Induction for Anovulatory (PCOS)

Adam Balen Department of Leeds Teaching Hospitals, UK

ESHRE Campus, Kiev, May 2010

Ovulation Induction for PCOS

Learning Objectives

1. Options for OI 2. Weight reduction 3. Oral agents (Clomiphene Citrate, Aromatase Inhibitors) 4. Gonadotrophin therapy 5. Laparoscopic ovarian diathermy 6. Metformin The Rotterdam ESHRE/ASRM Consensus Group Revised 2003 Diagnostic Criteria for PCOS 2 out of 3 criteria required Oligo- and/or Hyperandrogenism (clinical and/or biochemical) Polycystic ovaries Exclusion of other causes of menstrual disturbance and hyperandrogenism

Human Reproduction 2004; 19: 41-47. Fertility & Sterility, 2004; 81: 19-25.

Ultrasound Assessment of the Polycystic Ovary: International Consensus Definitions The polycystic ovary contains 12 or more follicles measuring 2-9 mm in diameter

and/or

increased ovarian volume (>10 cm3)

Balen, Laven, Tan & Dewailly; Hum Reprod Update 2003; 9: 505 ESHRE/ASRM Consensus 2003

Elevated Luteinising Hormone:

- not mandatory for diagnosis - most likely to be elevated in slim women - may help predict outcome of fertility therapy: - Worse outcome after CC if elevated day 8 - Better prognosis for response to ovarian drilling 1741 Women with PCOS

symptoms CENTRAL OBESITY hormones

ultra- WEIGHT sound LOSS

INSULIN

Balen et al Hum Reprod 1995; 10: 2107

PCOS: Investigations

1. Testosterone (SHBG) 2. FSH, LH (E2) 3. AMH? 4. Prolactin / TFTs 5. Ultrasound scan 6. GTT, lipid profile

7. Semen analysis 8. Tubal patency assessment First line therapy for anovulatory PCOS

• Weight loss • Clomiphene citrate • Aromatase inhibitors

• GdthiGonadotrophins • of oocytes

• Ovarian surgery • Insulin sensitisers???sensitisers??? ?

1 2 3 4 Preconcepti GonadoGonado-- onal care tropins IVF ((nono (single ET) - diet Metformin or - exercise Aromatase - other inhibitorsinhibitors)) LOD

Should there be a cut off weight / BMI before any treatment?

• Reduced chance conception

• Increased risk miscarriage

• Increased rate of congenital anomalies

• Obstetrical problems ((GestGestDM, PET, delivery ….)

BalenBalen,, DresnerDresner,, Scott & Drife BMJ 2006;332;4342006;332;434--435435 Weight loss in PCOS

• 55--10%10% reduction in weight can achieve 30% reduction in visceral fat

• Metabolic & endocrine profile improve significantly

• Improvement reproductive function and outcomes

Kiddy et al Clin Endo 1992 36:105 Clark et al Hum Rep 1995 10:2705 Jakubowicz & Nestler JCEM 1997 82:556

Weight Reduction: RCOG Guidelines, 2007

No evidence for one type of diet

Strategies may include pharmacotherapy ((OrlistatOrlistat,, not sibutramineor rimonabant)rimonabant)

Bariatric surgery

Avoid during rapid weight loss

BFS Guidelines, 2007

“Treatment should be deferred until BMI < 35 kg/m2 although in those with more time (under 37y, normal ovarian reserve) a weight reduction to < 30 kg/m2 is preferable”

Balen & Anderson, Human Fertility 2007; 10: 195195--206206 Weight loss and exercise

BMI > 30, > 2y anovulatory infertility, CC resistance

13/18 completed 6 month study: weight loss improved endocrinology 12 - lower insulin, testosterone all ovulated 11 conceived (5 naturally)

Clark et al H. Rep 1995 10:2705

Clomifene Citrate

n = 5268 patients Ovulation - 3858 (73%) - 1909 (36%)

Miscarriage - 20% Multiple - 10%

Single live-live-birthbirth rate –25%– 25%

Homburg, Hum ReprodReprod,, 2005

To give hCG in CC cycles?

“ Routine addition of hCGat midmid--cyclecycle does not improve conception rates”

………but helps in timing of intercourse or IUI

Agrawal & Buyalos,Buyalos, 1995 Should we monitor clomiphene cycles with ultrasound?

3 cycles of CC

 Group 1 : N = 105, with U/S monitoring + hCG  Group 2: N=150, no U/S monitoring, no hCG

KonigKonig,, Homburg et al, ESHRE, 2009

With U/S + hCG No U/S or hCG 48% Cumulative conception rate 34.7%

35.6% Deliveries 26 .7%

0 Multiple pregnancies 1

Clomiphene Citrate

Starting…  on day 2,3,4 or 5 makes no difference (Wu, 19891989))  dose 50 mg/day, rising by 50mg if no ovulation  even without withdrawal bleeding ((FarhiFarhi,, 2009)2009)

Stopping…  when 6 ovulatory cycles fail to yield a pregnancy  when no ovulation with 150mg/day  if endometrial thickness <7mm at ovulation Non-Response to Clomiphene

Failure to ovulate

 FAI  BMI  LH  Insulin

Reasons for Clomiphene Failure

Ovulation but no conception

 Anti-estrogen effects - cervical mucus -

 High LH

CC ovulation induction in WHO 2 - outcomes, predictors, and nomogram

Outcomes

Nomogram

Predictors Modern use of clomiphene citrate in induction of ovulation

80 70 60 50 % 40 30 20 10 0 cycles 0123456 >6

Kousta, White & Franks. Hum Reprod Update 1997; 3: 359

Aromatase Inhibitors - Theoretical Advantages

Letrozole (2.5 mg) Do not block estrogen receptors –

 No detrimental effect on endometrium or cervical mucus

 Negative feedback mechanism not turned off – less chance of multiple follicular development

Aromatase inhibitors -questions

 Do they work?

 Better than CC for firstfirst--lineline treatment?

 Useful in CC resistance?

or anastrozoleanastrozole??

 Safety? Aromatase inhibitors for PCOS – RCT’s vs CC

 Superiority or equivalence, CC (100mg vs letrozole 2.5mg) 2.5mg) Atay et al, 2006; Bayar et al, 2006

 CCCC,, 100mg vs LetrozoleLetrozole,, 5mg  n=438 (1063 cycles)  Pregnancy/cycle – CC 17.9%, --letrozoleletrozole 15.1% (NS)

Badawy et al, 2007

Aromatase inhibitors vs CC

 MetaMeta--analysisanalysis,, 4 RCT’s  Clear superiority of aromatase inhibitors in pregnancy rates (OR 2. 0) and deliveries (OR 2.4).

Atay 2006; Bayar 2006; Sohrabvand 2008; Sipe 2006 MetaMeta--analysis:analysis: Polyzos et al, Fertil SterilSteril,, 2008

Letrozole induction of ovulation in women with CCCC––resistantresistant PCOS…

• OvulationOvulation-- 24/24/4444 cases (54.6%)

• Clinical pregnancypregnancy--6/44 cases (25%of ovulators)ovulators)

Elnashar et al, 2006 Anastrozole Anastozole (1mg/day) vs CC (100mg/day) Anastrozole produced fewer follicles, thicker endometrium.endometrium. May be used successfully for ovulation induction Wu et al , 2007 , n = 33

Anastrozole (1mg) vs Letrozole (2.5mg) Letrozole superior in ovulation and pregnancy rates AlAl--OmariOmari et al, 2004, n = 40

Outcome – Letrozole vs CC n=911 newborns in 5 centers

CC Letrozole Pregnancies 397 514

Congenital malformations + 19 (4.8%) 14 (2.4%) Chromosomal abnormalities Tulandi et al, 2006

Outcome – Letrozole vs CC

CC Letrozole Pregnancies 397 514

MjMajor malf ormati ons 12 (3%) 6 (1.2%)

VSD 4 (1.0%) 1 (0.2%)

Total cardiac anomalies 1.8% 0.2%

Tulandi et al, 2006 Regimens

 Step up

 Low dose step up

 Step down

Low dose rec-FSH

100-150 IU 7575--112.5112.5 IU 5050--7575 IU

14 7777 Days

Reduction of multiple pregnancy rate

• Low dose regimens

• Careful monitoring

• Strict criteria for hCG: 1 follicle > 17mm < 2 folls. in total > 14mm Gonadotrophin therapy in 103 women with PCOS

90 80 70 60 50 % 40 30 20 10 0 cycles 0123456789101112

Balen et al Human Reproduction 1994; 9:1563

Low Dose Summary of Results Patients - 1040, Cycles 2472

Pregnancies 411 (40%) Fecundity/ov.cycle 23% Uniovulation 71% OHSS 0.14% Multiple pregs. 5.1%

Updated from Homburg & HowlesHowles,, 1999

Results with low-dose gonadotrophins -100 women

No response 15 Ovulate 85

No conception 40 Conception 45

Miscarriage 9 Multiple pregs 2 Singleton live birth 34 Low-dose gonadotrophins -questions  StepStep--upup or step-step-down?down?

 Starting dose?

 Incremental dose rise?

 Use as firstfirst--lineline treatment?

21 14 days 1 100 75 50 StepStep--upup

If <10mm 1010mmmm

StepStep--downdown 100 75 50

3 days hCG

Conclusions

 StepStep--upup safer and more efficient than stepstep--downdown - Lower rate of overstimulation - High er rate of monofo llicul ar cycles - Higher ovulation rate

ChristinChristin--MaitreMaitre & HuguesHugues,, 2003 Comparison of 2 starting doses (37.5 vs 50 IU) r-hFSH for 14 days

N= 22: Mean Age 30.4 yrs: BMI 24.6 Increase after 14 days (37.5 & 50)

 Use of 37.5IU FSH as a starting dose resulted in similar outcome but with less IUs FSH vs 50 IU

37.5IU 50IU

(Balasch et al 2000)

Only minimal dose increment needed (Orvieto & Homburg, 2008)

 Incremental dose rise of 8.3 IU each week

64. 6 IU 58.3 IU 50 IU

7 14 21 Days

 N=25, PCOS, CC failures, 69 cycles

Only minimal dose increment needed (Orvieto & Homburg, 2008)  Treatment days – 10.8 ++\\-- 4.3 (range 5-5-25)25)

 Total dose of FSH (IU) – 622 +/-+/-286 (208-(208-1641)1641)

 Cycle cancellation – 1/69

 Ovulation rate – 98.5% of started cycles Only minimal dose increment needed (Orvieto & Homburg, 2008)  1 follicle only > 16mm 82.6% > 14mm 62.3%  Clinical ppgregnancies 20 ( 29% cy cles) Miscarriages 4  Live births 16 / 25 patients  Twins 1  OHSS 0

Predictors FSH ovulation induction - response dose, mono-follicle development, ongoing pregnancy

FSH response dose MonoMono--folliclefollicle Ongoing ddlevelopment pegnancy

Conventional OI (CC + FSH)

singleton live birth

predicted chance Pregnancy rates of 240 WHO anovulatory infertile women (CC, FSH, IVF)

Initial screening characteristics predicting treatment outcome in WHO 2 anovulatory infertility

The way forward towards patient tailored OI protocols CC or rec-FSH for first-line treatment?

PCOS Randomization

CC rec- rec-FSHFSH 3 cycles Randomized N=268 CC FSH

Allocated Allocated N=130 N=138

DropDrop--outsouts DropDrop--outsouts N=18 N=24

Analysed PerPer--protocolprotocol Analysed N=112 N=114

Results

CC FSH P Patients per protocol 112 114 Cycles 287 249

Pregnanci es 46 (41%) 64 (56%) 0. 02 Miscarriage rates 15% 12.5% Multiple pregnancies 0 2 (3%) Pregnancies/cycle 16% 26% 0.006 Live births 40 (35.7%) 56 (49%) 0.03

Cumulative live-birth rates

70% 60% 50%

40% CC 30% FSH 20% 10% 0% Cycle 1 2 3 After 3 cycles - CC 42%, FSH 62% Summary

Clear superiority of lowlow--dosedose FSH over CC for first line treatment of anovulatoryPCOS

Absolute difference -  of 24% in CCR over 3 cycles  of 10% in pregnancy rates/cycle  of 20% in cumulative live birth rates

 More than x2 chance of conception in 1st cycle  Shorter treatment to pregnancy time

Laparoscopic ovarian surgery

40W, monopolar,monopolar, 4 points, 4 seconds

LOD versus rFSH - RCT LOD rFSH nn8383 85 ovulatory 63% 64% pregnant 34% 67% CCR 6 cycles RR 0.54 (95%CI 0.390.39--0.760.76) 12m CCR 67% 67% RR 1.01 (95%CI 0.810.81--1.24)1.24) miscarriage 9% 13%

After 8w 45 received addition of CC  49% CCR and 21 then received rFSH  67% CCR at 12m Bayram et al, BMJ 2004; 328:192 LOD versus rFSH - RCT LOD rFSH nn8383 85 ovulatory 63% 64% pregnant 34% 67% CCR 6 cycles RR 0.54 (95%CI 0.390.39--0.760.76) 12m CCR 67% 67% RR 1.01 (95%CI 0.810.81--1.24)1.24) miscarriage 9% 13%

After 8w 45 received addition of CC  49% CCR and 21 then received rFSH  67% CCR at 12m Bayram et al, BMJ 2004; 328:192

LOD versus rFSH - RCT LOD rFSH nn8383 85 ovulatory 63% 64% pregnant 34% 67% CCR 6 cycles RR 0.54 (95%CI 0.390.39--0.760.76) 12m CCR 67% 67% RR 1.01 (95%CI 0.810.81--1.24)1.24) miscarriage 9% 13%

After 8w 45 received addition of CC  49% CCR and 21 then received rFSH  67% CCR at 12m Bayram et al, BMJ 2004; 328:192

LOD versus rFSH - RCT LOD rFSH nn8383 85 ovulatory 63% 64% pregnant 34% 67% CCR 6 cycles RR 0.54 (95%CI 0.390.39--0.760.76) 12m CCR 67% 67% RR 1.01 (95%CI 0.810.81--1.24)1.24) miscarriage 9% 13%

After 8w 45 received addition of CC  49% CCR and 21 then received rFSH  67% CCR at 12m Bayram et al, BMJ 2004; 328:192 LOD versus rFSH - RCT LOD rFSH nn8383 85 ovulatory 63% 64% pregnant 34% 67% CCR 6 cycles RR 0.54 (95%CI 0.390.39--0.760.76) 12m CCR 67% 67% RR 1.01 (95%CI 0.810.81--1.24)1.24) miscarriage 9% 13%

After 8w 45 received addition of CC  49% CCR and 21 then received rFSH  67% CCR at 12m Bayram et al, BMJ 2004; 328:192

Laparoscopic “drilling” by diathermy or laser in anovulatory PCOS

 studies small

 main outcomes ovulation & pregnancy

 6 month ppgregnancy rate vs 6 cy cles g onadotrop hin therapy: OR 0.48, 95% CI 0.28 ––0.810.81

 12 month pooled OR 1.27, 95% CI 0.77 –2.09– 2.09

Farquhar et al, Cochrane database 2002

Laparoscopic “drilling” by diathermy or laser in anovulatory PCOS

 miscarriage rates - similar

 multiple pregnancy rates - lower (OR 0.16, 95% CI 0.03 – 0.98)

Farquhar et al, Cochrane database 2002 Effects of metformin on PCOS

 Improve reproductive function

 Improve response to both clomifene and gonadotropin induced ovulation

Lord et al, 2003, Cochrane Review & BMJ Costello et al, 2003, Human Reproduction

A multi-centre randomised, placebo-controlled , double-blind study, of combined life-style modification & metformin in obese patients with PCOS

 8 centres U.K., co-ordinated by Leeds

 Placebo controlled, double blind RCT

 6 months metformin 850mg b.d.

 143 women randomised, with BMI > 30 kgm-2 mean BMI 38 kgm-2 power 0.90 for significance 0.05, requires 55 per arm of study)

Tang et al, Human Reproduction 2006; 21: 8080--89.89.

Randomised 143

Metformin Placebo 69 74

Withdrew Withdrew 13 8

Completed Completed 56 66 Metformin vs Placebo

Significant increase in number of cycles, and fall in BMI and waist circumference in both groups

No difference in ovulation rate between the groups

Improvements seen in those who lost weight in either group

Tang et al, Human Reproduction 2006; 21: 8080--89.89.

A randomised double blind clinical trial comparing clomifene citrate plus metformin with clomifene citrate plus placebo in newly diagnosed PCOS

228 women with PCOS

Randomly allocated to receive either metformin 2000 mg/d or placebo for 1 month

Then clomifene citrate 50 up to 150 mg for 6 ovulations or until CC-resistance

BMI ~ 28 kg/m2

Moll et al, BMJ; 332: 1485

Ovulation per dosage clomifene citrate

CC + metformin CC + placebo P

CC 50mg 49/80 (61%) 50/92 (54%) 0.36

CC 100mg 27/44 (61%) 35/53 (66%) 0.63

CC 150mg 8/17 (47%) 13/23 (57%) 0.55

Moll et al BMJ 2006; 332: 1485 Ovulation, pregnancy and spontaneous rates

CC CC Relative Risk + metformin + placebo (95% CI)

n=111 n=114

Ovulation 71 (64%) 82 (72%) 0.89 (0.7 - 1.1)

Ongoing Pregnancy 44 (40%) 52 (46%) 0.87 (0.6 - 1.2)

Spontaneous Abortion 13 (12%) 12 (11%) 1.11 (0.5 - 2.3)

Moll et al BMJ 2006; 332: 1485

Discontinuation due to side effects:

16% versus 5% (95% CI 5 - 16%)

Moll et al BMJ 2006; 332: 1485

CC and/or metformin alone or in combination

626 anovulatory PCOS

Metformin vs Placebo 2000 mg / day

Clomiphene or Placebo 50 – 150 mg for 5d

6 cycles or 30 weeks

Mean BMI ~ 35 kg/m2

Legro et al, NEJM 2007, 356:551 CC and/or metformin alone or in combination

CC M CC + M Conception 39.5% 8.4% 46.0% /ovulation Miscarriage 83%8.3% 20. 8% 92%9.2%

Live birth 22.5% 7.2% 26.8% (47/209) (15/208) (56/209)

CC superior to metformin and combination confers no advantage in achieving live birth Legro et al, NEJM 2007, 356:551 Clomiphene with Metformin or Placebo

Two very large RCTs have failed to show any benefit from metformin

Clomiphene alone results in highest livebirth rate

Moll et al, BMJ 2006; 332:1485 Legro et al, NEJM 2007; 356:551

Revised Cochrane Meta-analysis

Tommy Tang, Rob Norman, Adam Balen 2009

Metformin vs placebo or no treatment: Body weight

Metformin Control Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI Baillargeon 2004 61.4 1.6 28 61.4 1.6 30 96.3% 0.00 [-0.82, 0.82] Kelly 2002 91 24 10 94 31 10 0.1% -3.00 [-27.30, 21.30] Lord 2006 94.7 27.1 16 94.9 15.5 15 0.3% -0.20 [-15.62, 15.22] Pasquali 2000 94 17 10 97 18 8 0.2% -3.00 [-19.33, 13.33] Tang 2006 99 15 56 99.2 17.3 66 2.0% -0.20 [-5.93, 5.53] Trolle2007 92.9 19 42 96.1 21.1 45 0.9% -3.20 [-11.63, 5.23] Vandermolen 2001 96.9 26.53 11 106.9 23.2 14 0.2% -10.00 [-29.84, 9.84]

Total (95% CI) 173 188 100.0% -0.06 [-0.87, 0.75] Heterogeneity: Chi² = 1.70, df = 6 (P = 0.94); I² = 0% -10 -5 0 5 10 Test for overall effect: Z = 0.15 (P = 0.88) Favours metformin Favours control Live birth rate: OR 1.00 95% CI 0.16, 6.39 OR -0.06-0.06 95% CI -0.87,-0.87, 0.75 Metformin versus placebo or no treatment: Live birth rate

Metformin Control Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Ng 2001 1 9 2 9 79.6% 0.44 [0.03, 5.93] Yarali 2002 1 16 0 16 20.4% 3.19 [0.12, 84.43]

Total (95% CI) 25 25 100.0% 1.00 [0.16, 6.39] Total events 2 2 Participa Heteroggyeneity: Chi² =Outcome 0.87 , df or = Subgroup1 ( P = 0.35 ); I²Studies = 0% Statistical Method Effect Estimate nts 00010.001 010.1 1 10 1000 Test for overall effect: Z = 0.00 (P = 1.00) Favours control Favours metformin

Live birth rate: OR 1.00 95% CI 0.16, 6.39

Metformin versus Clomifene Citrate: Live birth Rate

Metformin Clomifene Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Legro 2007 15 208 47 209 87.2% 0.27 [0.14, 0.50] Palomba 2005 26 50 9 50 0.0% 4.94 [1.99, 12.26] Zain 2008 4 42 7 41 12.8% 0.51 [0.14, 1.90]

Total (95% CI) 300 300 100.0% 0.30 [0.17, 0.52] Total events 45 63 Heterogeneity: Chi² = 0.76, df = 1 (P = 0.38); I² = 0% 0.01 0.1 1 10 100 Test for overall effect: Z = 4.25 (P < 0.0001) Favours Clomifene Favours Metformin

OR 0.30 95% CI 0.17, 0.52

Live birth rate: OR 1.00 95% CI 0.16, 6.39

Metformin plus ovulation induction agent vs ovulation induction agent alone: Ovulation Rate Treatment Control Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 3.3.1 PCOS and clomifene sensitive Jakubowicz 2001 26 28 22 28 5.5% 3.55 [0.65, 19.37] Subtotal (95% CI) 28 28 5.5% 3.55 [0.65, 19.37] Total events 26 22 Heterogeneity: Not applicable Test for overall effect: Z = 1.46 (P = 0.14)

3.3.2 PCOS and clomifene resistant Hwu 2005 17 40 5 40 8.2% 5.17 [1.68, 15.98] Kocak 2002 21 27 4 28 6.8% 21.00 [5.21, 84.66] Malkawi 2002 11 16 3 12 5.6% 6.60 [1.23, 35.44] Ng 2001 4 9 1 9 3.4% 6.40 [0.55, 74.89] Sturrock 2002 5 12 4 14 5.8% 1.79 [0.35, 9.13] Vandermolen 2001 9 12 4 15 5.4% 8.25 [1.45, 46.86] Subtotal (95% CI) 116 118 35. 2% 655[3401263]6.55 [3.40, 12.63] Total events 67 21 Heterogeneity: Tau² = 0.05; Chi² = 5.36, df = 5 (P = 0.37); I² = 7% CC resistant Test for overall effect: Z = 5.61 (P < 0.00001) OR 6.55 95% CI 3.40, 12.63 3.3.3 PCOS and clomifene sensitivity not defined El-Biely 2001 35 45 29 45 9.3% 1.93 [0.76, 4.90] Khorram 2006 7 16 1 15 3.9% 10.89 [1.14, 103.98] Legro 2007 582 964 462 942 12.9% 1.58 [1.32, 1.90] Moll 2006 84 141 98 168 11.9% 1.05 [0.67, 1.66] LiveNestler birth 1998 rate:19 OR21 1.002 25 4.4%95%109.25 CI [14.04, 850.33]0.16, 6.39 Sahin 2004 38 51 34 55 9.8% 1.81 [0.79, 4.15] Zain 2008 38 41 24 41 7.1% 8.97 [2.37, 33.91] Subtotal (95% CI) 1279 1291 59.2% 2.75 [1.48, 5.11] Total events 803 650 Heterogeneity: Tau² = 0.42; Chi² = 29.18, df = 6 (P < 0.0001); I² = 79% CC sensitive Test for overall effect: Z = 3.20 (P = 0.001) OR 2.75 95% CI 1.48, 5.11 Total (95% CI) 1423 1437 100.0% 3.93 [2.32, 6.65] Total events 896 693 Heterogeneity: Tau² = 0.55; Chi² = 53.17, df = 13 (P < 0.00001); I² = 76% All OR 3.93 95% CI0.01 2.32,0.1 16.6510 100 Test for overall effect: Z = 5.08 (P < 0.00001) Favours control Favours treatment Metformin plus ovulation induction agent vs ovulation induction agent alone: Live Birth Rate

Treatment Control Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Legro 2007 56 209 47 209 50.7% 1.26 [0.81, 1.97] Moll 2006 21 111 31 114 36.5% 0.62 [0.33, 1.17] Sahin 2004 3 11 3 10 3.4% 0.88 [0.13, 5.82] Vandermolen 2001 4 12 1 15 0.9% 7.00 [0.66, 73.93] Zain 2008 7 41 7 41 8.6% 1.00 [0.32, 3.16]

Total (95% CI) 384 389 100.0% 1.04 [0.75, 1.46] Total events 91 89 Heterogeneity: Chi² = 5.79, df = 4 (P = 0.22); I² = 31% 0.01 0.1 1 10 100 Test for overall effect: Z = 0.25 (P = 0.80) Favours control Favours metformin

OR 1.04 95% CI 0.75, 1.46 Live birth rate: OR 1.00 95% CI 0.16, 6.39

Insulin sensitising agents in PCOS: ESHRE/ASRM Consensus, 2007

• No clear role of metformin in management anovulatory infertility either alone or in combination

• No evidence of improvement in pregnancy outcome

Human Reproduction 2008; 23:462 Fertility & Sterility 2008; 89: 505

RCOG Scientific Advisory Committee Guideline, 2008

Ovulation Induction for PCOS

Learning Objectives

1. Options for OI 2. Weight reduction 3. Oral agents (Clomiphene Citrate, Aromatase Inhibitors) 4. Gonadotrophin therapy 5. Laparoscopic ovarian diathermy 6. Metformin Metformin vs placebo or no treatment: Ovulation rates

Metformin Control Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI 1.3.1 All patients Baillargeon 2004 27 32 1 32 0.3% 167.40 [18.40, 1523.16] Fleming 2002 37 45 30 47 11.5% 2.62 [0.99, 6.90] Hoeger 2004a 4 9 3 9 3.7% 1.60 [0.24, 10.81] Hoeger 2004b 3 9 6 11 7.9% 0.42 [0.07, 2.58] Jakubowicz 2001 8 28 0 28 0.8% 23.63 [1.29, 433.02] Lord 2006 9 22 9 22 11.7% 1.00 [0.30, 3.33] Nestler 1996 5 11 1 13 1.1% 10.00 [0.94, 105.92] Nestler 1998 12 35 1 26 1.7% 13.04 [1.57, 108.36] Ng 2001 3 9 3 9 4.4% 1.00 [0.14, 7.10] Onalan 2005a 17 153 20 150 39.6% 0.81 [0.41, 1.62] Onalan 2005b 5 63 5 51 11.2% 0.79 [0.22, 2.91] Sturrock 2002 0 12 1 14 3.0% 0.36 [0.01, 9.68] Vandermolen 2001 1 12 1 15 1.8% 1.27 [0.07, 22.72] Yarali 2002 6 16 1 16 1.4% 9.00 [0.94, 86.52] Subtotal (95% CI) 456 443 100.0% 2.21 [1.57, 3.10] Total events 137 82 All Heterogeneity: Chi² = 40.58, df = 13 (POR = 0.0001); I² 2.21= 68% 95% CI 1.57, 3.10 Test for overall effect: Z = 4.57 (P < 0.00001)

1.3.2 Patients with BMI < 30kg/m2 Baillargeon 2004 27 32 1 32 0.8% 167.40 [18.40, 1523.16] Ng 2001 3 9 3 9 9.6% 1.00 [0.14, 7.10] Onalan 2005a 17 153 20 150 86.6% 0.81 [0.41, 1.62] Yarali 2002 6 16 1 16 3.0% 9.00 [0.94, 86.52] Subtotal (95% CI) 210 207 100.0% 2.33 [1.43, 3.81] Total events 53 25 Heterogeneity: Chi² = 25.45, df = 3 (P < 0.0001); I² = 88% BMI < 30 Test for overall effect: Z = 3.39 (P = 0.0007)OR 2.33 95% CI 1.43, 3.81 1.3.3 Patients with BMI > 30Kg/m2 Fleming 2002 37 45 30 47 21.2% 2.62 [0.99, 6.90] LiveHoeger birth2004a rate:4 9 OR3 9 1.006.8% 1.60 95% [0.24, 10.81] CI 0.16, 6.39 Hoeger 2004b 3 9 6 11 14.6% 0.42 [0.07, 2.58] Jakubowicz 2001 8 28 0 28 1.4% 23.63 [1.29, 433.02] Lord 2006 9 22 9 22 21.6% 1.00 [0.30, 3.33] Nestler 1996 5 11 1 13 2.0% 10.00 [0.94, 105.92] Nestler 1998 12 35 1 26 3.1% 13.04 [1.57, 108.36] Onalan 2005b 5 63 5 51 20.6% 0.79 [0.22, 2.91] Sturrock 2002 0 12 1 14 5.4% 0.36 [0.01, 9.68] Vandermolen 2001 1 12 1 15 3.3% 1.27 [0.07, 22.72] Subtotal (95% CI) 246 236 100.0% 2.11 [1.31, 3.37] Total events 84 57 Heterogeneity: Chi² = 15.35, df = 9 (P = 0.08); I² = 41% BMI > 30 Test for overall effect: Z = 3.09 (P = 0.002)OR 2.11 95% CI 1.31, 3.37

0.001 0.1 1 10 1000 Favours control Favours metformin Metformin vs placebo or no treatment: Clinical pregnancy rates Metformin Control Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI 1.2.1 All patients Nestler 1996 1 11 0 13 2.9% 3.86 [0.14, 104.65] Yarali 2002 2 16 0 16 3.0% 5.69 [0.25, 128.50] Kocak 2002 1 28 0 28 3.4% 3.11 [0.12, 79.64] Fleming 2002 4 23 1 19 6.4% 3.79 [0.39, 37.20] Lord 2006 3 22 2 22 12.3% 1.58 [0.24, 10.52] Tang 2006 6 69 2 74 12.5% 3.43 [0.67, 17.60] Ng 2001 1 9 2 9 12.6% 0.44 [0.03, 5.93] Karimzadeh 2007 40 100 11 100 46.9% 5.39 [2.57, 11.34] Subtotal (95% CI) 278 281 100.0% 3.84 [2.21, 6.68] Total events 58 18 Heterogeneity: Chi² = 4.41, df = 7 (P = 0.73); I² = 0% All Test for overall effect: Z = 4.76 (P < 0.00001) OR 3.84 95% CI 2.21, 6.68

1.2.2 Patients with BMI < 30kg/m2 Yarali 2002 2 16 0 16 4.8% 5.69 [0.25, 128.50] Ng 2001 1 9 2 9 20.2% 0.44 [0.03, 5.93] Karimzadeh 2007 40 100 11 100 75.0% 5.39 [2.57, 11.34] Subtotal (95% CI) 125 125 100.0% 4.41 [2.24, 8.66] Total events 43 13 Heterogeneity: Chi² = 3.33, df = 2 (P = 0.19); I² = 40% BMI < 30 Test for overall effect: Z = 4.31 (P < 0.0001) OR 4.42 95% CI 2.24, 8.66

1.2.3 Patients with BMI > 30kg/m2 Nestler 1996 1 11 0 13 7.7% 3.86 [0.14, 104.65] LiveKocak 2002birth rate:1 28OR 0 1.0028 9.0% 95%3.11 [0.12,CI 79.64] 0.16, 6.39 Fleming 2002 4 23 1 19 17.2% 3.79 [0.39, 37.20] Lord 2006 3 22 2 22 32.8% 1.58 [0.24, 10.52] Tang 2006 6 69 2 74 33.4% 3.43 [0.67, 17.60] Subtotal (95% CI) 153 156 100.0% 2.89 [1.09, 7.64] Total events 15 5 Heterogeneity: Chi² = 0.52, df = 4 (P = 0.97); I² = 0% BMI > 30 Test for overall effect: Z = 2.14 (P = 0.03) OR 2.89 95% CI 1.09, 7.64

0.001 0.1 1 10 1000 Favours control Favours metformin

Metformin plus ovulation induction agent vs ovulation induction agent alone: Clinical Pregnancy Rate

Treatment Control Odds Ratio Odds Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI 3.2.1 All patients El-Biely 2001 13 45 4 45 3.4% 4.16 [1.24, 14.00] Hwu 2005 6 40 0 40 0.5% 15.26 [0.83, 280.72] Khorram 2006 5 16 0 15 0.4% 14.83 [0.74, 295.97] Kocak 2002 3 27 0 28 0.5% 8.14 [0.40, 165.53] Legro 2007 80 209 62 209 45.2% 1.47 [0.98, 2.21] Malkawi 2002 9 16 2 12 1.2% 6.43 [1.05, 39.33] Moll 2006 57 111 64 114 36.3% 0.82 [0.49, 1.39] Sahin 2004 5 11 3 10 2.0% 1.94 [0.32, 11.76] Sturrock 2002 3 12 4 14 3.3% 0.83 [0.15, 4.78] Vandermolen 2001 6 12 1 15 0.5% 14.00 [1.37, 142.89] Zain 2008 8 41 7 41 6.7% 1.18 [0.38, 3.62] Subtotal (95% CI) 540 543 100.0% 1.58 [1.20, 2.07] Total events 195 147 Heterogeneity: Chi² = 20.60, df = 10 (P = 0.02); I² = 51% All Test for overall effect: Z =OR 3.31 (P = 0.0009) 1.58 95% CI 1.20, 2.07 3.2.2 Patients with BMI < 30kg/m2 Hwu 2005 6 40 0 40 1.2% 15.26 [0.83, 280.72] Malkawi 2002 9 16 2 12 3.0% 6.43 [1.05, 39.33] Moll 2006 57 111 64 114 90.7% 0.82 [0.49, 1.39] Sahin 2004 5 11 3 10 5.1% 1.94 [0.32, 11.76] Subtotal (95% CI) 178 176 100.0% 1.23 [0.78, 1.93] Total events 77 69 BMI < 30 Heterogeneity: Chi² = 8.54,OR df = 3 (P = 0.04);1.23 I² = 65% 95% CI 0.78, 1.93 Test for overall effect: Z = 0.88 (P = 0.38) Live birth rate:3.2.3 Patients with OR BMI > 30kg/m2 1.00 95% CI 0.16, 6.39 El-Biely 2001 13 45 4 45 5.6% 4.16 [1.24, 14.00] Khorram 2006 7 16 1 15 1.1% 10.89 [1.14, 103.98] Kocak 2002 3 27 0 28 0.8% 8.14 [0.40, 165.53] Legro 2007 80 209 62 209 75.1% 1.47 [0.98, 2.21] Sturrock 2002 3 12 4 14 5.4% 0.83 [0.15, 4.78] Vandermolen 2001 6 12 1 15 0.9% 14.00 [1.37, 142.89] Zain 2008 8 41 7 41 11.1% 1.18 [0.38, 3.62] Subtotal (95% CI) 362 367 100.0% 1.83 [1.31, 2.56] Total events 120 79 Heterogeneity: Chi² = 10.53, df = 6 (P = 0.10); I² = 43% BMI > 30 Test for overall effect: Z =OR 3.52 (P = 0.0004) 1.88 95% CI 1.31, 2.56 0.01 0.1 1 10 100 Favours control Favours treatment