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
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