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PCOSandYourFertility
JimToner,MD,PhDAtlantaCenterforReproductiveMedicine
PCOS
Consequences
• Androgenexcess• Acne,oilyskin• Unwantedhair,malepatternbaldness
• Insulinexcess• Diabetes,heartdisease,highbloodpressure
• Anovulation• Infertility• Miscarriage• Endometrialcancer
Causesandconsequences
“bad”Genetics
Ovary
↑Androgens↑InsulinhighBodyMass
lowExercise
poorDietSkin
Metabolism
Medicinestocontrol
Inflammation
Cellulardisorder
ExcessinsulinsecretioninPCO
FertilityGoals
•Havingahealthychildsafely• Gettingpregnant
• Ensureovulation• Bypasshostilecervicalmucus
• Stayingpregnant• Reducingmiscarriagerisk
• Safepregnancy• Reducingriskstomom• Reducingriskstochild
Goal#1:Ovulation
• Firstline:• Improveddiet• Aerobicactivity• Inositol• Metformin
• Ifinsufficient:• Clomipheneorletrozole• Dexamethasone• Invitrofertilization
DietaryGoals
INCREASE: DECREASE:
•Complexcarbohydrates•Monosaturated fats• Fiber•Omega-3fattyacids
• Totalcaloricintake• Saturatedfats• Sugars
Dietaryrecommendations• Low“GlycemicIndex”food:
• Producesgreaterweightloss• Induceslessinsulinresistance
RobertsSBetal.,AmColl Nutr.21:140S,2002SpiethLEetal.,ArchPedAdol.154:947,2000JenkinsDJetal.,Curr Opin Clin Nutr Metab Care.6:165,2005
LowGI mostfruitandvegetables(butnotpotato),basmatirice,oats,All-bran
MediumGI sucrose,Marsbar
HighGI cornflakes,bakedpotato,jasminerice,whitebread,whiterice(Chinese/Japanese)
Exercise
•Musclecellsmetabolize80%ofglucose•Aerobicexercise:
• 3to4sessionsof20-30min/wk• Burns100-200kcal• 40%improvementininsulinsensitivitythatlasts2days.
DeFronzo etal.,Diabetes36:1379,1987.Seagal etal.,JAppl Physiol 71:2502,1991.
MedicinesforPCOS
• Inositol• Metformin• Clomiphene• Letrozole• Dexamethasone• Gonadotropins(FSH,LH)
Inositol• 2types,normallypresentinourbodies
• Myo-inositol– hasdirectovarianeffects• Precursorofinositoltriphosphate,asecondmessengerofinsulin,FSHandTSH
• D-chiro-inositol– actsoutsidetheovarianprimarily• Normallyconvertedbyinsulinepimeraseintomyo-inositol
• Normallypresentin40:1ratio
• Myo-inositol• FacilitatesglucoseuptakeandFSHaction
• D-Chiro-inositol• Facilitatesglucoseuptakeandglycogensynthesis
Dailydosing
Myo-inositol=2,000mgD-chiro-inositol=50mg
+
Metformineffects
• Decreases insulin secretion levels & LH
• Increased SHBG
• Decreases androgens§ Total T ß 38%§ Free T ß 58%§ Androstenedione ß 58%
§Reduction in weight§ Improved ovulation rates§ Improved pregnancy rates§Reduced miscarriage rates
Nestler J. N Engl J Med 1996;335:617Hass DA. Fertil Steril 2003;79:469.
Macial GA, Fertil Steril 2004;81(2):355Legro RS. N Engl J Med 2007:356:551
Metforminaction
Metformin
• Actstoreduceglucoseproductioninliver• IncreasedoseslowlytominimizeGIsideeffects
• Targetdose:750to2,500mgdaily• Extendedreleasecanbetakenoncedailywithdinner
Sufficient?
• Trackmenstrualperiods• Ifoccurringatintervalsbetween21and35days,likelyovulating
• CanuseOPKs(ovulationpredictorkits)toverify:• Ensuregoingfromnegativetopositive• Usuallyoccurs2weeksbeforeperiodbegins
• Ifsufficient,noneedtoaddothermedications• TimeintercoursetodayofandafterLHsurgeonOPK
Clomipheneversusletrozole
clomiphene
letrozole
Advantagesofletrozoleoverclomiphene
• MorepregnanciesinPCOandoverweightpatients• Fewersideeffects
• Headaches,hotflashes,moodeffects• Lessimpactoncervicalmucus• Shorterhalflife
• Fewercysts• Gonebeforeimplantation,solowerriskofaffectingfetaldevelopment
Roleofdexamethasone
• Ifclomipheneandletrozolealonefail
• Reducesandrogenlevels,allowingforbetterovarianresponse
• Dose:0.5to2.0mgdailyeachmorningfromdays3toovulation
Dexamethasonecanhelp
• dexamethasone 0.5 mg with clomiphene
Daley et. al., F&S, 1984; 41:844-9Isaac JD, F&S, 1997; 641-3
0102030405060708090
100
Ovulation PREG
Clomiphene
CC + Dex
Cyclemanagementforconception
3……………..75……………..9
letrozoleorclomiphene
(-)(-)(+)Ovul
IUI
intercourse
inositol
metforminER
dexamethasone
Ultrasoundtoverify
response
Progesteronetoverifyovulation
Goal2:stayingpregnant
•Controldiabetespre-conceptually• HemoglobinA1c<8%
• Insulinresistanceassociatedwithmoremiscarriages• Inositoland/ormetformin
Group Design Metformin Miscarriage rate
ref
PCO retrospectiveN=99 preg
Yes 9% JCEM 87:524-9, 2001.
No 42%
PCO ProspectiveN=32 preg
Yes 10% F&S 75:46-52, 2001.
No 73%
ReducingmiscarriagesinPCO
Goal3:Safepregnancy
• Striveforoptimalweightbeforeconception• Improvecardiovascularhealthbeforeconception•Closemonitoringofpregnancy
Risksofbeingoverweight
• Tomom:• Highbloodpressure/pre-eclampsia• Diabetes• C-section
• Tochild:• Miscarriage• Prematuredelivery• Stillbirths• Fetalmacrosomia
Summary
• Diet,exercisehasmanybenefits• Ifoverweight,a5%losscanleadtospontaneousovulation• Toimprovemetabolicfunction:
• inositol• metformin
• Toinduceovulation:• letrozoleormetformin• IVF(butnotFSH/IUI)
Recommended