MR & GR MR & GR

AdrenalsAdrenals-- TheThe firstfirst descriptiondescription ofof adrenalsadrenals originsorigins from from thethe yearyear 1563. 1563. ItIt isis an illustration donean illustration done by by Bartolomeo EustachioBartolomeo Eustachio ””GGlandulae Renibus landulae Renibus IIncumentesncumentes”” ((published in published in 1714) 1714) ..

-- In In 1849 1849 Thomas AddisonThomas Addison publishedpublished thethedescriptiondescription ofof lethallethal effectseffects ofof adrenal failureadrenal failure,,which began the which began the modernmodern researchresearch ofof adrenaladrenalcortexcortex physiologyphysiology..

-- Till theTill the halfhalf ofof XX XX centurycentury most most experimentsexperimentson on adrenaladrenal cortexcortex focusedfocused on on carbohydratescarbohydrates andandglucocorticoidsglucocorticoids..

-- GluGlucocrticoids were regarded cocrticoids were regarded as as compounds of compounds of both glucocorticoid and mineralocorticoid both glucocorticoid and mineralocorticoid activitiesactivities. .

Aldosterone and cortisol synthesis

AldosteroneAldosterone is at 1000 fold is at 1000 fold lowerlower concentrations than concentrations than cortisolcortisol

-- AldosteronAldosterone e was was isolated inisolated in 1953 (21 mg 1953 (21 mg aldosteronaldosteronee fromfrom 500 kg 500 kg of bovine adrenalsof bovine adrenals), a ), a year later its stucture year later its stucture was was characterizedcharacterized..

-- Most Most aldosteronealdosterone isis synthetizedsynthetized inin adrenaladrenal cortexcortex, , inin zona glomerulosazona glomerulosa..

-- AldosteronAldosterone is also produced in other tissuese is also produced in other tissues, e.g. , e.g. in the heartin the heart, , blood vessels and brainblood vessels and brain..

-- In In thethe bloodblood onlyonly ~50% ~50% aldosteronealdosterone isis boundbound to to transportingtransporting proteinsproteins ((mostly albuminsmostly albumins) ) ((cortisolcortisol: 90: 90--95% 95% isis boundbound to to proteinsproteins).).

-- HalfHalf--lifelife timetime inin thethe bloodblood for for aldosteronealdosterone isis ~20 ~20 minutesminutes ((cortisolcortisol: ~70 : ~70 minutesminutes). ).

-- 90% 90% alalddosteronosteronee isis removedremoved afterafter single single passingpassing throughthrough thethe liverliver ((herehere aldosterone is aldosterone is bound bound to to glucoronideglucoronide acidacid, , whichwhich increasesincreases itsits waterwater sulubilitysulubility andand facilitatesfacilitates itsits removalremovalwith thewith the urineurine; ; similarlysimilarly inin thethe casecase ofof cortisolecortisole))

Aldosterone in the bloodAldosterone in the blood

Overproduction of aldosteroneOverproduction of aldosterone –– ConnConn’’s s diseasedisease((described indescribed in 1955 by J.W.1955 by J.W. ConnConn; ; it fact it it fact it was was first described first described by M. by M. LityLityńński in ski in 1953, but 1953, but he he

published it in the polish journalpublished it in the polish journal))

CauseCause::

-- MostlyMostly tumorstumors developingdeveloping fromfrom adrenaladrenal cortexcortex cellscells ((adrenaladrenal adenomaadenoma), ), usually at the usually at the age age 3030--50. 50. It can It can be be also caused also caused by by adrenal hyperplasiaadrenal hyperplasia..

SymptomsSymptoms::

•• Strong hypertensionStrong hypertension,,•• HHypoypoccalemiaalemia, , •• AlcalosisAlcalosis, , •• LightLight hypernatremiahypernatremia,,•• PolyuriaPolyuria,,•• TirednessTiredness,,•• WeaknessWeakness ofof musclesmuscles..

adrenal hyperplasiaadrenal hyperplasia

normal adrenalsnormal adrenals

Schematic structure of the human Schematic structure of the human MR MR and and GRGR

Variable proportions of aldosterone Variable proportions of aldosterone (MR) (MR) and glucocorticoid and glucocorticoid (GR) (GR) binding binding sites among human tissuessites among human tissues

Mineralocorticosteroid Mineralocorticosteroid receptorreceptor ((MRMR))-- MR MR was was cloned in cloned in 1987.1987.

-- TheThe MRMR gene consists ofgene consists of 1010 exonsexons. . It has two exonsIt has two exons 1 (1 (exonexon 11αα and exonand exon 11ββ),), each with each with an alternative promoteran alternative promoter. . HoweverHowever,, the finally translatedthe finally translated MR proteinMR protein is theis the same.same.

Mineralocorticosteroid Mineralocorticosteroid receptorreceptor ((MRMR))-- Major lMajor ligandigands s of of MR:MR:

* * aldosteronaldosteronee –– major MRmajor MR ligand exerting physiological effectsligand exerting physiological effects..

* * cortisolcortisol –– hashas higherhigher affinityaffinity to Mto MR R thanthan aldosteronaldosteronee,, but but in in major major target tissues target tissues for for aldosterone aldosterone (e.g. (e.g. in kidneysin kidneys) ) enzymeenzyme 1111ββ--hydroxysteroid dehydrogenase hydroxysteroid dehydrogenase ((1111ββ--HSDHSD2) 2) metabolizesmetabolizes cortisolcortisol to to cortisonecortisone, , whichwhich doesdoes not not bindbind to MR. In to MR. In the case of defect orthe case of defect ordeficiencydeficiency ofof thisthis enzyme cortisol startsenzyme cortisol starts to to actact as aas a mineralocorticoidmineralocorticoid. .

RXRRXR

-- RegulaRegulation of ligand selectivity tion of ligand selectivity for MR for MR does does not not occur at the occur at the receptor receptor levellevel, but , but at the at the level of level of 1111ββ--HSDHSD22 activityactivity ((epitheliumepithelium inin kidneykidney tubulestubules, , bladderbladder, , gastrointestinal tractgastrointestinal tract, , salivasaliva glandsglands, , sweat glandssweat glands, , vascularvascular smoothsmooth musclemuscle cellscells andand endotheliumendothelium)) only only aldosteronealdosterone may may activate activate MRMR. In . In thethe brainbrain andand miocytesmiocytes, , whichwhich do not do not expressexpress 1111ββ--HSDHSD22–– the the major major MR MR activator is cortisolactivator is cortisol..

Activity of Activity of aldosteronaldosteronee

-- Major Major task task for for aldosterone is aldosterone is to to safesafe water and sodium water and sodium as as well well as as mainain the mainain the appropriate volume of extracellular fluids appropriate volume of extracellular fluids ((volume of primary urine reachesvolume of primary urine reaches ~170 L/~170 L/day day and and ~1.5 kg ~1.5 kg of of salt...).salt...).

-- Major Major target site target site for for aldosterone are aldosterone are kidneys and their distal and collecting tubuleskidneys and their distal and collecting tubules, , where aldosterone increases thewhere aldosterone increases the resorption of resorption of Na+, Na+, decreasing removal of decreasing removal of Na+ Na+ withwithurineurine. On . On thethe otherother handhand, , itit increasesincreases removalremoval ofof K+ K+ andand H+, H+, becausebecause Na+ Na+ ionsions areareexchangedexchanged to K+ to K+ andand H+.H+.

-- AAldosteronldosteronee increasesincreases thethe volumevolume ofof extracellularextracellular fluidsfluids andand increasesincreases bloodblood pressurepressure. .

-- AAldosteronldosterone decreases the loss of sodium with sweat and salivae decreases the loss of sodium with sweat and saliva..

E.g. E.g. if in responseif in response to to training someone starts training someone starts to to sweatsweat, , the first perspirate contains the first perspirate contains a lot a lot of of sodiumsodium. . HoweverHowever, , decrease in volume of extracellular decrease in volume of extracellular fluid fluid leads leads to to increased synthesis of increased synthesis of aldosterone and decreased loss of sodiumaldosterone and decreased loss of sodium. . The sweat becomes in practice sodiumThe sweat becomes in practice sodium--freefree((thusthus, , drinking the drinking the ””balancedbalanced”” or or ””isotonic drinksisotonic drinks”” is usually uselessis usually useless). ).

Sodium absorption Sodium absorption by by the renal tubular the renal tubular systemsystemaldosterone actions

Regulation of sodium Regulation of sodium absorptionabsorption

-- Aldosterone bindsAldosterone binds toto thethe MR; MR;

-- Activation ofActivation of MRMR leadsleads to to increased expression of Sgkincreased expression of Sgk--1, 1, which phosphorylates which phosphorylates Nedd4Nedd4--2. 2.

-- PhosphorylatedPhosphorylated Nedd4Nedd4--2 no2 nolonger interacts with internalised longer interacts with internalised the ENaCthe ENaC,, leadingleading to to increased increased expression of ENaCexpression of ENaC at the apical at the apical membranemembrane. .

-- Activation of Activation of MR MR also leadsalso leads totoincreased expression ofincreased expression of Na+/K+Na+/K+--ATPaseATPase, , thus causingthus causing a neta netincrease in sodium uptake from increase in sodium uptake from the renal filtratethe renal filtrate. .

apical basal

ENaC

Nedd4-2

SgkGR

MR

Na/K-ATPaseNa/K-ATPase

cortisol

aldosterone

cortisone

11βHSD2

Na+

Na+

K+

-- ConcentrationConcentration of aldosteroneof aldosterone decreasesdecreases inin responseresponse to to increseincrese inin thethe volumevolume ofof extracellularextracellular fluid.fluid.

I.I. HyperHypervvolemiaolemia isis checkedchecked inin atrium atrium ofof thethe heartheart, , whichwhichreleasesreleases atrialatrial natriureticnatriuretic peptidepeptide (ANP) (ANP) inin responseresponse to to atrialatrial dystensiondystension.. ANP ANP bindsbinds to to thethe receptorsreceptors inin zona zona glomerulosaglomerulosa andand decreasesdecreases thethe synthesissynthesis ofof aldosteronealdosterone..

Regulation of aldosterone actionRegulation of aldosterone action

II.II. HyperHypervolemia is also checked in volemia is also checked in juxtaglomerular juxtaglomerular apparatusapparatus (JGA)(JGA) inin thethe kidneykidney.. In In response response to to hypervolemiahypervolemia the production of the production of reninrenin decreases leading decreases leading to to reduced synthesis of reduced synthesis of angiotensinangiotensin--II (II (AngIIAngII)) and decreased and decreased synthesis of aldosteronesynthesis of aldosterone. . Even small changes in AngII leadEven small changes in AngII leadtoto strong reponses in the aldosterone levelstrong reponses in the aldosterone level..

* * Silent KillerSilent Killer –– harmfulharmfulcomplicationscomplications,,

** causescauses dizziness, headache, dizziness, headache, and visual difficulties,and visual difficulties,

* L* Leadingeading risk factor risk factor inincardiovascular diseasescardiovascular diseases

* * Number one reason for Number one reason for drug prescription.drug prescription.

* * 25% of population25% of population; ; among among themthem:: ~~35% aware35% aware,, ~~5% ..!5% ..!

HypertensionHypertension

NormalNormal: : 120/80 +/120/80 +/-- 10/510/5

Mild + 20, Moderate +40Mild + 20, Moderate +40,, Severe +80Severe +80; ; Malignant Malignant -- > 210/120> 210/120

Consequences of Hypertension:Consequences of Hypertension:

CardiovascularCardiovascular system:system:

Hypertensive cardiomyopathyHypertensive cardiomyopathy AtherosclerosisAtherosclerosis

Consequences of Hypertension:Consequences of Hypertension:Brain:Brain:

HaemorrhageHaemorrhageStrokeStroke ((infarctioninfarction))

Consequences of Hypertension:Consequences of Hypertension:

EyeEye::

Hypertensive Hypertensive retinopathyretinopathy

-- HighHigh concentrationsconcentrations ofof aldosteronealdosterone, , especiallyespecially combinedcombined with with a a highhigh--salt diet salt diet leadsleadstoto cardiac fibrosiscardiac fibrosis. .

-- ThisThis effecteffect inin inhibitedinhibited by by spironolaspironolacctontonee lublub eplerenoneeplerenone –– MR MR antagonistsantagonists..

-- AldosteronAldosterone e in the heart may lead in the heart may lead to to necrosis of cadiomyocytes and activation of necrosis of cadiomyocytes and activation of macrophagesmacrophages..

-- Fibrosis is possibleFibrosis is possible aa secondary repairsecondary repairprocessprocess. .

-- The primary cause of injury is inflamThe primary cause of injury is inflam--mation and necrosis of cardiomyocytesmation and necrosis of cardiomyocytes. .

Aldosterone in the heartAldosterone in the heart

eplerenone

Rocha et al.Rocha et al. AmAm J J Physiol Heart Circ PhysiolPhysiol Heart Circ Physiol, 2002, 2002

Inflammatory infiltrateInflammatory infiltrate Healthy myocardiumHealthy myocardium

Rocha et al.Rocha et al. AmAm J J Physiol Heart Circ PhysiolPhysiol Heart Circ Physiol, 2002, 2002

Rat Rat heartheart

RALES RALES trialtrial(1600 (1600 patients patients

with severe heart failurewith severe heart failure))

SpironolactoneSpironolactonecompetitively antagonizes competitively antagonizes aldosterone bindingaldosterone binding butbut may may cause endocrine cause endocrine disturbances disturbances as aas a result of result of its nonselective binding its nonselective binding affinityaffinityforfor progesterone andprogesterone andandrogenandrogen receptorsreceptors..

-- corticosterids arecorticosterids are notnot storedstored, , butbut are always synthetisedare always synthetised dede novo fromnovo from cholesterolcholesterol

-- level of circulatinglevel of circulating corticosterids is the highest in the morningcorticosterids is the highest in the morning,,

-- circulatingcirculating corticosterids are associated with transcortinecorticosterids are associated with transcortine ((cortisol bindingcortisol binding globulin, globulin, CBG, CBG, αα22--globulinglobulin glycoproteinglycoprotein, 75, 75--80%) i 80%) i albuminsalbumins (15%). 5(15%). 5--10% 10% is freeis free. .

CortisolCortisol

transcortinetranscortine

albuminalbumin

free cortisolfree cortisol

-- OnOn cells there are cells there are membrane receptorsmembrane receptors forfor transcortinetranscortine.. Binding the ligandsBinding the ligands ((complex complex transcortinetranscortine--cortisolcortisol)) leadsleads toto elevation of cAMP and elevation of cAMP and mediates nonmediates non--genomic effects of genomic effects of cortisolcortisol..

Hypoactivity of adrenal cortexHypoactivity of adrenal cortex –– Addison diseaseAddison disease

•• FatiqueFatique, no, no tolerancytolerancy forfor even small stresseven small stress, , •• FeverFever,,•• Insuline oversensitivityInsuline oversensitivity,,•• Fasting hFasting hypoglyypoglyccemiaemia,,•• No No apetiteapetite,,•• NuseaNusea,,•• Loss of weighLoss of weigh,,•• Anemia,Anemia,•• WeaknessWeakness,,•• Low blood pressureLow blood pressure,,•• Consuming large amounts ofConsuming large amounts of salt,salt,•• Increased number of lymphocytes and eosinophilsIncreased number of lymphocytes and eosinophils, , decreased neutrophilsdecreased neutrophils,,•• Hair lossHair loss,,•• Increased pigmentation ofIncreased pigmentation of skinskin and mucosaand mucosa ((because because of increased secretion ofof increased secretion of ACTHACTH and activation of propioand activation of propio--melanocortinemelanocortine). ).

normalnormal

hypotrophichypotrophic

CausesCauses::-- treatment with pharmacological doses of corticosteroidstreatment with pharmacological doses of corticosteroids-- overproduction ofoverproduction of ACTH (e.g. ACTH (e.g. pineal cancerpineal cancer, , hyperplasiahyperplasia ofof pinealpineal glandgland))

SymptomsSymptoms::-- abdominal obesityabdominal obesity with bull hump and round facewith bull hump and round face,,-- oosteoporosteoporosissis, , -- thinthin skinskin withwith redred striaestriae, , -- muscle weakness and atrophymuscle weakness and atrophy, , -- brushes after even weakbrushes after even weak traumatrauma,,-- hair losshair loss, , -- impaired wound healingimpaired wound healing, , -- weak responseweak response toto infectionsinfections,,-- hyperglycemia and increased neoglucogenesishyperglycemia and increased neoglucogenesis, , -- aggressiveness and depressionaggressiveness and depression-- high blood pressurehigh blood pressure

Hyperactivity of adrenal cortexHyperactivity of adrenal cortex –– Cushing syndromeCushing syndrome

••↑↑ glukoneogeneglukoneogenesissis, , ↓↓ insulininsulin sensitivitysensitivity; ; results in hyperglycemiaresults in hyperglycemia

••↑↑ lipollipolysisysis ((mostly in the extremitiesmostly in the extremities), ), ↓↓ lipogenelipogenesissis,, fat fat redredistributionistribution –– abdominal abdominal obesityobesity ((bellybelly,, corpuscorpus,, faceface))

••↓↓ proproduction of collagen typeduction of collagen type II, , ↓↓ maturition ofmaturition of osteoblastosteoblast progenitorsprogenitors, , ↓↓ calcium calcium aabsorbsorbtionbtion in intestinein intestine; ; too high level of cortisol leadstoo high level of cortisol leads toto osteoporosisosteoporosis..

in cardiovascularin cardiovascular systemsystem it contributesit contributes toto regulation of normal blood pressureregulation of normal blood pressure: : ↑↑ heart heart beatingbeating,, ↑↑ response of arteriolesresponse of arterioles toto catechloamines which increases blood pressurecatechloamines which increases blood pressure, , ↓↓production of vasodilating prostaglandinproduction of vasodilating prostaglandin, , ↓↓endothelium permeabilityendothelium permeability,, which protects which protects against edema in inflammed tissuesagainst edema in inflammed tissues..

in the kidneys it acts in in the kidneys it acts in aa opposite wayopposite way toto aldosteronealdosterone: : ↑↑ removal of water from removal of water from organismorganism, , ↓↓ secretion of vasopresinesecretion of vasopresine ((aann antantiidiuretdiuretic hormoneic hormone)) from hypothalamusfrom hypothalamus..

Cortisol activityCortisol activity

Glucocorticoid receptorsGlucocorticoid receptors

-- GR GR is commonly expressedis commonly expressed in the cells in number ofin the cells in number of 3 0003 000 -- 30 00030 000 moleculesmolecules perper cellcell..

-- GR GR without ligands are located in the cytoplasmwithout ligands are located in the cytoplasm,, where are bound withwhere are bound with Hsp90Hsp90

-- GRGR is activeis active as aas a homodimerhomodimer,, which recognize the palindromic sequencewhich recognize the palindromic sequence TGTTCTTGTTCT

-- GRGR exists in two splicing formsexists in two splicing forms::* * αα (777 (777 aminoaminoacidsacids))* * ββ (742 (742 aminoaminoacidsacids, , lack oflack of CC--terminal fragmentterminal fragment) )

-- IsoformIsoform ββ cannotcannot bind ligandsbind ligands, , although it may bindalthough it may bind

to DNAto DNA. . Possibly it may inhibit activity of glucocorticoidsPossibly it may inhibit activity of glucocorticoids. .

Effect of Effect of GC GC

(e.g. (e.g. increased transcriptionincreased transcription))

•• in pharmacological doses is usedin pharmacological doses is used asas an antiinflammatory compoundan antiinflammatory compound,, which prevents also which prevents also transplant rejectiontransplant rejection

•• induinduces lipocortineces lipocortine,, which inhibits phospholipasewhich inhibits phospholipase A2A2 producing arachidonic acidproducing arachidonic acid, a, aprecursor of prostaglandinsprecursor of prostaglandins;; thus it thus it inhibits prostaglandin synthesisinhibits prostaglandin synthesis

•• stabilistabilizes lysosomal membraneszes lysosomal membranes,, decreasing local release of proteolytic enzymes and decreasing local release of proteolytic enzymes and hialuronidase in the site of inflammationhialuronidase in the site of inflammation

•• decreases proliferation of mastocytesdecreases proliferation of mastocytes and thereby inhibits production of histamine in the and thereby inhibits production of histamine in the inflammed tissueinflammed tissue ((butbut doesdoes notnot inhibits release of histamine from existing mastocytesinhibits release of histamine from existing mastocytes))

•• decreases leukocytic infiltrationsdecreases leukocytic infiltrations,, decreasing the synthesis of chemoattractantsdecreasing the synthesis of chemoattractants,, and and decreasing the permeability of endotheliumdecreasing the permeability of endothelium

•• cortisol cortisol inhibits the expression ofinhibits the expression of e.g. e.g. ILIL--1, IL1, IL--6, IFN6, IFNγγ,, TNFTNFαα (but(but may upregulates their may upregulates their receptorsreceptors onon the target cellsthe target cells))

Cortisol and immunologicalCortisol and immunological systemsystem

Cellular effects of glucocorticosteroidsCellular effects of glucocorticosteroids

Corticosteroids and gene transcriptionCorticosteroids and gene transcription

-- The synovial joint is composed of two The synovial joint is composed of two adjacentadjacent bonybony ends each covered withends each covered with aa layer layer of cartilageof cartilage,, separatedseparated by aby a joint space and joint space and surroundedsurrounded byby the synovial membrane and the synovial membrane and joint capsulejoint capsule. .

-- The synovial membrane is normallyThe synovial membrane is normally <100 <100 μμmmthick and the synovial lining consists ofthick and the synovial lining consists of aa thinthin(1(1––33 cellscells)) layer of synoviocyteslayer of synoviocytes ((macrophage macrophage derived andderived and fibroblastfibroblast derivedderived); );

-- OnlyOnly aa fewfew,, if anyif any,, mononuclear cells are mononuclear cells are interspersed in the sublining connective tissue interspersed in the sublining connective tissue layerlayer,, which has considerable vascularitywhich has considerable vascularity.. The The synovial membrane covers all intrasynovial membrane covers all intra--articular articular structures exceptstructures except forfor cartilage and small areas cartilage and small areas of exposed bone and inserts near the cartilageof exposed bone and inserts near the cartilage––bone junctionbone junction. .

Healthy synovial jointHealthy synovial joint

-- Rheumatoid arthritisRheumatoid arthritis (RA)(RA) is characterizedis characterized byby an an inflammatory response of the synovial membrane inflammatory response of the synovial membrane conveyedconveyed by aby a transendothelial influx andtransendothelial influx and//or local or local activation ofactivation of T T cellscells, B, B cellscells,, plasma cellsplasma cells,, dendritic dendritic cellscells,, macrophagesmacrophages,, mast cellsmast cells, as, as wellwell as byas by new new vessel formationvessel formation. .

The lining layer becomes hyperplasticThe lining layer becomes hyperplastic (a (a thickness thickness ofof >20>20 cellscells)) and the synovial membrane expands and the synovial membrane expands and forms villiand forms villi. .

-- The hallmark ofThe hallmark of RARA is bone destructionis bone destruction. . The The destructive cellulardestructive cellular elementelement is the osteoclastis the osteoclast;;destruction mostly starts at the cartilagedestruction mostly starts at the cartilage––bonebone––synovial membrane junctionsynovial membrane junction.. Bone repairBone repair bybyosteoblasts usually does osteoblasts usually does notnot occur in activeoccur in active RA. RA.

-- The neutrophils' enzymesThe neutrophils' enzymes,, together with enzymes together with enzymes secretedsecreted byby synoviocytes and chondrocytessynoviocytes and chondrocytes,, leadlead totocartilage degradationcartilage degradation..

Rheumatoid arthritisRheumatoid arthritis

arthritichealthy

Rheumatoid arthritisRheumatoid arthritis

Rheumatoid Arthritis:Rheumatoid Arthritis: Key FeaturesKey Features

•• Symptoms >6 weeksSymptoms >6 weeks’’ durationduration•• Often lasts the remainder of the patientOften lasts the remainder of the patient’’s lifes life

•• Inflammatory Inflammatory synovitissynovitis•• Palpable Palpable synovialsynovial swellingswelling•• Morning stiffness >1 hour, fatigueMorning stiffness >1 hour, fatigue

•• Symmetrical and Symmetrical and polyarticularpolyarticular (>3 joints)(>3 joints)

Rheumatoid ArthritisRheumatoid Arthritis

Affects approximately 1% of the adult U.S. populationAffects approximately 1% of the adult U.S. population

Incidence increases with ageIncidence increases with age

Occurs 2Occurs 2--44 times more often in womentimes more often in women

Shortens lifespan by 3Shortens lifespan by 3--18 years 18 years (average of 10 years)(average of 10 years)

Role of Tumor Necrosis Factor in Role of Tumor Necrosis Factor in Rheumatoid ArthritisRheumatoid Arthritis

TNF

bone bone resorptionresorption

bone erosionbone erosion

joint joint inflammationinflammation

cartilage cartilage degradationdegradation

joint space joint space narrowingnarrowing

pain/joint pain/joint inflammationinflammation

Kirvan Kirvan et al. Z et al. Z RheumatolRheumatol, 2000, 2000

-- Inflammatory reaction and reversible constInflammatory reaction and reversible const--ruction ruction of musclesof muscles..

-- Oversensitivity of bronchiolesOversensitivity of bronchioles..

-- Mild and moderate asthmaMild and moderate asthma::

** infiltrainfiltrationtion of airways with lymphocytes and of airways with lymphocytes and eosinophilseosinophils** injury and lost ofinjury and lost of respiratoryrespiratory epitheliumepithelium* * degranuladegranulation of tion of mastocytmastocyteses* * accumulation of collagen under basal membranesaccumulation of collagen under basal membranes

-- InIn advanced asthmaadvanced asthma::

* * occlussion of airwaysocclussion of airways byby mucusmucus* * hyperplahyperplasiasia//hypertrophy of smooth muscle cellshypertrophy of smooth muscle cells* * hyperplahyperplasia of epithelial cellssia of epithelial cells

AsthmaAsthma

-- EoEosinophilssinophils areare oneone of theof the majormajor cells in response cells in response to to parasites ofparasites of respiratory systemrespiratory system

-- They playThey play aa crucialcrucial rolerole in pathogenesis of asthma and other allergic diseasesin pathogenesis of asthma and other allergic diseases. . InIn patients patients with asthma there are massive eosinophil infiltration in the airwith asthma there are massive eosinophil infiltration in the airwaysways..

-- Treatment with corticosteroidsTreatment with corticosteroids papatients with asthmatients with asthma decreases inflammationdecreases inflammation in airwaysin airways,,mostly throughmostly through induinduction of eosinophil apoptosisction of eosinophil apoptosis, , then eosinophiles are phagocytedthen eosinophiles are phagocyted bybymacrophages and epithelial cellsmacrophages and epithelial cells..

-- Some patients Some patients do notdo not respond respond forfor treatment with treatment with corticosteroidscorticosteroids.. It canIt can bebe associated with the presenceassociated with the presenceofof ββ splicingsplicing formform ofof GRGR

-- EoEosisinonophils isolated from patients with asthma resisphils isolated from patients with asthma resis--tanttant toto corticosteroid are also resistantcorticosteroid are also resistant toto corticosteronecorticosterone--induced apoptosisinduced apoptosis. .

EosinophilsEosinophils –– asthmaasthma-- glucocorticoidesglucocorticoides

-- InIn the case of massive apoptosis important isthe case of massive apoptosis important is aa fast phagocytosis of the dead cellsfast phagocytosis of the dead cells.. IfIf not not –– the secondary necrosis can occurthe secondary necrosis can occur.. The content of cells is released and induces The content of cells is released and induces inflammationinflammation..

-- MajorMajor cells responsiblecells responsible forfor removal of apoptotic eosinophils are macrophagesremoval of apoptotic eosinophils are macrophages..GluGlucocrticosteroids increase phagocytosis of eosinophilscocrticosteroids increase phagocytosis of eosinophils by by macrophagesmacrophages andand epithelialepithelialcellscells. .

EosinophilsEosinophils –– asthmaasthma-- glucocorticoidsglucocorticoids

phagocytosis of eosinophils phagocytosis of eosinophils by by epithelial cellepithelial cell

-- GluGlucocorticoids are the basic drugs in treatment of asthmacocorticoids are the basic drugs in treatment of asthma..

-- Currently theCurrently the majormajor way of corticosteroid applicationway of corticosteroid application is inhalationis inhalation. .

AnabolicAnabolic--androgenic steroids (AAS) androgenic steroids (AAS) AAS AAS are syntheticare synthetic derivatives of testosterone originally designed to providederivatives of testosterone originally designed to provideenhanced anabolic (tissueenhanced anabolic (tissue--building) potency with negligiblebuilding) potency with negligible androgenic androgenic ((masculinizingmasculinizing) effects. ) effects.

•• Approximately,Approximately, 60 different AAS are available that vary in their chemical60 different AAS are available that vary in their chemicalstructure and thus in their metabolic fate and physiologicalstructure and thus in their metabolic fate and physiological effects.effects.

•• Three mainThree main classes of AAS have been describedclasses of AAS have been described::

I.I. Injectable comInjectable compounds derived frompounds derived from esterificationesterification of the 17of the 17ββ--hydroxyl group of hydroxyl group of testosteronetestosterone (e.g. (e.g. testosterone propionatetestosterone propionate,, testosteronetestosterone cypionatecypionate)). . EsterificationEsterification retards retards degradation and prolongsdegradation and prolongs the duration of actionthe duration of action..

II. III. Injectablenjectable androgenandrogen esters called 19esters called 19--nornor--testosterone derivativestestosterone derivatives (e.g.(e.g. nandrolone nandrolone decanoatedecanoate)). The substitution at C19 extends the. The substitution at C19 extends the halfhalf--life.life.

III. III. OrallyOrally activeactive ccompoundsompounds thatthat are are alkylatedalkylated at C17at C17 (e.g. (e.g. 1717αα--methyltestosteronemethyltestosterone,,oxymetholoneoxymetholone, , methandrostenolonemethandrostenolone, and , and stanozololstanozolol))..

CClass I and II AASlass I and II AAS may be aromatized and act at themay be aromatized and act at the estrogen receptorestrogen receptor, whereas , whereas class III AAS are believed toclass III AAS are believed to have minimal estrogen receptor actionshave minimal estrogen receptor actions..

****

•• AAS were originally developed for the treatment ofAAS were originally developed for the treatment of hypogonadalhypogonadal dysfunction in dysfunction in men, initiation of delayedmen, initiation of delayed puberty, and growth promotionpuberty, and growth promotion . .

•• They continue to beThey continue to be used today for these treatments, as well as for therapy inused today for these treatments, as well as for therapy inchronic conditions including HIV/AIDS, severechronic conditions including HIV/AIDS, severe burns, anemia, burns, anemia, etc.etc.

•• HowHoweeverver, AAS administration is now predominantly, AAS administration is now predominantly one of abuse, and the one of abuse, and the medical benefits of low doses of AASmedical benefits of low doses of AAS stand in sharp contrast to the potential stand in sharp contrast to the potential health riskshealth risks associated with the associated with the excessive doses selfexcessive doses self--administered byadministered by athletesathletes..ASSASS are usedare used,, very often very often in concentrationsin concentrations > 40> 40 times higher than therapeutic dosestimes higher than therapeutic doses..

•• AAt that time, more than one million adultt that time, more than one million adult Americans had or were using AAS to Americans had or were using AAS to increase physicalincrease physical strength, endurance, athletic ability or muscle mass. strength, endurance, athletic ability or muscle mass.

•• RRecentecent reports highlight the factreports highlight the fact that the more insidious growth in the abuse of that the more insidious growth in the abuse of these drugs isthese drugs is not among elite athletes, but not among elite athletes, but among adolescent boys andamong adolescent boys and girlsgirls. .

•• Present estimations Present estimations in the in the USA USA are are ththee 4% of high school4% of high school students have used students have used AAS, and the greatestAAS, and the greatest increase in AAS use over the past decade has been increase in AAS use over the past decade has been reportedreported in adolescent girls.in adolescent girls.

•• AAS AAS increase aggressiveness both in men and womenincrease aggressiveness both in men and women. .

•• AAS appear to modulate neural transmissionAAS appear to modulate neural transmission both by classical both by classical ARAR--dependent changes independent changes in gene transcription and by gene transcription and by nongenomicnongenomic, , allostericallostericmodulationmodulation of specific receptors.of specific receptors.

•• ASS ASS activate activate AR AR and possibly may increase its expression and possibly may increase its expression ((some may some may possibly decrease the expression of possibly decrease the expression of PR PR or or ER).ER).•• ASS ASS change the expression ofchange the expression of GABAGABAAA receptorreceptor and allosterically modulate its and allosterically modulate its activityactivity, as, as wellwell asas the expression of enzymes responsiblethe expression of enzymes responsible forfor the synthesis of the synthesis of endogenous allosteric modulatorsendogenous allosteric modulators. .

•• The GABAThe GABAA A receptor provides the receptor provides the major mechanism for fast actingmajor mechanism for fast actinginhibition in the adult mammalian inhibition in the adult mammalian nervous system. nervous system. It isIt is tthe molecular he molecular targets of an extraordinarily diverse targets of an extraordinarily diverse range ofrange of toxins and toxins and drugs thatdrugs that includes includes anxiolytic benzodiazepinesanxiolytic benzodiazepines, sedative, sedativebarbiturates, anticonvulsants, barbiturates, anticonvulsants, convulsantsconvulsants (including a number of (including a number of insecticides), general anesthetics,insecticides), general anesthetics,ethanolethanol..

AAS AAS in menin men

-- ASSASS increasesincreases thethe levellevel ofof liverliver enzymesenzymes in the bloodin the blood((e.g.e.g. AST, ALT, AP, LDH)AST, ALT, AP, LDH)

-- ASSASS decreasesdecreases the synthesisthe synthesis ofof endogenousendogenousandrogensandrogens, , leading after longer treatment leading after longer treatment to to hypogonadism hypogonadism ((atrophy of testesatrophy of testes, , decreased decreased spermatogenesisspermatogenesis)).. These changes usually reverse after These changes usually reverse after finishing the treatmentfinishing the treatment. .

-- The second The second symptom symptom is is growth of breastsgrowth of breasts ((becausebecausethethe level of estrogenslevel of estrogens isis increasedincreased) ) andand thesethese changeschangescan can be be unreversibleunreversible. .

-- Libido Libido isis increasedincreased, but , but inin thethe same same timetime increased increased is also frequencyis also frequency ofof erectileerectile disordersdisorders..

AAS AAS in womenin womenASS ASS leadsleads to:to:

-- disturbunces of ovulation and menstrual disturbunces of ovulation and menstrual cyclecycle..-- malemale--type baldnesstype baldness, , -- decreased voicedecreased voice, , -- increasedincreased libido, libido, -- development of hair pattern typicaldevelopment of hair pattern typical forformenmen, , -- development of development of malemale--type musculaturetype musculature. .

Treatment with androgens in pregnant Treatment with androgens in pregnant women may leadwomen may lead to to pseudohermapseudoherma--froditism in childrenfroditism in children (girls)(girls) and fetal and fetal growth retardadiongrowth retardadion. .

SideSide--effectseffects ofof AAS AAS

What wouldWhat would bebe profitableprofitable toto remember in Juneremember in June::

-- Ligands Ligands for MR for MR –– why cortisol acts why cortisol acts as as mineralocorticoid only in some tissuesmineralocorticoid only in some tissues

-- Regulation of aldosterone synthesis Regulation of aldosterone synthesis –– effect effect on on hypertensionhypertension

-- antiinflammatory activities of corticosteroidsantiinflammatory activities of corticosteroids

-- differences between activity of GRdifferences between activity of GRαα and GRand GRβ β –– implications implications in therapyin therapy

SSlides canlides can bebe found in the library and at the found in the library and at the Heme OxygenaseHeme Oxygenase FanFan Club pageClub page::

https://https://biotkabiotka.mol..mol.ujuj..eduedu.pl/~.pl/~hemeoxygenasehemeoxygenase

Thank you and see you next weekThank you and see you next week