Source, synthesis and metabolism of androgens

Source, synthesis and metabolism of androgens

1. SOURCE , SYNTHESIS,
METABOLISM AND
PHYSIOLOGICAL ROLE OF
ANDROGENS
M.THILAKAR
LS 1154
4’th M.Sc. LIFE
SCIENCES,
BDU.

2. O
OH
HH
H
TESTOSTERONE O
OH
HH
H
H
DIHYDROTESTOSTERONE ANDROGENS

3. TESTOSTERONES
Testosteroneistheprincipalandrogensecretedbythematuretestis.
Normalyoungmenproduceabout7mgeachday,ofwhichlessthan5%isderivedfromadrenal
secretions.
Thisamountdecreasessomewhatwithage,sothatbytheseventhdecadeandbeyond,
testosteroneproductionmayhavedecreasedto4mgperday,butintheabsenceofillnessor
injury,Aswiththeothersteroidhormones,testosteroneinbloodislargelyboundtoplasma
protein,withonlyabout2to3%presentasfreehormone.
Abouthalfisboundtoalbumin,andslightlylesstosexhormone-bindingglobulin(SHBG),whichis
alsocalledtestosterone-estradiol-bindingglobulin(TeBG).
Thisglycoproteinbindsbothestrogenandtestosterone,butitssinglebindingsitehasahigher
affinityfortestosterone.
ItsconcentrationinplasmaisdecreasedbyandrogenConsequently,SHBGismorethantwiceas
abundantinthecirculationofwomenthanmen.
Inadditiontoitsfunctionsasacarrierprotein,SHBGmayalsoactasanenhancerofhormone
action.

4. BIOSYNTHESIS OF ANDROGEN
SITE :synthesized in the interstitial tissue by the leydigcells response to LH .
To a minor extent by adrenal glands in both the sexes.
Ovariesalso produce a small amount of androgens
PRECURSOR: Cholesterol
It is first converted to pregnenolone by cytochrome p450 side chain cleavage
enzyme which then forms androstenedioneby two pathways:
1. Through progesterone (Progesterone (or ∆4) pathway)
2. Through 17-hydroxypregnenolone.(Dehydroepiandrosteroneor ∆5
pathway)

5. HORMONAL CONTROL OF MALE
REPRODUCTIVE SYSTEM

8. SYNTHESIS
OF
TESTOSTERO
NE IN
TESTES

9. ENZYMES REQUIRED FOR THE
PRODUCTION OF ANDROGENS
The conversion of pregnenolone to testosterone requires the
action of five enzyme activities contained in three proteins:
3β-hydroxyl steroid dehydrogenase (3β-HSD) and ∆5,4-
isomerase;
17α-hydroxylase and C17-20 Lyase and
17β-hydroxyl steroid dehydrogenase (17β-OHSD).
The ∆5 route appears to be most used in human testes.

10. REGULATION
The production of androgens is under the control of LH and FSH.
Regulated by feedback mechanism
The rate limiting step is the delivery of cholesterol to testosterone by StAR.
Steroidogenic acute protein (StAR)

11. DIAGRAMMATIC REPRESENTATION OF THE ANDROGEN SYNTHETIC
PATHWAY IN THE LEYDIGCELLS OF THE TESTIS.
PREFERRED PATHWAYS ARE SHOWN BY HEAVY ARROWS.
ONLY SMALL AMOUNTS OF DIHYDROTESTOSTERONEARE
SYNTHESIZED FROM TESTOSTERONE WITHIN THE LEYDIGCELL.
LH REGULATION OF
LEYDIG CELLS

12. LH REGULATION OF LEYDIG CELLS
LHbindstohighaffinityGprotein-coupledplasmamembranereceptorsonLeydig
cells.
Followingbinding,LHreceptorsaggregate,undergoaconformationalchangeand
bindG
sprotein.
Guanosinetriphosphate(GTP)thenbindstoG
sαsubunit,displacingguanosine
diphosphate(GDP),andG
sαbindsandactivatesadenylatecylaseresultingin
generationofcyclicadenosinemonophosphate(cAMP).
cAMPthenbindstotheregulatorysubunitsofproteinkinaseA,releasingactivated
catalyticsubunitsthatphosphorylateanumberofproteinsintheLeydigcelland
resultinstimulationofsteroidogenesisandtestosteroneproduction
BothLHandhCGbindtotheLHreceptorandadministrationofhighconcentrations
ofeitherhormonecausesadecrease(downregulation)ofLHreceptornumberand
reductioninresponsivenesstofurtherstimulationbyLHorhCG(desensitization).
IncontrasttothesuppressionofpituitaryLHproductioninducedbycontinuous
high-dosageGnRHadministration,productionoftestosteroneisnotinhibitedby
highdosageLHorhCGadministration,raisingquestionsregardingtheclinical
significanceofLHreceptordownregulationandLeydigcelldesensitization.

13. FSH REGULATION OF SERTOLICELL
FUNCTION
FSHbindstohigh-affinityGprotein-coupledplasmamembranereceptorsonSertoli
cells.
SignaltransductionfollowsapathwaythatisanalogoustothatforLHwithFSH
receptorbindingleadingtoGproteinactivationofadenylatecyclase,generationof
cAMPthatactivatesproteinkinaseA,followedbyproteinphosphorylation.
AswiththeregulationofLHreceptorsbyLHorhCG,FSHadministrationalsodown
regulatesthenumberofFSHreceptorsonSertolicells,butthephysiological
significanceofdown-regulationisnotknown.
FSHbindinghasalsobeenreportedinratspermatogonia,butdirecteffectsofFSH
onthesestemcells

14. METABOLISM OF ANDROGEN
14
FIRST PATHWAY :
Involves oxidation at the 17 position,
Occurs in many tissues, including liver and produces 17-ketosteroidsthat are
generally inactive or less active than the parent compound.
SECOND PATHWAY :
Occurs primarily in target tissues
Dihydrotestosterone is Formed From Testosterone in Peripheral tissues.
Involves reduction of the A ring double bond and the 3 Ketosterone, a reaction
catalyzed by the NADPH-dependent 5 αreductase
5 mg of testosterone is produced daily by testes. Approximately 400 µg of DHT is
produced daily
Some estradiol is formed from the peripheral aromatization of testosterone.

15. TRANSPORT OF ANDROGENS
In the plasma testosterone and DHT bind to two proteins-
1. Sex hormone binding globulin ( SHBG)binds 97 to 99% and
2. Testosterone-estrogen binding globulin( TEBG).
A small fraction is in free form.
Both these proteins are synthesized in liver.
The plasma testosterone level in normal men is about 0.7 µg/dl while in
women it is < 0.1 µg/dl.

16. METABOLISM OF ANDROGEN

17. MODE OF ACTION
Bothtestosteroneanddihydrotestosteronebindtoasingleclassof
receptorsonthetargettissues.
TheaffinityofDHTforthereceptorismuchhighercomparedto
testosterone.
Receptorsitesforandrogensarefoundinmuscle,brain,andothertarget
tissues.

18. ANDROGEN ACTION
Diagrammaticrepresentationofthemetabolismof
testosterone.AftersecretionbytheLeydigcell,
testosteronetravelsthroughtheplasmatotheliver
ortargettissues.Aftermetabolismandconjugation,
productsareexcretedintotheurine.

19. PHYSIOLOGICAL FUNCTIONS OF
ANDROGEN
The androgens influence
1. Growth, development and maintenance of male reproductive organs.
2. Sexual differentiation and secondary sexual characteristics.
3. Spermatogenesis.
4. Male pattern of aggressive behavior.
5. Pubertal transformation:
Enlargement of testes, penis and scrotum.
Pubic and axillary hair.
Bone growth.
RBC mass increase.
Skeletal muscle mass increase.
Larynx enlarges -deepening of the voice
Increase in sebaceous glands -often cause of acne
Development of Beard

20. BIOCHEMICAL FUNCTIONS OF
ANDROGEN
EFFECT ON PROTEIN METABOLISM:
Androgens promote
RNA synthesis( transcription)
Protein synthesis( translation).
Rapid growth of muscular-skeletal system associated with puberty.
EFFECT ON CARBOHYDRATE AND FAT METABOLISM :
Glycolysis,
Production of D-fructose from D-glucose by seminal vesicles.
Fatty acid synthesis and
Citric acid cycle.
EFFECTS ON MINERAL METABOLISM :
Androgens promote
Mineral deposition and bone growth
Kidney reabsorption of Na+, Cl-and water.

21. ABNORMALITIES ASSOCIATED
WITH MALE SEX HORMONES
Hypogonadisn is a disorder characterized by a defectin testosterone synthesis.
It may be of two types.
1. PRIMARY HYPOGONADISM : is caused by a failure of testes to produce
testosterone.
2. SECONDARY HYPOGONADISM : isdue to an impairment in the release of
gonadotropins.

22. ANDROGENS IN WOMEN
Becauseofadeficiencyonbothovarianand
adrenalandrogens,somewomen with
hypopituitarismhavediminishedlibidodespite
adequateestrogentherapy.
Althoughexperienceislimited,smalldosesoflong-
actingandrogens(testosteroneenanthate,25-50
mgintramuscularlyevery4-8weeks)maybehelpful
inrestoringsexualactivitywithoutcausing
hirsutism.
Inaddition,somereportshavesuggestedthatoral
dehydroepiandrosterone(DHEA)indosesof25to
50mg/dmayrestoreplasmatestosteronelevelsto
normal.
Atransdermaldeliverysystemisbeingevaluated
foruseinwomen,butefficacyappearstobe
modestandthelong-termsafetyisunknown.
ANDROGENS IN MEN
Thetreatmentofmalehypogonadism.
Testosteronegels(availableinpacketsindosesof
2.5,5,or10g,orfromametered-dosepumpin
1.25gincrements)andtestosteronepatches(in
dosesof2.5or5mg)areapplieddaily.
Othertherapeuticpreparationsinclude
intramusculartestosteroneenanthateorcypionate
indosesof100mgeveryweekor200mgevery2
weeks.
Testosteroneundecanoateisanintramuscular
preparationavailableinseveralcountriesthatcan
begivenevery3months.
Oraltestosteronepreparationsavailableinthe
UnitedStatesarerarelyusedoutofconcernfor
hepaticsideeffects.

23. REFERENCES
1.BASIC ENDOCRINOLOGY by H. Maurice Goodman –4’th Ed (2009).
Elsevier’s Science & Technology. [245-248]
2.ENDOCRINOOLOGY AT GLANCE by Ben Greenstein (1994).
Blackwell sciences Ltd. [60-65]
3.GRETENSPAN'S BASIC & CLINICAL ENDOCRINOLOGY by Gardner D
and Shoback–9’th Ed(2011). The McGraw-Hill Companies
4.ENDOCRINOLOGY AND METABOLISM by Felig, Philip; Frohman,
Lawrence A. –4’th Ed (2001). The McGraw-Hill Companies

24. Thank
u dudes…!!