A Life of PCOSA Life of PCOS

Roy HomburgRoy Homburg

Barzili Medical Centre, Ashkelon and Maccabi Medical Barzili Medical Centre, Ashkelon and Maccabi Medical Services, IsraelServices, Israel

Homerton Fertility Centre, LondonHomerton Fertility Centre, London

PCOS – A typical case historyPCOS – A typical case history

A life in 25 minutes of ………..A life in 25 minutes of ………..

Polly SistikPolly Sistik

Polly SistikPolly Sistik

Age 16, schoolgirl.Age 16, schoolgirl.c/o irregular periods, acne, hirsutism.c/o irregular periods, acne, hirsutism.All symptoms started age 13.5 when had All symptoms started age 13.5 when had first period, since then 3-4 periods/year. first period, since then 3-4 periods/year.

o/e o/e Obese – BMI 31.5Obese – BMI 31.5Abdo circ. 92cmAbdo circ. 92cmAcne face and backAcne face and backMild hirsutismMild hirsutism

PCOS revised diagnostic criteriaPCOS revised diagnostic criteria~ 2003 Rotterdam consensus ~~ 2003 Rotterdam consensus ~

2 out of 3 criteria 2 out of 3 criteria requiredrequired

Oligo- and/or anovulationOligo- and/or anovulation

Hyperandrogenism (clinical and/or Hyperandrogenism (clinical and/or biochemical)biochemical)

Polycystic ovariesPolycystic ovaries

Exclusion of other aetiologiesExclusion of other aetiologies

ultra-sound

hormones

symptoms OBESITY

INSULININSULIN

after Dewailly, 2003

Treatment aims & optionsTreatment aims & options

• Life-style changesLife-style changes

• Anti-androgens / OC pillAnti-androgens / OC pill

•? metformin? metformin

Cure acne and hirsutism

Regulate menstruation

ultra-sound

hormones

symptoms

OBESITY

INSULININSULIN

WEIGHTLOSS

after Dewailly, 2003

HIRSUTISM/ACNEHIRSUTISM/ACNETREATMENTTREATMENT

- Cyproterone acetate + ethinyl estradiol- Cyproterone acetate + ethinyl estradiol - Drosperinone + ethinyl estradiol- Drosperinone + ethinyl estradiol

- Contraceptive pills- Contraceptive pills

- Cosmetic treatmentCosmetic treatment

- Metformin not recommended as first line treatment Metformin not recommended as first line treatment

Polly Sistik – age 24Polly Sistik – age 24

• Engaged to be married.Engaged to be married.

• BMI now 28BMI now 28

• Amenorrhea for the last 6 months.Amenorrhea for the last 6 months.

• Wants to know her chances of Wants to know her chances of conceiving.conceiving.

72%72%

Polly Sistik – age 25Polly Sistik – age 25

• Married. Married.

• Trying to conceive for 6 months.Trying to conceive for 6 months.

• 4 periods in the last year.4 periods in the last year.

• ExaminationsExaminations

• TreatmentTreatment

Multiple ChoiceMultiple Choice

• Weight lossWeight loss• Clomiphene citrate (CC)Clomiphene citrate (CC)• Aromatase inhibitorsAromatase inhibitors• Insulin lowering medicationsInsulin lowering medications

• Low dose FSHLow dose FSH• Laparoscopic ovarian drillingLaparoscopic ovarian drilling• IVF/IVMIVF/IVM

ClomipheneClomiphene

Homburg, Hum Reprod, 2005Homburg, Hum Reprod, 2005

n = 5268 patientsn = 5268 patients

Ovulation - 3858 Ovulation - 3858 (73%)(73%)

Pregnancies - 1909 Pregnancies - 1909 (36%)(36%)

Miscarriage - 827 Miscarriage - 827 (20%)(20%)

Multiple pregnancy rateMultiple pregnancy rate - - 8%8%

Single live-birth rate – 25%Single live-birth rate – 25%

Should we give hCG in CC cycles? Should we give hCG in CC cycles? Agarwal & Buyalos, 1995Agarwal & Buyalos, 1995

No improvement in conception ratesNo improvement in conception rates

Deaton et al, 1997Deaton et al, 1997

No differenceNo difference

Viahos et al, 2005Viahos et al, 2005

hCG may be beneficialhCG may be beneficial

Kosmas et al, 2007 Meta-analysisKosmas et al, 2007 Meta-analysis

Favoured hCG but noFavoured hCG but no significant differencesignificant difference

Brown et al, 2009, Cochrane reviewBrown et al, 2009, Cochrane review

No difference No difference

NO

NO

Maybe

Yes

NO

Should we monitor clomiphene Should we monitor clomiphene cycles with ultrasound?cycles with ultrasound?

Konig, Homburg et al, ESHRE, 2009 Konig, Homburg et al, ESHRE, 2009

With U/S + hCGWith U/S + hCGNo U/S or hCGNo U/S or hCG

nn105105150150

Cumulative Cumulative pregnancy ratepregnancy rate48%48%34.7%34.7%

DeliveriesDeliveries35.6%35.6%26.7%26.7%

Multiple Multiple pregnanciespregnancies0011

Reasons for Clomiphene FailureReasons for Clomiphene Failure

Ovulation Ovulation

but no conceptionbut no conception

• Anti-estrogen effectsAnti-estrogen effects

- Cervical mucus- Cervical mucus

- Endometrium- Endometrium

• High LHHigh LH

Failure to ovulateFailure to ovulate

• FAIFAI

• BMIBMI

• LHLH

• InsulinInsulin

Failure to ovulateFailure to ovulate

• FAIFAI

• BMIBMI

• LHLH

• InsulinInsulin

Clomiphene Citrate TreatmentClomiphene Citrate Treatment

ERER

ERER

E2E2FSHFSH

Day 5Day 5

CCCC

ERER

ERER

Anti-estrogen effect on endometriumAnti-estrogen effect on endometrium

• Endometrial thinning in 15-50% Endometrial thinning in 15-50%

(Gonen &Casper, 1990;Dickey et al, 1993)(Gonen &Casper, 1990;Dickey et al, 1993)

• Causes ER downregulation and depletion.Causes ER downregulation and depletion.• Suppresses pinopode formation Suppresses pinopode formation (Creus et al, 2003)(Creus et al, 2003)

• No pregnancies when endometrial thickness at midcycle No pregnancies when endometrial thickness at midcycle < 7mm< 7mm

• Not dose related and recurs in repeat cycles Not dose related and recurs in repeat cycles

(Homburg et al, 1999)(Homburg et al, 1999)

Aromatase Inhibitor Treatment:Aromatase Inhibitor Treatment:Day 3-7 of CycleDay 3-7 of Cycle

ERER

ERER

E2E2FSHFSH

AIAI

ERER

ERER

Casper & MitwallyCasper & Mitwally

Aromatase Inhibitors:Aromatase Inhibitors:Theoretical AdvantagesTheoretical Advantages

• Do not block estrogen receptorsDo not block estrogen receptors • No detrimental effect on endometrium No detrimental effect on endometrium or cervical mucusor cervical mucus • Negative feedback mechanism not Negative feedback mechanism not turned off—less chance of multiple turned off—less chance of multiple follicular development follicular development

ERER

ERER

E2E2FSHFSH

Day 5Day 5

Clomiphene Citrate TreatmentClomiphene Citrate Treatment

ERER

ERER

Day 10Day 10

FSHFSH

E2E2

CCCC CCCC

ERER

ERER

ERER

ERER

Casper & MitwallyCasper & Mitwally

ERER

ERER

E2E2FSHFSH

AIAI

Day 5Day 5

Aromatase Inhibitor TreatmentAromatase Inhibitor Treatment

ERER

ERER

E2E2

FSHFSH

Day 10Day 10

ERER

ERER

ERER

ERER

Casper & MitwallyCasper & Mitwally

Aromatase InhibitorAromatase InhibitorQuestionsQuestions

• Do they work?Do they work?

• Better than CC for first-line treatment?Better than CC for first-line treatment?

• Safety?Safety?

Aromatase Inhibitors vs CCAromatase Inhibitors vs CC

• Meta-analysis, 4 RCTsMeta-analysis, 4 RCTs

• Clear superiority of aromatase inhibitors Clear superiority of aromatase inhibitors in pregnancy rates (OR 2.0) and in pregnancy rates (OR 2.0) and deliveries (OR 2.4)deliveries (OR 2.4)

Polyzos et al, Fertil Steril, 2008Polyzos et al, Fertil Steril, 2008

Letrozole vs CCLetrozole vs CC

• 911 newborns in 5 centers911 newborns in 5 centers

CC LetrozoleCC LetrozolePregnancies 397Pregnancies 397 514514

Congenital Congenital 19 19 (4.8%)(4.8%) 14 14 (2.7%)(2.7%)

malformationsmalformations

Major malformations 12 Major malformations 12 (3%)(3%) 6 6 (1.2%)(1.2%)Total cardiac anomalies Total cardiac anomalies 1.8%1.8% 0.2%0.2%

Tulandi et al, 2006Tulandi et al, 2006

Aromatase InhibitorsAromatase Inhibitors

• Letrozole 2.5-10 mg/day, n=1102Letrozole 2.5-10 mg/day, n=1102

• Pregnancies 368 (33.4%)Pregnancies 368 (33.4%)

– Miscarriages 99 (26.9%)Miscarriages 99 (26.9%)

– Twins 2 (0.5%)Twins 2 (0.5%)

– Fetal anomalies 1 (0.2%)Fetal anomalies 1 (0.2%)

Aghssa et al, 2007 (PCOS, eds Allahbadia, Agrawal)Aghssa et al, 2007 (PCOS, eds Allahbadia, Agrawal)

Metformin for ovulation Metformin for ovulation induction?induction?

Live birth ratesLive birth rates

CCCC MetforminMetformin CC+metforminCC+metformin

22.5% 7.2% 26.8%22.5% 7.2% 26.8% Legro et al, NEJM, 2007Legro et al, NEJM, 2007

15.4% 7.9% 21.1%15.4% 7.9% 21.1%

Zain et al, Fertil Steril, 2009Zain et al, Fertil Steril, 2009

Insulin-sensitising drugs for women with Insulin-sensitising drugs for women with PCOS, oligo/amenorrhea and subfertilityPCOS, oligo/amenorrhea and subfertility

• Tang et al. Cochrane Database, 2009Tang et al. Cochrane Database, 2009

There is no evidence that metformin improves live There is no evidence that metformin improves live birth rates whether it is used alone or in birth rates whether it is used alone or in combination with clomiphene, or when compared combination with clomiphene, or when compared with clomiphene. with clomiphene.

Therefore, the use of metformin in improving Therefore, the use of metformin in improving reproductive outcomes in women with PCOS reproductive outcomes in women with PCOS appears to be limited.appears to be limited.

Maitake mushroomMaitake mushroomChen JT et al, J Altern Complement Med, 2010Chen JT et al, J Altern Complement Med, 2010

• Maitake mushroom extract improves insulin Maitake mushroom extract improves insulin resistance.resistance.

• Capable of inducing ovulation in PCOS (77%)Capable of inducing ovulation in PCOS (77%)

• 6/8 CC resistant ovulated with CC+Maitake6/8 CC resistant ovulated with CC+Maitake

CONVENTIONAL REGIMEN CONVENTIONAL REGIMEN WITH GONADOTROPHINSWITH GONADOTROPHINS

55 55 55DAYSDAYS

7575

7575

7575

55

Results of Conventional TherapyResults of Conventional Therapy14 series, 1966-1984, WHO I & II14 series, 1966-1984, WHO I & II

Conceived 46% (16-78)

Multiple pregs. 34% (22-50)

Miscarriages 23% (12-30)

Severe OHSS 4.6% (1.3-9.4)

Hamilton-Fairley & Franks, 1990

Low dose rec-FSHLow dose rec-FSH

75-112.5 IU50-75 IU

100-150 IU

14 7 7

Days

Low dose gonadotropinsLow dose gonadotropinsSummary of resultsSummary of results

Patients - 841, Cycles 1556Patients - 841, Cycles 1556

Pregnancies 320 (40%)

Fecundity/cycle 20%

Uniovulation 70%

OHSS 0.14%

Multiple pregs. 5.7%

Updated from Homburg & Howles, 1999Updated from Homburg & Howles, 1999

Low-dose FSHLow-dose FSH

• Only a low-dose protocol should be used Only a low-dose protocol should be used for ovulation induction in PCOS.for ovulation induction in PCOS.

• Small starting and incremental dose Small starting and incremental dose increases recommended with no dose increases recommended with no dose change for 14 days.change for 14 days.

Duration of Initial Dose: 14 or 7 Days?Duration of Initial Dose: 14 or 7 Days? 14 days 14 days 7 days7 days

FSH required FSH required - Amps - Amps 22 1722 17- Days - Days 17.4 1317.4 13

1 large follicle/cycle 74% 60%1 large follicle/cycle 74% 60%

E2 (pmol/L) 1659 2072E2 (pmol/L) 1659 2072Pregnancies 10 (40%) 14 Pregnancies 10 (40%) 14

(56%)(56%)OHSS 0 0OHSS 0 0Multiple pregnancies 0 Multiple pregnancies 0 2/14 2/14

N=50, 107 cyclesN=50, 107 cycles

Homburg, 1999Homburg, 1999

Multiple pregnanciesMultiple pregnancies

14 days 0/1014 days 0/10

7 days 6/29 7 days 6/29

Homburg, 1999Homburg, 1999

Extended StudyExtended Study

How long does it take?How long does it take?

• With a starting dose of 75 IU FSH, With a starting dose of 75 IU FSH, unchanged for a minimum of 14 days, unchanged for a minimum of 14 days, 90% will get to the criteria for hCG90% will get to the criteria for hCGwithin 14 dayswithin 14 days

Homburg & Howles, 1999Homburg & Howles, 1999

Factors affecting outcome of LOD for PCOSFactors affecting outcome of LOD for PCOS

CCR: 54% after 12 monthsCCR: 54% after 12 months 75% after 30 months75% after 30 months

CC and low-dose FSH may be added if no ovulation after 3 CC and low-dose FSH may be added if no ovulation after 3 monthsmonths

One-off treatment with low multiple pregnancy rate and no OHSSOne-off treatment with low multiple pregnancy rate and no OHSS

Best if < 3 years infertility, thin and high LHBest if < 3 years infertility, thin and high LH

Maternal PCOS in pregnancyMaternal PCOS in pregnancy

Increased prevalence of:Increased prevalence of:

• Early pregnancy lossEarly pregnancy loss

• Gestational diabetesGestational diabetes

• Pregnancy induced hypertensionPregnancy induced hypertension

• SGA babiesSGA babies

Polly Sistik – age 44Polly Sistik – age 44

• Happy mother with 2 kids.Happy mother with 2 kids.

• The futureThe future

Effect of aging on PCOSEffect of aging on PCOS

• Women with PCOS Women with PCOS gain regular gain regular menstrual cycles menstrual cycles when agingwhen aging

• Menstrual cycle Menstrual cycle restored in those restored in those with a smaller with a smaller follicle countfollicle count

Elting et al, 2000, 2003Elting et al, 2000, 2003

Sleep Disorders in PCOSSleep Disorders in PCOSPCOS n=53, controls n=452PCOS n=53, controls n=452

0102030405060708090

SleepApnea

DaytimeSleepiness

PCOS N=53Controls N

=452

Risk of Sleep Risk of Sleep Apnea in PCOSApnea in PCOS

Odds Ratio 29 Odds Ratio 29

(95% CI 5-294)(95% CI 5-294)

Adjusted for Adjusted for differences in differences in

BMIBMI

Vgontzas et al, Vgontzas et al, JCEM, 2001JCEM, 2001

PCOS - Late sequelaePCOS - Late sequelae

Hyperinsulinemia / hyperandrogenism / obesityHyperinsulinemia / hyperandrogenism / obesity

•Diabetes mellitus x7Diabetes mellitus x7

•Hypertension x4Hypertension x4

•Low HDL/high LDLLow HDL/high LDL

*All are risk factors for *All are risk factors for cardiovascular disease and CVAcardiovascular disease and CVA

Polly Gone