EBM Management of Polycystic Ovary

EBMManagementof

PolycysticOvary

Dr. Marwan AlhalabiAssistant Professorin Faculty of medicineDamascus University

And

Orient Hospital Assisted Reproduction Center Damascus – Syria

PCOS- claimsintheliterature-

Prevalence

• 5-10% general female population

• Up to 30% of infertility population

PCOS- diagnosticdillema’s -

Clinicalfeatureshirsutism/acneobesityanovulation

EndocrinefeatureshighandrogenshighLHinsulinresistance

Polycysticovariesincreasedfollicle#increasedstromaincreasedovarianvolume

5

6

RotterdamPCOSconsensusworkshop,May2003F&S,Jan2004HR,Jan2004

PCOSdiagnosticcriteriaoligo and/oranovulationhyperandrogenemiapolycysticovaries

8

Polycysticovarysyndrome(PCOS)

Criteria*:

• oligo- oranovulation

• clinicaland/orbiochemicalsignsofhyperandrogenism

• polycysticovariesonultrasound

*2003RotterdamPCOSconsensus

Maximalexpressionoccursinpreantralandsmallantralfollicles1,2

Expressiondisappearsinmaturingpre-ovulatory follicles(expressionrestrictedtoGCsofthecumulus)2

1.Laven etal. JClin Endocrinol Metab2004;89:318–323;2.Weenen etal.Mol HumReprod 2004;10:77–83;3.Cook etal.Fertil Steril 2000;73:859–861;4. LaMarcaetal.HumReprod 2004;19:2738–2741;5.LaMarcaetal.HumReprod 2006;21:3103–3107

Anti-Müllerian hormone(TGF-β superfamily:Müllerian ductregressioninmaleembryos)

AMH

AMHisexpressedinpre-antralandsmallantral

follicles.

AMHisthusagoodindicatorofthesizeoftheovarianantralfolliclepool.

AMH concentrations

AMH measured by Beckman-Coulter Gen II assay

Groups No AMH (pmol/l)

Controls 90 23.6 (15.0)*

PCOM 35 52.2 (35.0)**

PCOS 90 77.6 (61.0)***

P<0.05

P<0.001

PCOM vs PCOS

Controls vs PCOMControls vs PCOS

• WomenwithPCOSgainregularmenstrualcycleswhenaging

• Menstrualcyclerestoredinthosewithasmallerfolliclecount

Elting etal,2000,2003

EffectofagingonPCOS

AnovulationA excess LH +insulin

Multiple small follicles

AMH

FSH action

Anovulation progesterone

IncreaseInGnRH Pulsatility

ß LH FSH

Increase AndrogenSynthesis

Inhibitionoffolliculogenesis

Oligo/Anovulation- hormoneserumprofile-

Normal

E2 (pg/ml)

FSH (IU/L)

10

High

Low

Normal

Low1

40

10

ClassificationofAnovulatoryinfertility

Serum Gonadotropins&

Serum Estradiol levels

FSH & LH: Low&

Estradiol: Low

FSH : NormalLH: Normal / Elevated

&Estradiol: Normal

FSH & LH: Elevated&

Estradiol: Low

WHO I WHO II WHO III

Ovulation InductionGn-RH, FSH and LH

Eventually IVF

Ovulation InductionCC and/or rFSHEventually IVF

Ovulation Induction ?IVF ?

Egg Donation

10 % 10 %80 %

PCOS- hyperandrogenemia -

• Testosteronetotalorfree(unbound)

• Freeandrogenindex(Tx100/SHBG)

• Androstenedione• Otherandrogens• combination

SerumEndocrinology

• ­FastingInsulin.

• ­Androgens(Testosteron andAndrostendion).

• ­LH(UsuallyNormalFSH).

• S̄HBG.

• ­FreeAndrogenindex.

• ­Estradiol.

• ­Prolactine.

PCOS- polycysticovaries-

• Transabdominal versustransvaginal• Fewcontrolledstudies• Folliclenumber>12mm• Folliclesize<10• localisation??• Ovarianstroma

objective???• Ovarianvolume

Balen, HRU 2003

Treatment

Irregularbleeding Hirsutism infertilityGeneral

healthrisk

Oralcontraceptive

MedicalOvulationinduction

Metformin

PCOSChronicanovulationAndandrogenexcess

OralContraceptiveandspironolactone

Ifoverweight,behavioralweightreduction

Ovarianstimulation

• Anovulation

• Singledominantfollicledevelopment

• Normalcycle

• Multipledominantfollicledevelopment

Ovulationinduction

Ovarian(hyper)stimulation

ElementsoftheIdealOvulationInductionProtocolforPCOS

• Minimizeamountofmedication.• Easeofcompliance.• Nomultiples(ashighas15%-20%)• NoOHSS(10%-15%)• Nocancellations(poorresponse/highresponseorprematureluteinization 10%-40%)

• Nomiscarriages(30%-50%higher)

Type1: OvulationFailure

Type2: ConceptionFailure

Type3: Pregnancyloss(Miscarriages)

PCOS- ClomipheneCitrateResistance-

PCOS- Therapeutic Plan -

Management of clomiphene resistance (1)

Weight Reduction

Persistently poor

Ceevical mucus and

endometrial response

Raised Serum

DHEAS or testosterone

Raised Serum

prolactin

Fasting Serum insuline >25IUFasting blood

sugar : insuline ratio >4.5

Tamoxifen 20mg/day from day 2-5X5 days

Gonadortopins

Letrozole 2.5-5mg/day from day 2-5X5 days Dexamethasone 0.5mg/day

Prednisolone 5g/dayContinuously or in follicular phase

Bromocriptine 2.5mg b.d or t.d.sCarbogoline 0.5 3mg/week

Surgical ovulation induction

Metformin 1500mg/dayRosiglitazone 45mg/dayPioglitazone 4mg/day

D-chiro inositol 1200 mg/day

One time treatment

No monitoring required

No hyperstimula

tion

Management of clomiphene resistance (2)

Persistent luteinized

unruptured follicle

GnRH antagonist added along with FSH from Day7to

suppress LH surge

Gonadotropins with clomiphene

Clomiphene for 7-10 Days

Raised LH

Inj. HCG 5000-10000IU when follicle is 18-20 mm

Clomiphene 100mg from day 2-6

FSH 150 IU Day 6 onwards

Ovarian Suppression

GnRH agonist

OralContraceptives

Combined treatment

Greater LH SuppressionNo estrogen deficiency

Ovarianstimulationbyinterferencewith

Efeedback

• Clomiphene citrate• Tamoxifen• Other SERMs ?• Aromatase inhibitors

Why isPCOSdifferent?

Greater sensitivity to gonadotrophinstimulation

therefore:

Multiple(“explosive”)folliculardevelopment

Whymultifollicular responsetogonadotrophins?

• Insulin,growthfactor,bindingproteinratios

• VEGF

• Androgensinfollicularfluid

• Toomanyantral follicles

Lowdoseprotocols

• Step-down(Fauser)

• Sequentialstep-up/step-down(Hugues)

100

75

If <10mm10mm

3 days hCG

50

5075

100

14 days21

1

Step-up

Step-down

Conclusions1

• Step-upsaferandmoreefficientthanstep-down

- lowerrateofoverstimulation

- higherrateofmonofollicular cycles

- higherovulationrate

Christin-Maitre&Hugues

TechniqueofOvariandrilling

ÜLaparoscopyÜ3-4porttechniqueÜ IrrigationÜAvoidthehilumandtheovarianligamentÜPuncturesundervision,donotloosesightoftheneedle

ÜRecommended4diathermypointsperovary,4secs and40W

Laparoscpic OvarianDrilling

4 4 40Armeretal

OvulationafterLODinrelationtothenumberofpunctures

6972717374

88

77

66

9080706050403020100

>2 3 4 5 6 7 8 <8

IndicationofLOD

1.Clomifene resistance.

2.Persistenthypersecretion ofLH.

3. Combinedwithpelvicassessment.

4. Gonadotropinresistance.

5.Persistentoverstimulation.

Advantages

ÜHighprevalenceofmono-folliculargrowthÜLowermultiplepregnanciesÜReductioninmiscarriagesÜSuccessful“OneOff” procedure”ÜLowerOHSSÜIfovulationdoesnotoccurin2-3months,thenusingthesameearliermedication,ovariesaremoreresponsive

Etiology

PCOSManagementOligo/anovulation

+PCOS

clomifenex4-6ovulatorycyclesornoresponse

Pregnancy

Weightloss± metformin

Clomiphenefailure

+metformin

Low-doseFSHx4-6ovulatorycycles

Pregnancy

Laparoscopicovariandrilling(± CCorFSH)

IVF/ET Pregnancy

Letrozol

Highresponders- whyantagonist?

• AshorterdurationofstimulationwithGnRHantagonist

• Gonadotrophin requirementsaredecreasedcomparedtoGnRH agonists

• OHSSincidencedecreased

• Allowstheuseofanagonisttrigger.

FSH

hCG

FSH

hCG

0.25mg/dayantagonist

Day5,6or7antagoniststartFIXED

0.25mg/dayantagonist

day8/9

Folliclesize14mm- startantagonistFlexibleregime

FSH

GnRHagonist

FSH

0.25mg/dayantagonist

Day5,6or7antagoniststart FIXED

0.25mg/dayantagonist

day8/9

Folliclesize14mm- startantagonist

Flexible GnRHagonist

GnRH agonisttriggervs hCG

• ProducesanendogenousLHsurgesimilartoanaturalcycle.

• SmalleramplitudethanhCG

• Muchshorterhalf-life.

• ReleaseslessVEGF

FSH

GnRHagonist

0.25mg/dayantagonist

Day5startFIXED

Lutealphasesupportpossibilities:1.MassivedosesProgesterone(i/m50mg/day)+E2

2.1500IUhCG ondayOPU(Humaidan 2009)

3.Freezeallembryosandtransferinnaturalcycle

FSH

GnRHagonist

0.25mg/dayantagonist

Day5startFIXED

Lutealphasesupport:1500IUhCGondayOPU(Humaidan2009)

NosignificantdifferenceinoutcomecomparedwithhCGtrigger

Advice

• If>25follicles>11mm

Freezeall!

MetformininIVF

• Shorttermco-treatmentwithmetforminforPCOSinIVF/ICSI:

• Doesnotimproveresponsetostimulation• Improvespregnancyrates?• ReducestheriskofOHSS

Tang,Bart&Balen,2005

Thank you...

Thankyou