FEMALE REPRODUCTIVE FEMALE REPRODUCTIVE HORMONEHORMONE

BIOCHEMISTRY DEPARTMENTBIOCHEMISTRY DEPARTMENT

Pathophysiology of the Pathophysiology of the R p d ti C l R p d ti C l Reproductive Cycle Reproductive Cycle

Molecular medicine case studies :Molecular medicine case studies :M f h F H d LH M f h F H d LH Mutations of the FSH and LH Mutations of the FSH and LH receptors (which have similar receptors (which have similar structure)structure)structure)structure)Primary ovarian failure caused by a Primary ovarian failure caused by a point mutation in the FSH receptor point mutation in the FSH receptor point mutation in the FSH receptor point mutation in the FSH receptor gene.gene.Chromosome 2p C to T in nucleotide Chromosome 2p C to T in nucleotide Chromosome 2p C to T in nucleotide Chromosome 2p C to T in nucleotide 566 of exon 7 of the FSH receptor 566 of exon 7 of the FSH receptor gene Alanine to Valine substitution at gene Alanine to Valine substitution at gene. Alanine to Valine substitution at gene. Alanine to Valine substitution at residue 189 of the protein. residue 189 of the protein.

Pituitary HormonesPituitary HormonesPituitary HormonesPituitary Hormones

Posterior pituitaryPosterior pituitary

Stores and releases 2 hormones that areStores and releases 2 hormones that areproduced in the hypothalamus:produced in the hypothalamus:produced in the hypothalamus:produced in the hypothalamus:

oo Antidiuretic hormone Antidiuretic hormone (ADH/vasopressin):(ADH/vasopressin):(ADH/vasopressin):(ADH/vasopressin):

oo OxytocinOxytocin::

OxytocinOxytocinOxytocinOxytocin

9 i id tid d d i il9 i id tid d d i il9 amino acid peptide, produced primarily 9 amino acid peptide, produced primarily by paraventricular nucleus and small by paraventricular nucleus and small amount by supraoptic nucleusamount by supraoptic nucleusamount by supraoptic nucleusamount by supraoptic nucleusTargets: Uterus and mammary glandsTargets: Uterus and mammary glandsC t ti f t tC t ti f t tContraction of pregnant uterusContraction of pregnant uterusStimulates contractions of the mammary Stimulates contractions of the mammary l d l lil d l ligland alveoli.gland alveoli.

MilkMilk--ejection reflex.ejection reflex.

Pituitary HormonesPituitary HormonesPituitary HormonesPituitary HormonesAnterior pituitaryAnterior pituitary

Prolactin Prolactin G th H (GH)G th H (GH)Growth Hormone (GH)Growth Hormone (GH)Thyroid Stimulating Hormone (TSH)Thyroid Stimulating Hormone (TSH)Ad ti t i H (ACTH)Ad ti t i H (ACTH)Adrenocorticotropic Hormone (ACTH) Adrenocorticotropic Hormone (ACTH) FollicleFollicle--stimulating Hormone (FSH) stimulating Hormone (FSH) L t i i i H (LH)L t i i i H (LH)Luteinizing Hormone (LH)Luteinizing Hormone (LH)

PROLACTINPROLACTIN

Protein hormone of 199 amino acids.Protein hormone of 199 amino acids.In females it stimulates milk production by In females it stimulates milk production by the mammary glands..the mammary glands..R l i i hibit d iR l i i hibit d i ttRelease is inhibited in nonRelease is inhibited in non--pregnant pregnant women. women. As estrogen and progesterone levels riseAs estrogen and progesterone levels riseAs estrogen and progesterone levels rise As estrogen and progesterone levels rise late in pregnancy, it stimulates prolactin late in pregnancy, it stimulates prolactin release.release.Hyperprolactinaemia can cause menstrual Hyperprolactinaemia can cause menstrual problems in females and breast problems in females and breast enlargement in malesenlargement in malesenlargement in males.enlargement in males.

HypoHypo--PitPit--Gonadal AxesGonadal AxesHypoHypo PitPit Gonadal AxesGonadal Axes

HORMONAL CONTROL OVER GONADAL FUNCTIONHORMONAL CONTROL OVER GONADAL FUNCTION

An Overview

estrogensGnRH Lh+fsh

androgens

Hypothalamus Anterior pituitary Gonads -Hypothalamus(synthesizesGonadotropin releasing

Anterior pituitary(synthesizes Gonadotropins:luteinizing hormone

synthesizegonadal hormones

releasinghormone)

luteinizing hormonefollicle stimulating hormone)

RESEPTOR RESEPTOR RESEPTOR RESEPTOR Reseptor Hormon umumnya di Reseptor Hormon umumnya di

b l t did l b l t did l membran plasma atau didalam membran plasma atau didalam sitoplasma.sitoplasma.I t k i HI t k i H R R i l i l Interaksi HInteraksi H--R R signal signal transduction kedalam sel.transduction kedalam sel.R t l i d d R t l i d d Reseptor mengalami up and down Reseptor mengalami up and down RegulationRegulationTRH TSH d T3TRH TSH d T3 T4 l i T4 l i TRH,TSH dan T3TRH,TSH dan T3--T4 : regulasi T4 : regulasi melalui reseptor masingmelalui reseptor masing--masing masing dalam mekanisme negative dalam mekanisme negative dalam mekanisme negative dalam mekanisme negative feedback. feedback.

RESEPTOR RESEPTOR RESEPTOR RESEPTOR Hal ini dipengaruhi oleh a.l.Hal ini dipengaruhi oleh a.l.

1 jumlah hormon tsb yang 1 jumlah hormon tsb yang 1. jumlah hormon tsb yang 1. jumlah hormon tsb yang disekresikan, misalnya reseptor disekresikan, misalnya reseptor Insulin akan up regulate bila Insulin akan up regulate bila Insulin akan up regulate bila Insulin akan up regulate bila Insulin sedikitInsulin sedikit

2. 2. pengaruh dari hormon lain,misalnya pengaruh dari hormon lain,misalnya p g , yp g , yreseptor LH akan meningkat oleh reseptor LH akan meningkat oleh sekresi FSHsekresi FSH

Struktur reseptor LH mirip dengan Struktur reseptor LH mirip dengan reseptor FSH, hCG sel luteal dan TSH reseptor FSH, hCG sel luteal dan TSH ReseptorReseptor--reseptor tersebut dapat reseptor tersebut dapat bermutasi bermutasi timbul kelainan.timbul kelainan.

RESEPTOR RESEPTOR RESEPTOR RESEPTOR

Beberapa obat dapat berinteraksi dengan Beberapa obat dapat berinteraksi dengan b breseptor tersebutreseptor tersebut

Efek yang timbul : agonist (menyerupai Efek yang timbul : agonist (menyerupai f k li d b ) t f k li d b ) t efek ligand yang sebenarnya) atau efek ligand yang sebenarnya) atau

antagonist (berlawanan dengan efek antagonist (berlawanan dengan efek ligand nya misalnya menghambat ligand nya misalnya menghambat ligand nya, misalnya menghambat ligand nya, misalnya menghambat transduksi signal)transduksi signal)Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak Reseptor juga dipunyai oleh banyak molekul lain, seperti Interleukin, molekul lain, seperti Interleukin, Interferon, Antigen, Neurotransmiter, Interferon, Antigen, Neurotransmiter, ggLDL dll.LDL dll.

Action of GnRHAction of GnRHA system stimulation of phosphatidylinositol is GnRH A system stimulation of phosphatidylinositol is GnRH actionactionGnRH binds to receptors in the cell membrane of the GnRH binds to receptors in the cell membrane of the gonadotropegonadotropePhospholipase C is activated, catalyzes the hidrolysis of Phospholipase C is activated, catalyzes the hidrolysis of PIPPIP2 2 to form DAG andto form DAG and IPIP3 3

DAG activates protein kinase C (PKC) whichDAG activates protein kinase C (PKC) whichDAG activates protein kinase C (PKC), which DAG activates protein kinase C (PKC), which phosphorylates specific proteinphosphorylates specific proteinIt participate in the resulting secretory process to It participate in the resulting secretory process to transport LH and FSH to cell exteriortransport LH and FSH to cell exteriorIPIP3 3 stimulates of Castimulates of Ca2+ 2+ from calcium stroge particle, from calcium stroge particle, cause increased stimulation of PKCcause increased stimulation of PKCcause increased stimulation of PKCcause increased stimulation of PKC

participates in exocytosis of LH and FSH from cellparticipates in exocytosis of LH and FSH from cell

Action of GnRHAction of GnRHAction of GnRHAction of GnRH

GONADOTROPINSGONADOTROPINSGONADOTROPINSGONADOTROPINS

FollicleFollicle--stimulating hormone (FSHstimulating hormone (FSH))FollicleFollicle stimulating hormone (FSHstimulating hormone (FSH))

Target: Ovaries and TestesTarget: Ovaries and TestesTarget: Ovaries and TestesTarget: Ovaries and TestesStimulates the maturation of sperm and Stimulates the maturation of sperm and egg in the females causes the release ofegg in the females causes the release ofegg, in the females causes the release of egg, in the females causes the release of estrogenestrogen

GONADOTROPINSGONADOTROPINSGONADOTROPINSGONADOTROPINS

Luteinizing Hormone (LH)Luteinizing Hormone (LH)Luteinizing Hormone (LH)Luteinizing Hormone (LH)

T t O i d T tTarget: Ovaries and TestesMale: Production of testosteroneIn females works with FSH to cause follicle In females works with FSH to cause follicle development, and then independently is development, and then independently is p , p yp , p yresponsible for ovulation. responsible for ovulation.

Sex HormonesSex HormonesSex HormonesSex Hormones

Gonad and AdrenalGonad and AdrenalGonad and AdrenalGonad and Adrenal

E tE tEstrogenEstrogenProgesteroneProgesteroneDihydrotestosteroneDihydrotestosteroneTestosteroneTestosteroneTestosteroneTestosterone

Ovarian hormonesOvarian hormones

SteroidsSteroidsSteroidsSteroidsoo ����EstrogensEstrogens

A dA doo ����AndrogensAndrogensoo ����ProgesteroneProgesterone

PeptidesPeptides

A Steroid Molecule A Steroid Molecule

OVARIAN STEROID HORMONESOVARIAN STEROID HORMONESOVARIAN STEROID HORMONESOVARIAN STEROID HORMONES

���� Produced in both interstitial andProduced in both interstitial andf lli l llf lli l llfollicular cellsfollicular cells

���� Derivatives of cholesterol (comingDerivatives of cholesterol (comingfrom LDLfrom LDL--lipoproteins and de novolipoproteins and de novosynthesis)synthesis)sy t es s)sy t es s)

Stimulasi sintesis hormonStimulasi sintesis hormon steroidsteroid

SYNTHESISSYNTHESISSYNTHESISSYNTHESIS

ESTROGENESTROGEN

���� Chemical structure: C18Chemical structure: C18

ESTROGENESTROGEN

���� Chemical structure: C18Chemical structure: C18Source:Source:

oo follicular cellsfollicular cellsoo follicular cellsfollicular cellsoo ���� corpus luteumcorpus luteumoo ���� placentaplacentaoo ���� placentaplacentaoo ���� adrenal cortexadrenal cortexoo ���� adipose tissue (DHEA androstenedioneadipose tissue (DHEA androstenedioneoo ���� adipose tissue (DHEA → androstenedione adipose tissue (DHEA → androstenedione

→ E1)→ E1)

SYNTHESISSYNTHESISSYNTHESISSYNTHESIS

First step happens in mitochondriaFirst step happens in mitochondriap ppp pp���� All the rest in smooth ERAll the rest in smooth ER���� Reduction in number of carbon atomsReduction in number of carbon atoms���� Estrogens are primarily synthesized inEstrogens are primarily synthesized in

granulosa cellsgranulosa cells����Aromatization of Androstenedione andAromatization of Androstenedione andTestosterone within tissue is a major sourceTestosterone within tissue is a major sourceof Estrogens in the male and postof Estrogens in the male and postmenopausal female.menopausal female.

Ovarian Steroid HormonesOvarian Steroid HormonesH mH mEstrogen produced by thecal cells : the Estrogen produced by thecal cells : the major steroid in the circulationmajor steroid in the circulationmajor steroid in the circulationmajor steroid in the circulationEstrogen synthesized by granulosa cells : Estrogen synthesized by granulosa cells : a local role possibly related to ovum a local role possibly related to ovum a local role, possibly related to ovum a local role, possibly related to ovum maturation maturation FSH regulate production and subsequent FSH regulate production and subsequent FSH regulate production and subsequent FSH regulate production and subsequent induction and activation of Aromatase in induction and activation of Aromatase in the granulosa cellsthe granulosa cellsggEstradiol (E2) is oxidized to Estrone Estradiol (E2) is oxidized to Estrone within the liver and Estrone hydrated to within the liver and Estrone hydrated to Estriol (E3).Estriol (E3).

Estrogens in circulationEstrogens in circulation

EstradiolEstradiolo �� Secreted by the ovary

E t�� Estroneo �� Derived from peripheral conversion of

estradiol and androstenodione�� Estriol�� Estriol

o �� Liver metabolite of estrone

TRANSPORT IN BLOODTRANSPORT IN BLOOD

Mostly carrierMostly carrier--bound (albumin sexbound (albumin sexMostly carrierMostly carrier bound (albumin, sexbound (albumin, sexhormonehormone--binding globulin)binding globulin)

T kT k���� Two peaksTwo peaksoo ���� Before ovulationBefore ovulationoo���� MidMid--luteal peakluteal peak

���� Levels : much higher in the follicularLevels : much higher in the follicularggfluid than in the plasma!fluid than in the plasma!

Mechanisms of ActionMechanisms of ActionCytoplasmic receptor binds to steroid hormone.Cytoplasmic receptor binds to steroid hormone.

Mechanisms of ActionMechanisms of ActionCytoplasmic receptor binds to steroid hormone.Cytoplasmic receptor binds to steroid hormone.Translocates to nucleus.Translocates to nucleus.DNADNA--binding domain binds to specific HRE ofbinding domain binds to specific HRE ofDNADNA--binding domain binds to specific HRE of binding domain binds to specific HRE of the DNA.the DNA.Dimerization occursDimerization occursDimerization occurs.Dimerization occurs.

Process of 2 receptor units coming together at the 2 Process of 2 receptor units coming together at the 2 halfhalf--sites.sites.

Stimulates transcription of particular genes.Stimulates transcription of particular genes.

Mechanisms of ActionMechanisms of ActionMechanisms of ActionMechanisms of Action

Metabolism Metabolism

Metabolized to glucuronides andMetabolized to glucuronides andsulfatessulfatessulfatessulfates

���� Recycled in enterohepatic circulationRecycled in enterohepatic circulation���� Excreted in urineExcreted in urine

PhysiologicalPhysiologicalPhysiological Physiological

Development and maintenance of uterusDevelopment and maintenance of uterusDevelopment and maintenance of uterus, Development and maintenance of uterus, uterine tubes,vagina, external genitalia uterine tubes,vagina, external genitalia and breastsand breastsand breastsand breastsCyclic changes in the endometrium, Cyclic changes in the endometrium, cervix vaginacervix vaginacervix, vaginacervix, vaginaGrowth of the ovarian folliclesGrowth of the ovarian folliclesMotility of the uterine tubes ↑Motility of the uterine tubes ↑

PhysiologicalPhysiologicalPhysiological Physiological

Pregnancy: uterine muscle mass ↑Pregnancy: uterine muscle mass ↑Pregnancy: uterine muscle mass ↑, Pregnancy: uterine muscle mass ↑, excitability ↑, breasts ↑excitability ↑, breasts ↑Female secondary sex characteristics Female secondary sex characteristics yy(fat deposits, etc)(fat deposits, etc)Estrous behavior in animals, increased Estrous behavior in animals, increased libid i hlibid i hlibido in humanslibido in humans

ProgesteronProgesteron

The most distinctive hormone betweenThe most distinctive hormone betweenThe most distinctive hormone betweenThe most distinctive hormone betweenmales and femalesmales and females

���� Chemical structure: C21Chemical structure: C21���� Chemical structure: C21Chemical structure: C21���� Source:Source:���� l tl too ���� c. luteumc. luteum

oo ���� placentaplacentaoo ���� follicles (small amount)follicles (small amount)oo ���� adrenal cortexadrenal cortex

BIOSYNTHESISBIOSYNTHESISBIOSYNTHESISBIOSYNTHESIS::

FSH promotes the growth of the follicle FSH promotes the growth of the follicle by acting through receptors on the by acting through receptors on the

l ll d i d i th l ll d i d i th granulosa cells and inducing the granulosa cells and inducing the Aromatase enzyme to convert Androgens Aromatase enzyme to convert Androgens to Estrogens.to Estrogens.E g .E g .The Androgens originate from the theca The Androgens originate from the theca which is stimulated by LH through its which is stimulated by LH through its

i i i ll h ll d i i i ll h ll d receptors initially on theca cells and receptors initially on theca cells and appear in the granulosa cells and are appear in the granulosa cells and are probably coupled to the same second probably coupled to the same second probably coupled to the same second probably coupled to the same second messenger (cAMP) as FSH receptorsmessenger (cAMP) as FSH receptors

BIOSYNTHESISBIOSYNTHESIS

Progesterone synthesis is an early Progesterone synthesis is an early step in the biosynthesis of androgen step in the biosynthesis of androgen and estrogen within the thecal cell.and estrogen within the thecal cell.But circulating progesterone is But circulating progesterone is produced by corpus luteumproduced by corpus luteump y pp y p

T tT tTransportTransport

2% free2% free���� 80% albumin80% albumin--boundbound���� 18% corticosteroid18% corticosteroid--binding proteinbinding protein���� 18% corticosteroid18% corticosteroid binding proteinbinding protein

(transcortin) (transcortin) --boundbound

PhysiologicalPhysiological

Cyclic changes in the endometrium

Physiological Physiological

Cyclic changes in the endometrium, cervix, and vaginaBreasts: supports the secretory functionBreasts: supports the secretory function during lactationI hibit LH tiInhibits LH secretionResponsible for preparing the reproductive tract for implantation and the maintenance of pregnancy

Mechanism of action of Ovarian Mechanism of action of Ovarian Steroid HormonesSteroid Hormones

E2 d P t i t t ith E2 d P t i t t ith E2 and Progesterone interact with E2 and Progesterone interact with cytoplasmic and/or nuclear protein cytoplasmic and/or nuclear protein receptorsreceptorsreceptors.receptors.Release of the two receptors subunits Release of the two receptors subunits with attached steroid hormones from with attached steroid hormones from with attached steroid hormones from with attached steroid hormones from association with a heatassociation with a heat--shock protein.shock protein.Either identical subunits singly or Either identical subunits singly or E ther dent ca su un ts s ng y or E ther dent ca su un ts s ng y or possibly together interact directly with possibly together interact directly with the DNA hormone responsive element to the DNA hormone responsive element to activate transcriptional events leading to activate transcriptional events leading to translation of a celltranslation of a cell--specific protein. specific protein.

AndrogensAndrogensAndrogensAndrogens

Androstenedione and Testosterone as Androstenedione and Testosterone as Androstenedione and Testosterone as Androstenedione and Testosterone as a precursors of estrogens are a precursors of estrogens are secreted by ovaries in the beginning secreted by ovaries in the beginning secreted by ovaries in the beginning secreted by ovaries in the beginning of Puberty.of Puberty.Development of secondary sexual Development of secondary sexual Development of secondary sexual Development of secondary sexual characters almost totally by the characters almost totally by the actions of estrogensactions of estrogensactions of estrogens.actions of estrogens.

AndrogensAndrogensggAndrogens of ovarian origin may be Androgens of ovarian origin may be influenced at a pubertyinfluenced at a pubertyinfluenced at a puberty.influenced at a puberty.Acne, results from sebaceous gland Acne, results from sebaceous gland activation by ovarian androgensactivation by ovarian androgensactivation by ovarian androgens.activation by ovarian androgens.Pubic and axillary hair growth are also Pubic and axillary hair growth are also attributed to androgens of ovarian attributed to androgens of ovarian attributed to androgens of ovarian attributed to androgens of ovarian and/or adrenal origin.and/or adrenal origin.Changes in enzymic (3Changes in enzymic (3ββ--hydroxysteroid hydroxysteroid Changes in enzymic (3Changes in enzymic (3ββ hydroxysteroid hydroxysteroid dehydrogenase, 1dehydrogenase, 1--hydroxylase and hydroxylase and 17,2017,20--desmolase) activity, increased desmolase) activity, increased production of adrenal androgensproduction of adrenal androgens

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONESR l iR l iRelaxinRelaxin

oo ���� Relaxes pelvic jointsRelaxes pelvic jointsoo ���� Softens and dilates cervixSoftens and dilates cervixoo ���� Softens and dilates cervixSoftens and dilates cervixoo ���� Sperm mobility Sperm mobility -- in malesin males

InhibinInhibinInhibinInhibinoo ���� Selective inhibitory control of FSHSelective inhibitory control of FSH

ActivinActivinActivinActivinoo ���� Selective stimulaton of FSHSelective stimulaton of FSHoo ���� Cell differentiationCell differentiationoo ���� Cell differentiationCell differentiation

OVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONESOVARIAN PEPTIDE HORMONES

FollistatinsFollistatinsoo ���� Inhibit FSH secretionInhibit FSH secretion

Gonadotropin surge attenuating factorGonadotropin surge attenuating factorGonadotropin surge attenuating factorGonadotropin surge attenuating factoroo ���� Prevents premature LH surgePrevents premature LH surge

Intrafollicular Polypeptide Intrafollicular Polypeptide R l t F tR l t F tRegulatory FactorsRegulatory Factors

Several peptides have been isolated Several peptides have been isolated Several peptides have been isolated Several peptides have been isolated from ovarian follicles and regulate from ovarian follicles and regulate oocyte maturation :oocyte maturation :oocyte maturation :oocyte maturation :

1 O t M t ti I hibit1 O t M t ti I hibit1. Oocyte Maturation Inhibitor1. Oocyte Maturation Inhibitor2. Ovarian Growth Factors2. Ovarian Growth Factors3. Inhibins3. Inhibins4. Activins4. Activins4. Activins4. Activins

Intrafollicular Polypeptide Intrafollicular Polypeptide R l t F tR l t F tRegulatory FactorsRegulatory Factors

1. Oocyte Maturation Inhibitor :1. Oocyte Maturation Inhibitor :yyLow molecular weightLow molecular weight--peptidepeptideIts concentration in antral fluid decreases Its concentration in antral fluid decreases as the follicle maturatesas the follicle maturatesas the follicle maturatesas the follicle maturatesGap junctions, present between cells of Gap junctions, present between cells of the corona radiata and the oocytethe corona radiata and the oocyte

l h f lll h f ll ll ll yy

structural pathway for cellstructural pathway for cell--toto--cell cell communication.communication.OMI may exert its action indirectly OMI may exert its action indirectly OMI may exert its action indirectly OMI may exert its action indirectly through an action on cumulus cells through an action on cumulus cells LH induced oocyte maturation may result LH induced oocyte maturation may result from an uncoupling between the cumulus from an uncoupling between the cumulus from an uncoupling between the cumulus from an uncoupling between the cumulus cells and the oocytecells and the oocyte

Intrafollicular Polypeptide Intrafollicular Polypeptide R l t F tR l t F tRegulatory FactorsRegulatory Factors

2. Ovarian Growth Factors :2. Ovarian Growth Factors :2. Ovarian Growth Factors :2. Ovarian Growth Factors :Induction of LH receptors is a critical Induction of LH receptors is a critical aspect of granulosa cell differentiation aspect of granulosa cell differentiation aspect of granulosa cell differentiation aspect of granulosa cell differentiation and ovarian follicular development and ovarian follicular development Pit it FSH f ti s s th i d Pit it FSH f ti s s th i d Pituitary FSH functions as the inducer Pituitary FSH functions as the inducer of granulosa cell LH receptor of granulosa cell LH receptor

isiti n isiti n acquisition acquisition This FSHThis FSH--dependent LH receptor dependent LH receptor

d h b d b EGF d FGFd h b d b EGF d FGFinduction is inhibited by EGF and FGFinduction is inhibited by EGF and FGF

Intrafollicular Polypeptide Intrafollicular Polypeptide R l t F tR l t F tRegulatory FactorsRegulatory Factors

3. Inhibin :3. Inhibin :..Inhibin is present in follicular fluid, Inhibin is present in follicular fluid, ovarian and granulosa cell extracts ovarian and granulosa cell extracts ggInhibin exerts a suppressive action on Inhibin exerts a suppressive action on both basal and GnRHboth basal and GnRH--stimulated stimulated pituitary FSH secretionpituitary FSH secretionCirculating levels of Inhibin are Circulating levels of Inhibin are g fg finversely related to plasma FSH levels.inversely related to plasma FSH levels.Inhibin can be detected in the plasma Inhibin can be detected in the plasma ppof women given FSH, but not in of women given FSH, but not in castrated subjects. castrated subjects.

Intrafollicular Polypeptide Intrafollicular Polypeptide Regulatory FactorsRegulatory FactorsRegulatory FactorsRegulatory Factors

3. Inhibin :3. Inhibin :Inhibin mp s d f t s b nits th t Inhibin mp s d f t s b nits th t Inhibin composed of two subunits that Inhibin composed of two subunits that are linked by disulfide bridges are linked by disulfide bridges

h b (h b ( ) d d b ) d d b The two subunits (The two subunits (αα, , ββ) encoded by ) encoded by separated genesseparated genesThe control of inhibin biosynthesis is The control of inhibin biosynthesis is at the level of transcription. at the level of transcription. pp

Intrafollicular Polypeptide Intrafollicular Polypeptide R l t F tR l t F tRegulatory FactorsRegulatory Factors

4. Activin :4. Activin :Purified fractions of follicular fluid Purified fractions of follicular fluid exhibited stimuli rather than inhibitory exhibited stimuli rather than inhibitory effects on FSH release from pituitaries effects on FSH release from pituitaries effects on FSH release from pituitaries effects on FSH release from pituitaries invitro.invitro.ββ Subunits of inhibin and transforming Subunits of inhibin and transforming growth factor growth factor ββ (TGF(TGFββ) were similar) were similargrowth factor growth factor ββ (TGF(TGFββ) were similar.) were similar.Dimers of the Dimers of the ββ subunits of inhibin, subunits of inhibin, ββAAββBB, , ββAAββAA and and ββBB ββBB were named Activin, Activin A were named Activin, Activin A ββAAββAA ββBB ββBB ,,and Activin Band Activin BActivin can enhance basal secretion of FSH Activin can enhance basal secretion of FSH in a dosein a dose--dependent manner in vitro without dependent manner in vitro without in a dosein a dose--dependent manner in vitro without dependent manner in vitro without affecting the secretion of LH.affecting the secretion of LH.