EBM Management of Polycystic Ovary
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EBMManagementof
PolycysticOvary
Dr. Marwan AlhalabiAssistant Professorin Faculty of medicineDamascus University
And
Orient Hospital Assisted Reproduction Center Damascus – Syria
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PCOS- claimsintheliterature-
Prevalence
• 5-10% general female population
• Up to 30% of infertility population
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PCOS- diagnosticdillema’s -
Clinicalfeatureshirsutism/acneobesityanovulation
EndocrinefeatureshighandrogenshighLHinsulinresistance
Polycysticovariesincreasedfollicle#increasedstromaincreasedovarianvolume
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RotterdamPCOSconsensusworkshop,May2003F&S,Jan2004HR,Jan2004
PCOSdiagnosticcriteriaoligo and/oranovulationhyperandrogenemiapolycysticovaries
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Polycysticovarysyndrome(PCOS)
Criteria*:
• oligo- oranovulation
• clinicaland/orbiochemicalsignsofhyperandrogenism
• polycysticovariesonultrasound
*2003RotterdamPCOSconsensus
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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)
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AMH
AMHisexpressedinpre-antralandsmallantral
follicles.
AMHisthusagoodindicatorofthesizeoftheovarianantralfolliclepool.
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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
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• WomenwithPCOSgainregularmenstrualcycleswhenaging
• Menstrualcyclerestoredinthosewithasmallerfolliclecount
Elting etal,2000,2003
EffectofagingonPCOS
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AnovulationA excess LH +insulin
Multiple small follicles
AMH
FSH action
Anovulation progesterone
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IncreaseInGnRH Pulsatility
ß LH FSH
Increase AndrogenSynthesis
Inhibitionoffolliculogenesis
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Oligo/Anovulation- hormoneserumprofile-
Normal
E2 (pg/ml)
FSH (IU/L)
10
High
Low
Normal
Low1
40
10
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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 %
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PCOS- hyperandrogenemia -
• Testosteronetotalorfree(unbound)
• Freeandrogenindex(Tx100/SHBG)
• Androstenedione• Otherandrogens• combination
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SerumEndocrinology
• FastingInsulin.
• Androgens(Testosteron andAndrostendion).
• LH(UsuallyNormalFSH).
• S̄HBG.
• FreeAndrogenindex.
• Estradiol.
• Prolactine.
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PCOS- polycysticovaries-
• Transabdominal versustransvaginal• Fewcontrolledstudies• Folliclenumber>12mm• Folliclesize<10• localisation??• Ovarianstroma
objective???• Ovarianvolume
Balen, HRU 2003
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Treatment
Irregularbleeding Hirsutism infertilityGeneral
healthrisk
Oralcontraceptive
MedicalOvulationinduction
Metformin
PCOSChronicanovulationAndandrogenexcess
OralContraceptiveandspironolactone
Ifoverweight,behavioralweightreduction
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Ovarianstimulation
• Anovulation
• Singledominantfollicledevelopment
• Normalcycle
• Multipledominantfollicledevelopment
Ovulationinduction
Ovarian(hyper)stimulation
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ElementsoftheIdealOvulationInductionProtocolforPCOS
• Minimizeamountofmedication.• Easeofcompliance.• Nomultiples(ashighas15%-20%)• NoOHSS(10%-15%)• Nocancellations(poorresponse/highresponseorprematureluteinization 10%-40%)
• Nomiscarriages(30%-50%higher)
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Type1: OvulationFailure
Type2: ConceptionFailure
Type3: Pregnancyloss(Miscarriages)
PCOS- ClomipheneCitrateResistance-
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PCOS- Therapeutic Plan -
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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
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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
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Ovarianstimulationbyinterferencewith
Efeedback
• Clomiphene citrate• Tamoxifen• Other SERMs ?• Aromatase inhibitors
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Why isPCOSdifferent?
Greater sensitivity to gonadotrophinstimulation
therefore:
Multiple(“explosive”)folliculardevelopment
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Whymultifollicular responsetogonadotrophins?
• Insulin,growthfactor,bindingproteinratios
• VEGF
• Androgensinfollicularfluid
• Toomanyantral follicles
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Lowdoseprotocols
• Step-down(Fauser)
• Sequentialstep-up/step-down(Hugues)
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100
75
If <10mm10mm
3 days hCG
50
5075
100
14 days21
1
Step-up
Step-down
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Conclusions1
• Step-upsaferandmoreefficientthanstep-down
- lowerrateofoverstimulation
- higherrateofmonofollicular cycles
- higherovulationrate
Christin-Maitre&Hugues
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TechniqueofOvariandrilling
ÜLaparoscopyÜ3-4porttechniqueÜ IrrigationÜAvoidthehilumandtheovarianligamentÜPuncturesundervision,donotloosesightoftheneedle
ÜRecommended4diathermypointsperovary,4secs and40W
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Laparoscpic OvarianDrilling
4 4 40Armeretal
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OvulationafterLODinrelationtothenumberofpunctures
6972717374
88
77
66
9080706050403020100
>2 3 4 5 6 7 8 <8
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IndicationofLOD
1.Clomifene resistance.
2.Persistenthypersecretion ofLH.
3. Combinedwithpelvicassessment.
4. Gonadotropinresistance.
5.Persistentoverstimulation.
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Advantages
ÜHighprevalenceofmono-folliculargrowthÜLowermultiplepregnanciesÜReductioninmiscarriagesÜSuccessful“OneOff” procedure”ÜLowerOHSSÜIfovulationdoesnotoccurin2-3months,thenusingthesameearliermedication,ovariesaremoreresponsive
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Etiology
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PCOSManagementOligo/anovulation
+PCOS
clomifenex4-6ovulatorycyclesornoresponse
Pregnancy
Weightloss± metformin
Clomiphenefailure
+metformin
Low-doseFSHx4-6ovulatorycycles
Pregnancy
Laparoscopicovariandrilling(± CCorFSH)
IVF/ET Pregnancy
Letrozol
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Highresponders- whyantagonist?
• AshorterdurationofstimulationwithGnRHantagonist
• Gonadotrophin requirementsaredecreasedcomparedtoGnRH agonists
• OHSSincidencedecreased
• Allowstheuseofanagonisttrigger.
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FSH
hCG
FSH
hCG
0.25mg/dayantagonist
Day5,6or7antagoniststartFIXED
0.25mg/dayantagonist
day8/9
Folliclesize14mm- startantagonistFlexibleregime
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FSH
GnRHagonist
FSH
0.25mg/dayantagonist
Day5,6or7antagoniststart FIXED
0.25mg/dayantagonist
day8/9
Folliclesize14mm- startantagonist
Flexible GnRHagonist
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GnRH agonisttriggervs hCG
• ProducesanendogenousLHsurgesimilartoanaturalcycle.
• SmalleramplitudethanhCG
• Muchshorterhalf-life.
• ReleaseslessVEGF
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FSH
GnRHagonist
0.25mg/dayantagonist
Day5startFIXED
Lutealphasesupportpossibilities:1.MassivedosesProgesterone(i/m50mg/day)+E2
2.1500IUhCG ondayOPU(Humaidan 2009)
3.Freezeallembryosandtransferinnaturalcycle
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FSH
GnRHagonist
0.25mg/dayantagonist
Day5startFIXED
Lutealphasesupport:1500IUhCGondayOPU(Humaidan2009)
NosignificantdifferenceinoutcomecomparedwithhCGtrigger
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Advice
• If>25follicles>11mm
Freezeall!
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MetformininIVF
• Shorttermco-treatmentwithmetforminforPCOSinIVF/ICSI:
• Doesnotimproveresponsetostimulation• Improvespregnancyrates?• ReducestheriskofOHSS
Tang,Bart&Balen,2005
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Thank you...
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Thankyou