k7 - female hormones, biochem

8/17/2019 K7 - Female Hormones, BIOCHEM

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Pathophysiology of thePathophysiology of theReproductive CycleReproductive Cycle

Molecular medicine case studies :Molecular medicine case studies :Mutations of the FSH and LH receptorsMutations of the FSH and LH receptors(which have similar structure(which have similar structure

Primary ovarian failure caused !y aPrimary ovarian failure caused !y apoint mutation in the FSH receptorpoint mutation in the FSH receptorgene"gene"

Chromosome #p C to $ in nucleotide %&&Chromosome #p C to $ in nucleotide %&&of e'on of the FSH receptor gene"of e'on of the FSH receptor gene")lanine to *aline su!stitution at residue)lanine to *aline su!stitution at residue+,- of the protein"+,- of the protein"


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Pituitary HormonesPituitary Hormones

Posterior pituitaryPosterior pituitary

Stores and releases 2 horones that areStores and releases 2 horones that are

!rod"#ed $n the h%!othala"s&!rod"#ed $n the h%!othala"s&

o Ant$d$"ret$# horone Ant$d$"ret$# horone

'ADH()aso!ress$n*&'ADH()aso!ress$n*&

o O+%to#$nO+%to#$n&&


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O+%to#$nO+%to#$n

, a$no a#$d !e!t$de- !rod"#ed !r$ar$l%, a$no a#$d !e!t$de- !rod"#ed !r$ar$l%.% !ara)entr$#"lar n"#le"s and sall.% !ara)entr$#"lar n"#le"s and sall

ao"nt .% s"!rao!t$# n"#le"sao"nt .% s"!rao!t$# n"#le"sTar/ets& Uter"s and aar% /landsTar/ets& Uter"s and aar% /lands

Contra#t$on o0 !re/nant "ter"sContra#t$on o0 !re/nant "ter"s

St$"lates #ontra#t$ons o0 the aar%St$"lates #ontra#t$ons o0 the aar%/land al)eol$1/land al)eol$1 M$l3e4e#t$on re0le+1M$l3e4e#t$on re0le+1


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PROLACTINPROLACTIN

Prote$n horone o0 8,, a$no a#$ds1Prote$n horone o0 8,, a$no a#$ds1

In 0eales $t st$"lates $l !rod"#t$on .%In 0eales $t st$"lates $l !rod"#t$on .%the aar% /lands11the aar% /lands11

Release $s $nh$.$ted $n non3!re/nantRelease $s $nh$.$ted $n non3!re/nant6oen16oen1

As estro/en and !ro/esterone le)els r$se As estro/en and !ro/esterone le)els r$selate $n !re/nan#%- $t st$"lates !rola#t$nlate $n !re/nan#%- $t st$"lates !rola#t$n

release1release1H%!er!rola#t$nae$a #an #a"se enstr"alH%!er!rola#t$nae$a #an #a"se enstr"al!ro.les $n 0eales and .reast!ro.les $n 0eales and .reastenlar/eent $n ales1enlar/eent $n ales1


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H%!o3P$t35onadal A+esH%!o3P$t35onadal A+es


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An Overview

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

Hypothalamus(synthesizes

Gonadotropin

releasing

hormone

GnRH

Anterior pituitary(synthesizes

Gonadotropins!

l"teini#ing hormone

$olli%le stim"lating hormone)

Lh+fsh

Gonads -synthesize

gonadal hormones

estrogens

androgens


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RESEPTORRESEPTOR

Hal ini dipengaru%i ole% a.l.Hal ini dipengaru%i ole% a.l.&. 'umla% %ormon tsb yang&. 'umla% %ormon tsb yangdisekresikan, misalnya reseptordisekresikan, misalnya reseptorInsulin akan up regulate bilaInsulin akan up regulate bila

Insulin sedikitInsulin sedikit(.(. pengaru% dari %ormon lain,misalnyapengaru% dari %ormon lain,misalnya

reseptor )H akan meningkat ole%reseptor )H akan meningkat ole%

sekresi *SH sekresi *SHStruktur reseptor )H mirip denganStruktur reseptor )H mirip denganreseptor *SH, %+ sel luteal dan TSHreseptor *SH, %+ sel luteal dan TSH

Reseptor-reseptor tersebut dapatReseptor-reseptor tersebut dapatbermutasibermutasi timbul kelainan. timbul kelainan.


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RESEPTORRESEPTOR

eberapa obat dapat berinteraksi denganeberapa obat dapat berinteraksi denganreseptor tersebutreseptor tersebut

E$ek yang timbul " agonist menyerupaiE$ek yang timbul " agonist menyerupai

e$ek ligand yang sebenarnya/ ataue$ek ligand yang sebenarnya/ atauantagonist berlawanan dengan e$ekantagonist berlawanan dengan e$ekligand nya, misalnya meng%ambatligand nya, misalnya meng%ambattransduksi signal/transduksi signal/

Reseptor 'uga dipunyai ole% banyakReseptor 'uga dipunyai ole% banyakmolekul lain, seperti Interleukin,molekul lain, seperti Interleukin,Inter$eron, 0ntigen, 1eurotransmiter,Inter$eron, 0ntigen, 1eurotransmiter,)2) dll.)2) dll.


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Action of GnRHAction of GnRH

A system stimulation of phosphatidylinositol is GnRHA system stimulation of phosphatidylinositol is GnRHactionaction

GnRH binds to receptors in the cell membrane of theGnRH binds to receptors in the cell membrane of the

gonadotropegonadotrope

Phospholipase C is activated, catalyzes the hidrolysis ofPhospholipase C is activated, catalyzes the hidrolysis ofPIPPIP22 to form AG andto form AG and IPIP!!

AG activates protein "inase C #P$C%, &hichAG activates protein "inase C #P$C%, &hich

phosphorylates specific proteinphosphorylates specific protein

It participate in the resulting secretory process toIt participate in the resulting secretory process totransport 'H and ()H to cell e*terior transport 'H and ()H to cell e*terior

IPIP!! stimulates of Castimulates of Ca2+2+ from calcium stroge particle,from calcium stroge particle,

cause increased stimulation of P$Ccause increased stimulation of P$C

participates in e*ocytosis of 'H and ()H from cellparticipates in e*ocytosis of 'H and ()H from cell


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A#t$on o0 5nRH A#t$on o0 5nRH


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5ONADOTROPINS5ONADOTROPINS

(olliclestimulating hormone #()H(olliclestimulating hormone #()H**

Tar/et& O)ar$es and TestesTar/et& O)ar$es and Testes

St$"lates the at"rat$on o0 s!er andSt$"lates the at"rat$on o0 s!er ande//- $n the 0eales #a"ses the release o0e//- $n the 0eales #a"ses the release o0estro/enestro/en


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5ONADOTROPINS5ONADOTROPINS

'uteinizing Hormone #'H%'uteinizing Hormone #'H%

Tar/et& O)ar$es and TestesMale& Prod"#t$on o0 testosterone

In 0eales 6ors 6$th FSH to #a"seIn 0eales 6ors 6$th FSH to #a"se

0oll$#le de)elo!ent- and then0oll$#le de)elo!ent- and then$nde!endentl% $s res!ons$.le 0or o)"lat$on1$nde!endentl% $s res!ons$.le 0or o)"lat$on1


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Se+ HoronesSe+ Horones

5onad and Adrenal5onad and Adrenal

Estro/enEstro/enPro/esteronePro/esterone

D$h%drotestosteroneD$h%drotestosterone

TestosteroneTestosterone


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O)ar$an horonesO)ar$an horones

Stero$dsStero$ds

o 99Estro/ensEstro/ens

o 99 Andro/ens Andro/enso 99Pro/esteronePro/esterone

Pe!t$desPe!t$des


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A Stero$d Mole#"le A Stero$d Mole#"le


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OVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

99 Prod"#ed $n .oth $nterst$t$al andProd"#ed $n .oth $nterst$t$al and

0oll$#"lar #ells0oll$#"lar #ells99 Der$)at$)es o0 #holesterol '#o$n/Der$)at$)es o0 #holesterol '#o$n/

0ro LDL3l$!o!rote$ns and de no)o0ro LDL3l$!o!rote$ns and de no)o

s%nthes$s*s%nthes$s*


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St$"las$ s$ntes$s horonSt$"las$ s$ntes$s horon stero$dstero$d


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)-./H0)I))-./H0)I)


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99 Che$#al str"#t"re& C8:Che$#al str"#t"re& C8:

So"r#e&So"r#e&

o 0oll$#"lar #ells0oll$#"lar #ells

o 99 #or!"s l"te"#or!"s l"te"

o 99 !la#enta!la#enta

o 99 adrenal #orte+adrenal #orte+

o 99 ad$!ose t$ss"e 'DHEA ; androstened$onead$!ose t$ss"e 'DHEA ; androstened$one

;; E8*E8*

ESTRO5ENESTRO5EN


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)-./H0)I))-./H0)I)

F$rst ste! ha!!ens $n $to#hondr$aF$rst ste! ha!!ens $n $to#hondr$a

99 All the rest $n sooth ER All the rest $n sooth ER

99 Red"#t$on $n n".er o0 #ar.on atosRed"#t$on $n n".er o0 #ar.on atos

99 Estro/ens are !r$ar$l% s%nthes$7ed $nEstro/ens are !r$ar$l% s%nthes$7ed $n /ran"losa #ells/ran"losa #ells

99)romati.ation of )ndrostenedione and)romati.ation of )ndrostenedione and

$estosterone within tissue is a ma/or source$estosterone within tissue is a ma/or source of 0strogens in the male and postof 0strogens in the male and post

menopausal female"menopausal female"


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1varian Steroid Hormones1varian Steroid Hormones

Estrogen produced by t%ecal cells " t%eEstrogen produced by t%ecal cells " t%ema'or steroid in t%e circulationma'or steroid in t%e circulation

Estrogen synt%esi3ed by granulosa cells "Estrogen synt%esi3ed by granulosa cells "a local role, possibly related to o#uma local role, possibly related to o#um

maturationmaturation*SH regulate production and subse4uent*SH regulate production and subse4uentinduction and acti#ation o$ 0romatase ininduction and acti#ation o$ 0romatase in

t%e granulosa cellst%e granulosa cellsEstradiol E(/ is o5idi3ed to EstroneEstradiol E(/ is o5idi3ed to Estronewit%in t%e li#er and Estrone %ydrated towit%in t%e li#er and Estrone %ydrated toEstriol E/.Estriol E/.


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Estro/ens $n #$r#"lat$on

Estrad$ol

o 9 Se#reted .% the o)ar%

9 Estroneo 9 Der$)ed 0ro !er$!heral #on)ers$on o0

estrad$ol and androstenod$one

9 Estr$olo 9 L$)er eta.ol$te o0 estrone


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TRANSPORT IN BLOODTRANSPORT IN BLOOD

Mostl% #arr$er3.o"nd 'al."$n- se+Mostl% #arr$er3.o"nd 'al."$n- se+

horone3.$nd$n/ /lo."l$n*horone3.$nd$n/ /lo."l$n*

99 T6o !easT6o !easo 99 Be0ore o)"lat$onBe0ore o)"lat$on

o99 M$d3l"teal !eaM$d3l"teal !ea

99 Le)els & "#h h$/her $n the 0oll$#"lar Le)els & "#h h$/her $n the 0oll$#"lar 0l"$d than $n the !lasa


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C%to!las$# re#e!tor .$nds to stero$d horone1C%to!las$# re#e!tor .$nds to stero$d horone1

Translo#ates to n"#le"s1Translo#ates to n"#le"s1

DNA3.$nd$n/ doa$n .$nds to s!e#$0$# HRE o0DNA3.$nd$n/ doa$n .$nds to s!e#$0$# HRE o0

the DNA1the DNA1

D$er$7at$on o##"rs1D$er$7at$on o##"rs1 Pro#ess o0 2 re#e!tor "n$ts #o$n/ to/ether at the 2Pro#ess o0 2 re#e!tor "n$ts #o$n/ to/ether at the 2

hal03s$tes1hal03s$tes1

St$"lates trans#r$!t$on o0 !art$#"lar /enes1St$"lates trans#r$!t$on o0 !art$#"lar /enes1

1echanisms of Action1echanisms of Action


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1echanisms of Action1echanisms of Action


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Meta.ol$sMeta.ol$sMeta.ol$7ed to /l"#"ron$des andMeta.ol$7ed to /l"#"ron$des and

s"l0atess"l0ates

99 Re#%#led $n enterohe!at$# #$r#"lat$onRe#%#led $n enterohe!at$# #$r#"lat$on

99 E+#reted $n "r$neE+#reted $n "r$ne


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Ph%s$olo/$#alPh%s$olo/$#al

De)elo!ent and a$ntenan#e o0 "ter"s-De)elo!ent and a$ntenan#e o0 "ter"s-

"ter$ne t".es-)a/$na- e+ternal /en$tal$a"ter$ne t".es-)a/$na- e+ternal /en$tal$a

and .reastsand .reasts

C%#l$# #han/es $n the endoetr$"-C%#l$# #han/es $n the endoetr$"-

#er)$+- )a/$na#er)$+- )a/$na

5ro6th o0 the o)ar$an 0oll$#les5ro6th o0 the o)ar$an 0oll$#les

Mot$l$t% o0 the "ter$ne t".es =Mot$l$t% o0 the "ter$ne t".es =


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Pre/nan#%& "ter$ne "s#le ass =-Pre/nan#%& "ter$ne "s#le ass =-e+#$ta.$l$t% =- .reasts =e+#$ta.$l$t% =- .reasts =

Feale se#ondar% se+ #hara#ter$st$#sFeale se#ondar% se+ #hara#ter$st$#s

'0at de!os$ts- et#*'0at de!os$ts- et#*Estro"s .eha)$or $n an$als- $n#reasedEstro"s .eha)$or $n an$als- $n#reasedl$.$do $n h"ansl$.$do $n h"ans


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Pro/esteronPro/esteron

The ost d$st$n#t$)e horone .et6eenThe ost d$st$n#t$)e horone .et6een

ales and 0ealesales and 0eales

99 Che$#al str"#t"re& C28Che$#al str"#t"re& C28

99 So"r#e&So"r#e&

o 99 #1 l"te"#1 l"te"

o 99 !la#enta!la#enta

o 99 0oll$#les 'sall ao"nt*0oll$#les 'sall ao"nt*

o 99 adrenal #orte+adrenal #orte+


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IOS61THESISIOS61THESIS

""

*SH promotes t%e growt% o$ t%e $ollicle*SH promotes t%e growt% o$ t%e $ollicleby acting t%roug% receptors on t%eby acting t%roug% receptors on t%e

granulosa cells and inducing t%egranulosa cells and inducing t%e0romatase en3yme to con#ert 0ndrogens0romatase en3yme to con#ert 0ndrogensto Estrogens.to Estrogens.

T%e 0ndrogens originate $rom t%e t%ecaT%e 0ndrogens originate $rom t%e t%eca

w%ic% is stimulated by )H t%roug% itsw%ic% is stimulated by )H t%roug% itsreceptors initially on t%eca cells andreceptors initially on t%eca cells andappear in t%e granulosa cells and areappear in t%e granulosa cells and areprobably coupled to t%e same secondprobably coupled to t%e same second

messenger c07P/ as *SH receptorsmessenger c07P/ as *SH receptors


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Progesterone synt%esis is an earlyProgesterone synt%esis is an early

step in t%e biosynt%esis o$ androgenstep in t%e biosynt%esis o$ androgenand estrogen wit%in t%e t%ecal cell.and estrogen wit%in t%e t%ecal cell.

ut circulating progesterone isut circulating progesterone is

produced by corpus luteumproduced by corpus luteum

IOS61THESISIOS61THESIS


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Trans!ortTrans!ort

2> 0ree2> 0ree

99 :?> al."$n3.o"nd:?> al."$n3.o"nd99 8:> #ort$#ostero$d3.$nd$n/ !rote$n8:> #ort$#ostero$d3.$nd$n/ !rote$n

'trans#ort$n* 3.o"nd'trans#ort$n* 3.o"nd


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C%#l$# #han/es $n the endoetr$"-

#er)$+- and )a/$na

Breasts& s"!!orts the se#retor% 0"n#t$on

d"r$n/ la#tat$on

Inh$.$ts LH se#ret$on

Res!ons$.le 0or !re!ar$n/ the re!rod"#t$)etra#t 0or $!lantat$on and the a$ntenan#e

o0 !re/nan#%



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Mechanism of action of 1varianMechanism of action of 1varianSteroid HormonesSteroid Hormones

E( and Progesterone interact wit%E( and Progesterone interact wit%cytoplasmic and8or nuclear proteincytoplasmic and8or nuclear proteinreceptors.receptors.

Release o$ t%e two receptors subunitsRelease o$ t%e two receptors subunitswit% attac%ed steroid %ormones $romwit% attac%ed steroid %ormones $romassociation wit% a %eat-s%ock protein.association wit% a %eat-s%ock protein.

Eit%er identical subunits singly orEit%er identical subunits singly orpossibly toget%er interact directly wit%possibly toget%er interact directly wit%t%e 210 %ormone responsi#e element tot%e 210 %ormone responsi#e element toacti#ate transcriptional e#ents leading toacti#ate transcriptional e#ents leading to

translation o$ a cell-speci$ic protein.translation o$ a cell-speci$ic protein.


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0ndrogens0ndrogens

0ndrostenedione and Testosterone as0ndrostenedione and Testosterone asa precursors o$ estrogens area precursors o$ estrogens aresecreted by o#aries in t%e beginningsecreted by o#aries in t%e beginning

o$ Puberty.o$ Puberty.2e#elopment o$ secondary se5ual2e#elopment o$ secondary se5ual

c%aracters almost totally by t%ec%aracters almost totally by t%e

actions o$ estrogens.actions o$ estrogens.


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0ndrogens0ndrogens

0ndrogens o$ o#arian origin may be0ndrogens o$ o#arian origin may bein$luenced at a puberty.in$luenced at a puberty.0cne, results $rom sebaceous gland0cne, results $rom sebaceous gland

acti#ation by o#arian androgens.acti#ation by o#arian androgens.

Pubic and a5illary %air growt% are alsoPubic and a5illary %air growt% are alsoattributed to androgens o$ o#arianattributed to androgens o$ o#arianand8or adrenal origin.and8or adrenal origin.

+%anges in en3ymic +%anges in en3ymic 99-%ydro5ysteroid-%ydro5ysteroidde%ydrogenase, &-%ydro5ylase andde%ydrogenase, &-%ydro5ylase and&:,(;-desmolase/ acti#ity, increased&:,(;-desmolase/ acti#ity, increasedproduction o$ adrenal androgensproduction o$ adrenal androgens


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23ARIA. P0P/I0 H2R12.0)23ARIA. P0P/I0 H2R12.0)

Rela+$nRela+$n

o 99 Rela+es !el)$# 4o$ntsRela+es !el)$# 4o$nts

o 99 So0tens and d$lates #er)$+So0tens and d$lates #er)$+

o 99 S!er o.$l$t% 3 $n alesS!er o.$l$t% 3 $n ales

Inh$.$nInh$.$n

o 99 Sele#t$)e $nh$.$tor% #ontrol o0 FSHSele#t$)e $nh$.$tor% #ontrol o0 FSH

A#t$)$n A#t$)$no 99 Sele#t$)e st$"laton o0 FSHSele#t$)e st$"laton o0 FSH

o 99 Cell d$00erent$at$onCell d$00erent$at$on


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23ARIA. P0P/I0 H2R12.0)23ARIA. P0P/I0 H2R12.0)

Foll$stat$nsFoll$stat$ns

o 99 Inh$.$t FSH se#ret$onInh$.$t FSH se#ret$on 5onadotro!$n s"r/e atten"at$n/ 0a#tor 5onadotro!$n s"r/e atten"at$n/ 0a#tor

o 99 Pre)ents !reat"re LH s"r/ePre)ents !reat"re LH s"r/e


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2ntrafollicular Polypeptide2ntrafollicular PolypeptideRegulatory FactorsRegulatory Factors

Se#eral peptides %a#e been isolatedSe#eral peptides %a#e been isolated$rom o#arian $ollicles and regulate$rom o#arian $ollicles and regulateoocyte maturation "oocyte maturation "

&. Oocyte 7aturation In%ibitor&. Oocyte 7aturation In%ibitor

(. O#arian rowt% *actors(. O#arian rowt% *actors

. In%ibins. In%ibins

!. 0cti#ins!. 0cti#ins


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&. Oocyte 7aturation In%ibitor "&. Oocyte 7aturation In%ibitor ")ow molecular weig%t-peptide)ow molecular weig%t-peptideIts concentration in antral $luid decreasesIts concentration in antral $luid decreasesas t%e $ollicle maturatesas t%e $ollicle maturatesap 'unctions, present between cells o$ap 'unctions, present between cells o$t%e corona radiata and t%e oocytet%e corona radiata and t%e oocyte structural pat%way $or cell-to-cellstructural pat%way $or cell-to-cellcommunication.communication.

O7I may e5ert its action indirectlyO7I may e5ert its action indirectlyt%roug% an action on cumulus cellst%roug% an action on cumulus cells)H induced oocyte maturation may result)H induced oocyte maturation may result$rom an uncoupling between t%e cumulus$rom an uncoupling between t%e cumulus

cells and t%e oocytecells and t%e oocyte


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(. O#arian rowt% *actors "(. O#arian rowt% *actors "

2nduction of LH receptors is a critical2nduction of LH receptors is a criticalaspect of granulosa cell differentiationaspect of granulosa cell differentiationand ovarian follicular developmentand ovarian follicular development

Pituitary FSH functions as the inducerPituitary FSH functions as the inducerof granulosa cell LH receptorof granulosa cell LH receptor

ac3uisitionac3uisition$his FSH4dependent LH receptor$his FSH4dependent LH receptorinduction is inhi!ited !y 05F and F5Finduction is inhi!ited !y 05F and F5F


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. In%ibin ". In%ibin "2nhi!in is present in follicular fluid62nhi!in is present in follicular fluid6ovarian and granulosa cell e'tractsovarian and granulosa cell e'tracts

2nhi!in e'erts a suppressive action on2nhi!in e'erts a suppressive action on!oth !asal and 5nRH4stimulated!oth !asal and 5nRH4stimulatedpituitary FSH secretionpituitary FSH secretion

Circulating levels of 2nhi!in areCirculating levels of 2nhi!in areinversely related to plasma FSH levels"inversely related to plasma FSH levels"

2nhi!in can !e detected in the plasma2nhi!in can !e detected in the plasmaof women given FSH6 !ut not inof women given FSH6 !ut not in

castrated su!/ects"castrated su!/ects"

2 f lli l P l id


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. In%ibin ". In%ibin "

2nhi!in composed of two su!units that2nhi!in composed of two su!units thatare lin7ed !y disulfide !ridgesare lin7ed !y disulfide !ridges

$he two su!units ($he two su!units (8866 99 encoded !y encoded !yseparated genesseparated genes

$he control of inhi!in !iosynthesis is$he control of inhi!in !iosynthesis isat the level of transcription"at the level of transcription"


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!. 0cti#in "!. 0cti#in "Purified fractions of follicular fluidPurified fractions of follicular fluide'hi!ited stimuli rather than inhi!itorye'hi!ited stimuli rather than inhi!itoryeffects on FSH release from pituitarieseffects on FSH release from pituitaries

invitro"invitro"99 Su!units of inhi!in and transformingSu!units of inhi!in and transforminggrowth factorgrowth factor 99 ($5F($5F99 were similar" were similar"imers of theimers of the 99 su!units of inhi!in6su!units of inhi!in6 99))99;;66

99))99)) andand 99;; 99;; were named )ctivin6 )ctivin )were named )ctivin6 )ctivin )and )ctivin ;and )ctivin ;)ctivin can enhance !asal secretion of FSH)ctivin can enhance !asal secretion of FSHin a dose4dependent manner in vitro withoutin a dose4dependent manner in vitro without

k7 - female hormones, biochem

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