AR AR androgen androgen receptorsreceptors

TlxTlx –– Tailless orphan Tailless orphan receptorreceptor•• Tlx isTlx is aa member of the member of the taillesstailless class of orphan nuclear receptorsclass of orphan nuclear receptors, a, a highly conserved highly conserved family in both vertebrates and invertebratesfamily in both vertebrates and invertebrates..

•• The evolutionary conservationThe evolutionary conservation of the pattern of Tlx expression in the embryonic of the pattern of Tlx expression in the embryonic forebrainforebrain,, midbrainmidbrain,, and optic vesicle in vertebrates suggested that Tlx may participand optic vesicle in vertebrates suggested that Tlx may participateatein the formation of in the formation of central central nervousnervous systemsystem--derived structuresderived structures..

•• OrphanOrphan receptorreceptor that bindsthat binds DNA as a DNA as a monomermonomer..

•• In mice In mice it is requiredit is required to to brain differentiationbrain differentiation. .

•• Involved in the regulation of retinal developmentInvolved in the regulation of retinal developmentand essentialand essential for for visionvision. .

•• TLXTLX--//-- mice show:mice show:

* central * central nervousnervous systemsystem cortical defectscortical defects* * progressive retinal and optic nerve degradation with associated progressive retinal and optic nerve degradation with associated blindnessblindness.

Section through optic nervesSection through optic nerves

WT Tlx-/-

.

TlxTlx –– Tailless orphan Tailless orphan receptorreceptor

•• TLX wasTLX was initially identifiedinitially identified asas an orphan nuclearan orphan nuclear receptorreceptor expressed in vertebrate expressed in vertebrate forebrains and is forebrains and is highly expressed in the adult brainhighly expressed in the adult brain. .

•• The brains ofThe brains of TLXTLX--nullnull micemice have been reportedhave been reported toto havehave nono obvious defects during obvious defects during embryogenesisembryogenesis;; howeverhowever,, maturemature micemice suffer from retinopathiessuffer from retinopathies, , reduced copulation and reduced copulation and progressively violent behaviourprogressively violent behaviour. .

•• The finding of neurogenesis in the adult brain ledThe finding of neurogenesis in the adult brain led toto the the discovery of adult neural stem cellsdiscovery of adult neural stem cells

•• TLX TLX maintains adult neural stem cells in an undifferentiatedmaintains adult neural stem cells in an undifferentiated, , proliferative stateproliferative state. TLX. TLX--expressing cells from adult brains can expressing cells from adult brains can proliferateproliferate,, selfself--renew and differentiate into all neural cell renew and differentiate into all neural cell types types in vitroin vitro. By. By contrastcontrast, TLX, TLX--null cells from adultnull cells from adult mutant mutant brains failbrains fail toto proliferateproliferate..

•• ThusThus, TLX , TLX playsplays a role a role in adult neurogenesisin adult neurogenesis..

TLXTLX•• In In neuralneural precursors the target gene precursors the target gene for TLX for TLX is is Pax2, a protein Pax2, a protein involved in retinalinvolved in retinaldevelopmentdevelopment. .

•• Tlx isTlx is aa key component of retinal development and vision acting key component of retinal development and vision acting as as anan upstreamupstreamregulatorregulator of theof the Pax2Pax2 signalingsignaling cascadecascade. .

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Histological sections through the eye Histological sections through the eye ofof a WT a WT and Tlxand Tlx−/−−/− mousemouse showing showing disorganization of the ganglion cell disorganization of the ganglion cell layer layer (GCL)(GCL) and the inner and the inner (INL) (INL) and and outer nuclear layersouter nuclear layers (ONL) as (ONL) as wellwell asasabsence of outer plexiform and outerabsence of outer plexiform and outersegmentsegment layerslayers. .

IPL,IPL, inner plexiform layerinner plexiform layer; ; OPL,OPL, outer plexiform layerouter plexiform layer; ; OS,OS, outer segmentsouter segments;;RPE,RPE, retinal pigmented epitheliumretinal pigmented epithelium..

PAX2 PAX2 and renal colobomaand renal coloboma•• Renal coloboma syndrome isRenal coloboma syndrome is aa recently described autosomalrecently described autosomal dominantdominant disorder disorder causedcaused byby mutations in themutations in the PAX2 PAX2 genegene. .

•• The syndromeThe syndrome presents with variable abnormalities in optic nerve and renalpresents with variable abnormalities in optic nerve and renaldevelopmentdevelopment, , including optic disc dysplasiaincluding optic disc dysplasia,, optic nerveoptic nerve colobomascolobomas, , and renal and renal hypoplasiahypoplasia..

•• Renal coloboma syndromeRenal coloboma syndrome classically comprises proteinuric renal failure and classically comprises proteinuric renal failure and colobomacoloboma of the eyeof the eye. . Of all the phenotypic abnormalitiesOf all the phenotypic abnormalities associated withassociated with PAX2PAX2mutationsmutations,, bilateral optic nerve colobomasbilateral optic nerve colobomas and renal hypoplasiaand renal hypoplasia,, with or without renal with or without renal failure have thefailure have the highest frequency of occurrencehighest frequency of occurrence. .

colobomacoloboma

Morphogenetic defects in network formation and abortive proangiogenic activities in retinal astrocytes of Tlx KO mice

CD31astrocytes endothelial cellsR-cadherin on astrocytes

AndrogAndrogeennss –– generalgeneral characteristicscharacteristics

-- TheThe most most abundantlyabundantly synthetizedsynthetized ligandligand ofof androgen androgen receptorsreceptors (7 mg/(7 mg/ddayay) ) isistestosterontestosteronee. . ItIt isis producedproduced by by thethe LeydigLeydig cellscells inin responseresponse to to luteinizingluteinizing hormonehormoneproducedproduced inin thethe pinealpineal glandgland..

-- ProductionProduction ofof testosteronetestosterone changes periodicallychanges periodically ((peaks are usuallypeaks are usually 6 6 timestimes//dayday); ); thethehighesthighest levellevel isis detecteddetected inin thethe morningmorning andand earlyearly eveningevening..

EstrogensGlucocorticoids

AndrogAndrogeennss –– generalgeneral characteristicscharacteristics

-- In In thethe targettarget cellscells testosteronetestosterone isis changedchanged intointo 2 2 activeactive metabolitesmetabolites: :

* * dihydrotestosterondihydrotestosteronee (DHT)(DHT) ((enzymenzymee: 5: 5αα--redureductasectase, , expressedexpressed inin 2 2 isoformsisoforms, I i II), I i II)* estradiol* estradiol ((enzymenzymee: : aromataaromatasese))

Mouse Leydig cell in primary culture.ActinActin fibersfibers stainedstained withwith labelledlabelled--phalloidinphalloidin (red), DNA ((red), DNA (blueblue). ).

DehydrostetosteroneDehydrostetosterone

55αα--redureducctatase se deficiencydeficiency::* * ItIt maymay leadlead to to malemale pseudohermaphroditismpseudohermaphroditism, , becausebecause therethere isis impairedimpaired productionproduction ofof

DHT DHT fromfrom testosteronetestosterone ((testosteronetestosterone productionproduction isis normalnormal). ).

* * Type ofType of developmentdevelopment ((appearenceappearence, , behaviorbehavior) ) isis typicaltypical for men. for men.

High expression of High expression of 5a 5a reductasereductase* * As As thethe androgenandrogen receptors function receptors function normallynormally, , testosteronetestosterone is ableis able toto bindbind totothem and provide normal sexual functionthem and provide normal sexual functionwith adequatewith adequate libido,libido, erectile functionerectile function,, and and spermatogenesisspermatogenesis,, butbut dihydrotestosterone dihydrotestosterone production is severproduction is severeely limitedly limited in prostate in prostate and scalpand scalp,, with low circulating levelswith low circulating levels..

** TheThe affected individuals haveaffected individuals have nono facial orfacial orbodybodyhairhair, do not, do not showshow temporal hairline temporal hairline recession recession or vertex baldingor vertex balding,, havehave normal scalp hairnormal scalp hair,,aand their prostate gland remainnd their prostate gland remainss smallsmall ((thusthus,,

non-balding scalp

balding scalp

-- AR was AR was clonedcloned inin 1988. 1988. ThereThere areare isoforms ofisoforms of ARAR (98.4(98.4--100 100 kDakDa). ).

-- DifferentDifferent sizessizes ofof AR AR proteinsproteins resultresult fromfrom thethe polymorphism ofpolymorphism of glycineglycine--reachreach sequencesequence(GGC) (GGC) oror glutamineglutamine--reachreach sequencesequence (GAC) (GAC) atat thethe NN--terminusterminus. .

-- FunctionFunction ofof thesethese repetitionrepetition isis not not fullyfully recognizedrecognized, but , but elongatedelongated GAC fragment GAC fragment decreasesdecreases transcriptionaltranscriptional activityactivity ofof AR protein.AR protein.

-- NN--terminal terminal repeatsrepeats ofof GGAAC C areare shortershorter inin thethe primatesprimates phylogeneticallyphylogenetically moremore distantdistantfromfrom humanhuman.

AR AR –– androgen androgen receptorsreceptors

.

ppolyoly--GlGlyy

-- AdditionallyAdditionally, , shortershorter AR AR isoformisoform (87 (87 kDakDa) ) cancan be be producedproduced as a as a resultresult ofof start start ofoftranslationtranslation fromfrom anan internalinternal metioninemetionine, but , but thethe role role ofof thisthis protein, protein, whosewhose activityactivity inin vitrovitroisis lowlow, , isis not not characterizedcharacterized..

-- Point Point mutationmutation inin AR AR maymay resultresult inin acquiring theacquiring the sensitivitysensitivity ofof AR protein to AR protein to thethe otherotherligandsligands ((includingincluding antianti--androgensandrogens). ). TheyThey cancan leadlead to to RReifensteineifenstein syndromesyndrome (a (a hereditaryhereditaryform form androgen androgen insensitivity leading insensitivity leading to to male male pseudohermaphroditismpseudohermaphroditism, a , a condition in whichcondition in whichthe malethe male hashas testestestes but but possessespossesses bothboth male male andand femalefemale sexual characteristicssexual characteristics))

-- Point Point mutations inmutations in AR AR maymay resultresult inin development development of breastof breast cancercancer..

AR AR –– androgen androgen receptorsreceptors

GynecomastiaGynecomastia inin a a manman withwith Reifenstein'sReifenstein's syndromesyndrome

Kennedy’sKennedy’s SyndromSyndromee

-- Neurogenerative diseaseNeurogenerative disease ((describeddescribed inin 1911 by1911 by Foster Foster KennedKennedyy)) manifestedmanifested withwith::

** decreasing sensitivitydecreasing sensitivity to to androgensandrogens inin adultadult men men ** contineous weaknesscontineous weakness andand atrophyatrophy ofof musclemuscle (e.g. (e.g. facialfacial). ).

-- Symptoms result fromSymptoms result from lostlost ofof motoricmotoric neuronsneurons..

-- Disease startsDisease starts fromfrom proximalproximal musclemuscle inin thethe thirdthird to to fifthfifth decadedecade andand begins frombegins from: :

* * weakness ofweakness of facialfacial andand armarm musclesmuscles,,* * tremor oftremor of handshands, , ** increased levelincreased level ofof kreatininkreatinin kinasekinase. .

-- TheThe most most pronouncedpronounced weaknessweakness isis observedobserved inin musclesmuscles ofof face face andand tonguetongue..

Kennedy’sKennedy’s SyndromSyndromee

--TheThe reasonreason isis thethe presencepresence ofof longlong polyglutaminepolyglutamine CAG fragment CAG fragment atat NN--terminal AR. terminal AR. PerhapsPerhaps longerlonger CAG fragment CAG fragment isis associatedassociated withwith earlierearlier onsetonset ofof thethe diseasedisease, but , but itit isis not not suresure..

-- Symptoms of insensitivitySymptoms of insensitivity toto androgens areandrogens are: :

** gynegyneccomastiomastiaa, , ** atrophy of testesatrophy of testes, , ** oligosperm or azoospermoligosperm or azoosperm, , ** increased level of gonadotropinincreased level of gonadotropin** absence of sense of smellabsence of sense of smell

-- WomenWomen withwith longlong CAG fragment CAG fragment inin AR do not show AR do not show anyany clinicalclinical symtomssymtoms, but , but theythey havehavesomesome subtlesubtle neurologicalneurological changeschanges whichwhich cancan be be detecteddetected duringduring detaileddetailed examinationexamination. .

I. Development of GonadsI. Development of GonadsA.A. Males and females have identical immature gonads during first Males and females have identical immature gonads during first

month of gestation month of gestation

B.B. During 2nd month, differentiation of immature gonads is controlDuring 2nd month, differentiation of immature gonads is controlled led by presence/absence of hormones.by presence/absence of hormones.

MALES:MALES:

•• a gene on the Y chromosome (a gene on the Y chromosome (SrySry gene) causes production of testisgene) causes production of testis--determining factor (determining factor (TTdfdf) ) -- early 2nd monthearly 2nd month

•• Tdf inducesTdf induces developmentdevelopment ofof the immature gonad to become testes the immature gonad to become testes

•• in absence of in absence of TTdfdf, immature gonads become ovaries, immature gonads become ovaries

II. Development of Internal Sex OrgansII. Development of Internal Sex Organs

A.A. 2nd month 2nd month -- embryo has bisexual internal organsembryo has bisexual internal organs

In In the the same person (male or female), the precursors for both male and fsame person (male or female), the precursors for both male and female emale internal organs are presentinternal organs are present::

Tissues that can become female internal organs Tissues that can become female internal organs -- MullerianMullerian systemsystem

Tissues that can become male internal organs Tissues that can become male internal organs -- WolffianWolffian systemsystem

B.B. Whether male or female internal parts development depends on thWhether male or female internal parts development depends on the e hormonal environmenthormonal environment

II. Development of Internal Sex OrgansII. Development of Internal Sex Organs

C.C. 3rd month (fetal period3rd month (fetal period))

MALEMALE -- To develop male internal organs, testes must begin to produce To develop male internal organs, testes must begin to produce hormones and receptors must respondhormones and receptors must respond

1. 1. AntiAnti--mullerianmullerian hormonehormone –– inhibitsinhibits developmentdevelopment ofof the the MullerianMulleriansystemsystem (potentially female)(potentially female)

2. 2. AndrogensAndrogens –– induce theinduce the WolffianWolffian system to develop into internal system to develop into internal male sex organsmale sex organs

Respective roles of testosterone (T) anddihydrotestosterone (DHT) in sex differentiation

TestosteronTestosteronee –– changeschanges withwith ageage

-- LevelLevel ofof testosterone graduallytestosterone gradually decreasesdecreases withwith ageage, but , but the clinicalthe clinical significance ofsignificance of thisthisdecreasedecrease isis not not clearclear. .

-- No data No data indicatesindicates thethe correlationcorrelation betweenbetween thethe levellevel ofof testosteronetestosterone andand sexualsexualbehaviorbehavior, , unlessunless thethe changeschanges areare withinwithin thethe physiologicalphysiological rangerange. .

-- In men In men withwith healthyhealthy gonadsgonads, but , but withwitherectileerectile dysfuctionsdysfuctions, , supplementationsupplementation withwithtestosterone does testosterone does not not give any benefitsgive any benefits. . In In hypogonadal hypogonadal men men it can give the it can give the increaseincrease inin ejaculationejaculation frequencyfrequency, but , but doesdoes not not improvesimproves erectionerection itselfitself..

-- AR AR expressionexpression startsstarts to to decreasedecrease from from thethe ageage 2020--3030..

ErectionErection-- SSexualexual stimulationstimulation andand excitementexcitement causecause thethe brainbrain, , nervesnerves, , thethe heartheart, , bloodblood vesselsvessels andandhormoneshormones to to workwork togethertogether to to produceproduce a a rapidrapid increaseincrease inin thethe amountamount ofof bloodblood flowingflowingto to thethe penis.penis.

-- AAs s thethe chamberschambers rapidlyrapidly fillfill withwith bloodblood, , theythey expandexpand, , andand thethe penis penis becomesbecomes firm firm andandelongatedelongated. . TheThe resultresult isis anan erectionerection..

Nitric oxide is released from nerve endings or from endothelial cells, which stimulate cGMP production. Thissecond-messenger molecule induces smooth-muscle relaxation by reducing the calcium ion concentration, thusproducing an erection. The enzyme PDE-5 reverses this cascade of events by rapidly converting cGMP to GMP. All of the PDE-5 inhibitors (sildenafil, vardenafil, and tadalifil) work to inhibit this enzyme, therebycontinuing smooth-muscle relaxation and prolonging an erection.

Carbonmonoxide

testosteron

EpidemiologyEpidemiology

•• Decline in sexual function with ageDecline in sexual function with age

•• 1290 subjects (401290 subjects (40--7070 yrs)yrs)

•• 9.6% complete ED9.6% complete ED ((5.1% at 405.1% at 40 yrs to 15% at age 70yrs to 15% at age 70))•• 25.2%25.2% moderate EDmoderate ED•• 17.2%17.2% minimal EDminimal ED

52%52%

ErectileErectile DysfunctionDysfunction (ED)(ED)

ErectileErectile DysfunctionDysfunction (ED)(ED)ED, once thought to be ED, once thought to be psychogenicpsychogenicLater, considered Later, considered androgenicandrogenicNow, found to be predominately Now, found to be predominately vasculogenicvasculogenic

Prostate gland

-- a sex a sex glandgland inin men. men.

-- aboutabout thethe sizesize ofof a a walnutwalnut, , surroundssurrounds thethe neckneck ofof thethe bladderbladderandand urethraurethra. .

-- partlypartly muscularmuscular andand partlypartlyglandularglandular, , withwith ductsducts openingopening intointothethe prostaticprostatic portionportion ofof thethe urethraurethra. .

-- mademade upup ofof threethree lobeslobes: a center : a center lobelobe withwith one one lobelobe on on eacheach sideside. .

-- secretessecretes a a slightlyslightly alkalinealkaline fluid fluid thatthat formsforms part part ofof thethe seminalseminal fluidfluid..

SomeSome nuclearnuclear receptorsreceptors (ER, (ER, ARAR, PR) , PR) stimustimu--late expressionlate expression ofof cyclincyclin D, D, whichwhich activatesactivatesCdk4. Cdk4. ItIt leadsleads to to phosphorylationphosphorylation ofof pRBpRB, , andandincreasesincreases transcriptiontranscription of genes increasing of genes increasing proliferationproliferation..

OthersOthers receptorsreceptors (VDR, RAR) (VDR, RAR) increaseincrease p21 p21 expressionexpression, , thusthus blockblock CdkCdk activityactivity, , whichwhichkeepskeeps cellscells atat G1 G1 phasephase. .

HumanHuman prostateprostate tissuetissuestainedstained withwith androgen androgen receptor receptor antibodyantibody..

ExpressionExpression ofof androgen receptor androgen receptor inin prostateprostate

Androgens are strong Androgens are strong mitogens mitogens for for prostate prostate cellscells

Stage A

- cancer that is only found by elevated PSA and biopsy

- not palpable

- localized to the prostate.

- usually curable,

Stage B

- cancer that can be felt on rectalexamination and is limited to theprostate.

- many Stage B prostate cancersare curable.

Stage D

-- cancercancer hashas alreadyalready spreadspread, , usuallyusually to to distantdistant lymphlymph nodesnodes, , bonesbones oror otherother sitessites..

-- stagestage D D cancercancer isis not not curablecurable but but isis treatable

Stage C

- cancer has already spread beyondthe capsule of the prostate intolocal organs or tissues, but has not yet metastasized or jumped to other sites.

- some Stage C cancers arecurable.

treatable

Symptoms which may inducate Symptoms which may inducate for for prostate cancerprostate cancer::

* * InabilityInability to to completely empty the bladdercompletely empty the bladder

* * Recurrent bleeding from prostateRecurrent bleeding from prostate

** Extremaly slow urinationExtremaly slow urination

** Any changes detected Any changes detected by by physician during physician during per per rectum examinationrectum examination

** Increase in Increase in PSAPSA

ButBut

Often prostate cancers growth slowly and many menOften prostate cancers growth slowly and many men do do well without any treatmentwell without any treatment

For For older men with other serious medical problems the risk involved older men with other serious medical problems the risk involved with surgery may with surgery may outweigh the potential benefitsoutweigh the potential benefits ((thusthus pharmacologicalpharmacological ””castrationcastration” ” isis a a methodmethod ofofchoicechoice). ).

ProstateProstate cancercancer

-- InIn americanamerican populationpopulation meanmean numbernumber ofof CAG (CAG (glutamineglutamine) ) repetitionrepetition was was inin suchsuchorder: order: AfrAfricicananss<<EuropeansEuropeans<<AsiansAsians.. ItIt correlatescorrelates withwith riskrisk ofof prostateprostate cancercancer..

-- In single In single describeddescribed casecase inin thethe healthyhealthy tissuestissues AR AR hadhad CAG=24, CAG=24, whilewhile inin tumor tumor CAG=18. CAG=18. HoweverHowever, , bothboth lengthslengths werewere withinwithin thethe normalnormal valuesvalues. .

-- In In americanamerican populationpopulation AsiansAsians areare less less riskedrisked for for prostateprostate cancercancer thanthan AfricansAfricans ((thethehighesthighest riskrisk) ) oror EuropeansEuropeans. . ApartApart fromfrom AR AR polymorphismpolymorphism, , thesethese differencesdifferences cancan alsoalsobe be associatedassociated withwith higherhigher levellevel ofof testosteronetestosterone inin AfricansAfricans andand//oror lowerlower activityactivity ofof 55ααredureductasectase inin AsiansAsians..

-- In In JapanJapan less less clinicalclinical casescases ofof prostateprostate cancercancer isis noticednoticed thanthan inin USA but USA but inin postpost--mortemmortem investigationsinvestigations thethe numbersnumbers ofof prepre--clinicalclinical oror latentlatent tumorstumors inin bothboth countries countries areare similarsimilar. .

AndrogensAndrogens andand prostateprostate cancercancer

-- ItIt hashas beenbeen shownshown that androgensthat androgens augment augment thethe growthgrowth ofof prostateprostate cancerscancers andand removal removal ofof androgensandrogens ((castrationcastration) ) stronglystrongly decreasesdecreases tumor tumor growthgrowth.. TillTill nownow, , castrationcastration ororpharmacologicalpharmacological inhibitioninhibition ofof androgen androgen pathways remainspathways remains thethe major major methodmethod ofof prostateprostatecancercancer treatmenttreatment, , despitedespite thethe high high raterate ofof failurefailure, , causedcaused by by hormonehormone--independent independent growthgrowth ofof tumorstumors..

-- At At earlyearly phasephase prostateprostate cancercancer respondsresponds to to decreaseddecreased levellevel ofof testosteronetestosterone, but , but laterlater on on itit cancan growgrow withoutwithout hormonehormone. . ItIt cancan resultresult fromfrom growthgrowth--factorfactor dependent dependent phosphorylationphosphorylation ofof AR AR andand testostosteronetestostosterone--independent AR independent AR activationactivation, , oror maybemayberelatedrelated to AR to AR mutationsmutations leadingleading to ligandto ligand--independent independent activationactivation..

-- AR AR mutationmutation maymay changechange thethe ligandligand--specificityspecificity, , thusthus AR AR activationactivation maymay occuroccur ininresponseresponse to to nonnon--specificspecific ligandsligands, e.g. , e.g. estrogensestrogens. . ItIt maymay leadlead to androgento androgen--independent independent tumor tumor growthgrowth, , despitedespite strongstrong expressionexpression ofof AR AR inin tumor tumor cancercancer.. AlsoAlso antianti--androgensandrogensmaymay usedused inin therapytherapy cancan stimulatestimulate thethe mutatedmutated ARAR..

Hormonal therapyHormonal therapy1. LHRH 1. LHRH therapytherapy

** administers Luteinizing hormoneadministers Luteinizing hormone--releasing hormone releasing hormone (LHRH) (LHRH) or its analogsor its analogs..

* * usually taken orally usually taken orally by by the patients the patients but but they can they can be be also longalso long--acting implantsacting implants

* * prevents the testes and adrenals from producing male hormonesprevents the testes and adrenals from producing male hormones

2. Androgen 2. Androgen blockersblockers

* * usually taken orallyusually taken orally byby the patientsthe patients butbut they canthey can bebe also longalso long--acting implantsacting implants

* * inhibitors of inhibitors of androgenandrogen--AR AR interactioninteraction

3. 3. Inhibitors of Inhibitors of 55αα--reductasereductase

* * in combonation with other drugs in combonation with other drugs (e.g. androgen (e.g. androgen blockersblockers))

Usually such treatmens improves clinical outcome evenUsually such treatmens improves clinical outcome even for for several yearsseveral years

Effects of antiandrogenic hormonal therapyEffects of antiandrogenic hormonal therapy

ThankThank youyou andand seesee youyou nextnext weekweek......

WhatWhat wouldwould be be profitableprofitable to to rememberremember inin JuneJune::

-- Effect ofEffect of AR AR polymorphismpolymorphism on on risk of diseasesrisk of diseases ((KennedyKennedy syndromesyndrome, , prostateprostate cancercancer))

-- Role Role of testosterone in development of male of testosterone in development of male reproductivereproductive systemsystem

-- Strategies of hormonal therapy in prostate cancerStrategies of hormonal therapy in prostate cancer

SSlideslides cancan be be foundfound inin thethe librarylibrary andand atat the the HemeHeme OxygenaseOxygenase Fan Fan ClubClub pagepage::

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