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SexSteroidHormoneBiosynthesisandAction
TesticularAndrogens:
Theconversionofpregnenolonetotestosteronerequirestheactionof5enzymes,all
foundintheERofthetestescells.
Theconversionofpregnenolonetotestosteroneisreferredtoasthe"Progesterone
Pathway":
(1)17Hydroxylase
(2)C17,20Lyase
(3)3HydroxysteroidDehydrogenase(3OHSD)
(4)54Isomerase
(5)17HydroxysteroidDehydrogenase(17OHSD)
AdrenalAndrogen(Testosterone)Biosynthesis:

Dihydrotestosterone(DHT),isthemostpotentandrogen,itisformedfrom
testosterone,bythereductionoftheAringthroughtheactionoftheenzyme5
Reductase.
Thetestesalsoproduce17estradiol,thefemalesexhormoneinsmallamounts,but
mostoftheestrogensproducedbythemalearederivedfromperipheralaromitzation
oftestosterone.
ActionsoftheTesticularHormones:

Theandrogens,principallytestosteroneandDHT,actingthroughnuclearreceptorsare
involvedin:
(1)sexualdifferentiation
(2)spermatogenesis
(3)developmentofsexualorgans
(4)anabolicmetabolismandgeneregulation
(5)malepatternbehavior

.Duringtheinitialstagesofgestation,thedevelopmentofmaleandfemaleembryos
isindistinguishable.

.Ataboutday56,hormonesbecomeinvolved.
.AllembryosspontaneouslydevelopintophenotypicfemalesintheabsenceofaY
chromosomeinducedevent.

.Amalespecificgenehasbeendetectedinmicewhichisassociatedwith
differentiationoftheprimitivegonad,andlieswithinthesexdeterminingregion(sry)
oftheYchromosome.

.WhenthesrygeneisinjectedintoXXfemaleembryos,normalmalemice
develop.........
OvarianSexSteroidHormones:
BiosynthesisofEstrogens:
Theovariesarebifunctionalorgansthatproducebothestrogensandprogestins.
Themostactivenaturallyoccurringhormonesoftheseclassesare17estradiol(E2)
andprogesterone.

FunctionsandBiochemicalActionsoftheOvarianHormones:
Femalesexsteroidsactthroughnuclearreceptorsto:
(1)Matureprimordialgermcells.
(2)Developtissuesforimplantationoftheblastocyst(fertilizedegg).
(3)Provide"hormonaltiming"forovulation.
(4)Establishthemilieurequiredformaintenanceofpregnancy.
(5)Providehormonalinfluencesforparturition(childbirth)andlactation.
SyntheticAgonistsandAntagonistsofEstrogensandProgestins:
Severalsyntheticcompoundshaveestrogenicactivity.
Mostmodificationsweredesignedtoresisthepaticmetabolismsothatthecompounds
canbetakenorally.

.17EthinylEstradiolandMestranolareusedinoralcontraceptives.
.Numerouscompoundswithantiestrogenicactivityhavebeensynthesized.
.Theseantagonistsactbycompetingwithestradiolforitsintracellularreceptor,
causingthereceptortoassumeaninactiveconformation.

.NafoxidineandTamoxifencombinewiththeestrogenreceptortoformstablebut
inactivecomplexes>inhibitingtheactionofestradiolforprolongedperiods.

.Theseantagonistsareusedinthetreatmentofestrogendependentbreastcancerand
inbreastcancerprevention.

.Aprogesteroneantagonist,RU486(the"MorningAfterPill"),functionstoblock
thepositiveeffectsofprogesteroneinsupportingpregnancy.

ClinicalCorrelates:
CancerandEstrogenReceptors:

.Hormonalstimulationisknowntobeafactorinthedevelopmentandgrowthof
breastcarcinomas.

.Byassayingfortheestrogenreceptorintumorbiopsies,astrongpositivecorrelation
wasfoundbetweenthepresenceofthereceptorandtheestrogendependencyofthe
tumor.

.Patientswithestrogenreceptorintheirtumorsrespondwelltoablationofthe
ovaries,whilereceptornegativecasesmustbetreatedbyothermeans.

.Apositiveassayindicatesthatremovaloftheovarieswilldepriveanymetastatic
cellsofestrogenandpreventtheirproliferation.

.Tamoxifencanalsobegivenasanantagonist.
Osteoporosis:
Estrogenactsdirectlyonosteoblaststoincreasetheirproliferationandtokeepthemin
balancewiththeboneresorbingosteoclasts,andtoattenuatethereleaseofcytokine
factorsthatstimulateosteoclasts.
Osteoclast:BoneResorbing
Osteoblast:BoneRegenerating
EstrogensPreventOsteoporosisBy:
1)Curbingperipheralbloodcellreleaseofcytokines(likeIL1)whichwould
normallystimulateosteoblaststoreleaseosteoclasticactivatingcytokineslikeIL6.
2)BlockingtheactionofPTHand1,25(OH)2D3whichstimulatetheosteoblastic
secretionofcytokines(IL6etc)thatcauseosteoclasticdifferentiationandactivation
ofexistingosteoclasts.
TheResult:thebalanceistippedinfavoroftheosteoblastovertheosteoclast.

EstrogenRegulatesBoneCellCytokines:
OB=osteoblast
OC=osteoclast
TNF=TumorNecrosisFactor
CSF=ColonyStimulatingfactor
PBM=PeripheralBloodMonocyte