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)