skin; sweating

Adrenal steroidsAdrenal steroids

(c) 2003 Brooks/Cole - Thomson Learning

Cholesterol

Pregnenolone

Progesterone 17-OH-Pregnenolone

Dehydroepi-androsterone

Corticosterone

Aldosterone Cortisol

17-OH-Progesterone Testosterone

Estradiol

Adrenal hormones are derivatives Adrenal hormones are derivatives ofof cholesterolcholesterol

Cortisol(glucocorticoid)

Aldosterone(mineralocorticoid)

Dehydroepiandrosterone(androgen)

- Cortisol (glucocorticoid),

- Aldosterone (mineralocorticoid)

- DHEA (androgen, minor male)

Three steroids are the primary Three steroids are the primary products of theproducts of the adrenal cortexadrenal cortex:

Dehydroepiandrosterone

17-OH-Pregnenolone

Pregnenolone

Cholesterol

Cortisol

17-OH-Progesterone

17-OH-Pregnenolone

Pregnenolone

Cholesterol

Aldosterone

Cholesterol

Pregnenolone

Progesterone

Corticosterone

Zona glomerulosaZona glomerulosa

Zona fasciculataZona fasciculata

Zona reticularisZona reticularis

• Cells take up and store cholesterol;

• Each cell makes steroids according to the enzymes it has.

GlucocorticoidsGlucocorticoidsCortisol

Circadianrhythms Stress

CRH

Hypothalamus

Anteriorpituitary

ACTH

Cortisol

Adrenalcortex

Corticotropes in hypothalamus

CRHCRH portal pituitary ACTHACTH adrenal cortex cortisolcortisol

HypothalamicHypothalamic ––pituitary adrenal axispituitary adrenal axis

Midnight AMTime of Day PM

Sleep

Plas

ma

Cor

tisol

Con

cent

ratio

n(a

rbitr

ary

unit)

CRH, ACTH, CRH, ACTH, cortisolcortisol show circadian sleepshow circadian sleep--wake rhythm, with peak at awakeningwake rhythm, with peak at awakening

Types of stress knownto increase cortisol secretion:

Physical stressPhysical stress

- Hypoglycemia

- Trauma

- Heavy exercise

Psychological stressPsychological stress

- Acute anxiety (e.g.novel situations, exams,airplane flight)

- Chronic anxiety

In times of danger, the body goes into a state of alarm by means of a link between the brain and the adrenal glands

ResistanceResistance to to stressstress

• When the human is exposed to the stressor the secretion of ACTHACTH rises and consequently the level of glucocorticoids is elevated. This is essential for survival.

• The stressors also activate the sympathetic nervoussympathetic nervoussystemsystem and the permissive effect of glucocorticoids on vascular reactivity to catecholamines is observed.

•• GlucocorticoidsGlucocorticoids are also necessary for the catecholaminescatecholamines to facilitate their full FFA-mobilizing action (FFA are an important emergency energy supply).

• The high glucocorticoids levels caused by stress are life-saving only in the short term but over longer periods they are harmful.

Describe changes in human body that occur during stress

EffectsEffects ofof cortisol cortisol onon carbohydratescarbohydrates::

1. Stimulation of gluconeogenesis

2. Decreased glucose utilization by the cells

3. Elevated blood glucose level and adrenal diabetes

Plasma Liver

Cortisol

Urea

UreacycleAmino

acids

GlucoseGlucose

Ammonia

Gluconeogenesis

Amino acidmetabolizing

enzymes

Glycogensynthesis

Cortisol accelerates liver urea cycle and

amino acid conversionto glucoseglucose

The effects of cortisol on liver metabolism

EffectEffect ofof cortisolcortisol onon pproteinroteinmetabolismmetabolism:

• reduction in cellular protein

•• increase of liver and plasma protein levelincrease of liver and plasma protein level

• increase of blood aa transport into the liver

• decrease of blood aa transport into the extrahepatic cells

• gluconeogenesis (formation of carbohydrates from proteins)

Plasma

Cortisol

Aminoacids

Cortisol

Muscleprotein

The effects of cortisol on skeletal

muscle

EffectEffect ofof cortisolcortisol onon fatfatmetabolismmetabolism::

• increased mobilization of fatty acids• increased oxidation of FA in the cells• ketogenic effect• obesity – increased

fat around neck („buffalo„buffalo--torso”torso”) and round face(„moon face„moon face”)

AntiinflammatoryAntiinflammatory effects ofeffects ofcortisolcortisol::

• stabilization of the lysosomal membranes

• decrease in permeability of the capilaries

• lowering of fever

• supression of the immune system (T-lymphocytes)

• inhibition of mast cells releasing histamine

Cortisol lowers the temperature by inhibiting the production of IL-1, which activates the temperature center

EffetsEffets ofof cortisolcortisol onon bloodblood cellscells:

•• inincreasecreasess the number of circulating neutrophilsneutrophils, platelets and red blood cells, platelets and red blood cells

• decreaes the number of other blood cells

SummarySummary ofof effectseffects ofof cortisolcortisolon on metabolismmetabolism::

LIVER:LIVER: gluconeogenesis, andglycogen synthesis

SKELETAL MUSCLE:SKELETAL MUSCLE: protein synthesis; protein degradation; glucose uptake;

ADIPOSE TISSUEADIPOSE TISSUE:: glucose uptake; lipid mobilization

What type of side effects may What type of side effects may be be related related with glucocorticoid administrationwith glucocorticoid administration??

CushingCushings syndromes syndrome –– long lasting long lasting increase in plasma corticoidsincrease in plasma corticoids

CushingCushings syndromes syndrome is the result ofis the result of::

• Administration of exogenous hormones

• Adrenocortical tumors• Hypersecretion of ACTH• Ectopic secretion of ACTH

CushingCushings syndromes syndrome• skin and subdermal tissues are thin, and muscles

are poorly developed• wounds heal poorly and minor trauma causes

bruises and ecchymoses• very severe osteoporosis • facial hair and acne• obesity with „buffalo torso” and „moon face”• adrenal diabetes• 80% of patients have

hypertension• mental symptoms and

sleep disorders• reduced sex drive and

fertility in man• irregular or stopped

menstrual cycles in women

Explain following symptoms in Explain following symptoms in Cushing’s syndromeCushing’s syndrome::

• Lack of menses in women; infertility in men

• Excess body hair in women and acne• Hypertension

OObesity with besity with „„buffalo torsobuffalo torso””

AcneAcne

CushingCushing ssyndromeyndrome

Mineralocorticoids Mineralocorticoids Aldosterone(z. glomerulosa)

If the aldosterone of ten million people were pooled together, only one gram of the hormone would result.

Effects ofEffects of mineralocorticoidsmineralocorticoids::

• They cause Na+ to be conserved in the ECF, while more K+ and H+ is excreted into the urine

• They also increase the reabsorption of Na+ and the secretion of K+ by the ducts of salivary and sweat glands

• Excessive amounts of aldosterone will cause: hypokalemia, muscle weakness and mild alkalosis

Cells in the kidney channels (collecting

tubule)

Liver

Lung

Angiotensin-convertingEnzyme (ACE)

ReninKidney

Angiotensinogen

Angiotensin I

Angiotensin II

Aldosterone

Zonaglomerulosa

cells

Mineralocorticoids

– RAARAA systemsystem

Decreased kidney blood pressure ( ECF) renin convertsangiotensinogen to angiotensin I. Lung ACE converts angiotensin I to II angiotensin II stimulates aldosterone release.

Aldosterone causesNa+ and H2Oretention, increase in ECF and finally inhibition of the primary stimuli

HyperaldosteronismHyperaldosteronism-- Conn’s syndromeConn’s syndrome

ECF, edema, alkalosis,hypertension, K+

depletion

Adrenals responding to low ECF

Edematous states, CHF, ascites, nephrosis

Secondary

ECF, alkalosis, hypertension, K+

depletion

Problem within adrenals

Adrenal tumor or adrenal hyperplasia

Primary (Conn’s syndrome)

EffectsSourceCauseType

Remember! Think about Conn’s Conn’s syndromesyndrome if your patient has

hypertension and very low K+ level

Adrenal androgensAdrenal androgens

Effects of adrenalEffects of adrenal androgens and androgens and estrogenesestrogenes

• Androgens are the hormones responsible for masculinizationmasculinization, and they also promote protein anabolism protein anabolism and growthand growth

• They cause epiphyses to fuse in the long bones, thus eventually stopping growth

• They slightly increase NaNa++, K, K++, H, H22O, O, CaCa++++, , sulfatesulfate and phosphateand phosphate retention and they increase the size of the kidneys.

The androgenital syndromeThe androgenital syndrome::

• typical masculine characteristics:

• much deeper voice• occasionally baldness• masculine distribution

of hair on the body• masculine features •• ssaltalt loosingloosing formform and

hypertensivehypertensive formform

Deficiency of 2121--betabetahydroxylasehydroxylase (salt loosing form)

Deficiency of 1111--beta beta hydroxylasehydroxylase– hypertensive form

Androgeniatal Androgeniatal syndromesyndrome

TheThe androgenital androgenital syndromesyndrome::

• Genitals of female babymasculinized by prenatal hypersecretion of adrenal androgens

Adrenal insufficiencyAdrenal insufficiency

Loss of glucocorticoid and mineralocorticoid action –

predict the typical findings

Addison's diseaseAddison's disease• Low plasma Na+, high

plasma K+

• inability to produce concentrated urine by the kidneys excessive urination

• Vomiting, loss of appetite, anorexia,dehydration

• Low blood pressure• Muscle weakness, fatigue• Low blood sugar• Excess pigmentation of

skin in some patients

The lack of all The lack of all adrenocorticoidsadrenocorticoids- Addison's diseaseAddison's disease

Weakness, fatigue, anorexia, hypotension, weight loss, hyperpigmentation (only in primary Addison’s), fasting hypoglycemia

Problem in adrenals

Problem in hypothalamic-pituitary axis

Idiopathic, infection, surgery, cancer

Hypothalamic-pituitary disease, Hypothalamic-pituitary inhibition(iatrogenic, ectopic steroids)

Corticoids ACTH

Corticoids ACTH

Primary

Secondary

EffectsSourceCausesHormone profile

Type