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
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
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.
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)
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 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