O l ti i d ti i PCOSOvulation induction in PCOS: regimens ... · EvidenceEvidence--based medicine (EBM) approach as strategy based medicine (EBM) approach as strategy for providing

O l ti i d ti i PCOSO l ti i d ti i PCOSOvulation induction in PCOS: Ovulation induction in PCOS: regimens with insulin sensitizersregimens with insulin sensitizersregimens with insulin sensitizersregimens with insulin sensitizers

Stefano PalombaStefano Palomba

Department of Obstetrics & GynecologyDepartment of Obstetrics & GynecologyUniversity “Magna Graecia” of CatanzaroUniversity “Magna Graecia” of Catanzaro

Catanzaro, Italy Catanzaro, Italy

Why insulin sensitizers are effective to induce Why insulin sensitizers are effective to induce ovulation in PCOS?ovulation in PCOS?

Direct mechanismsDirect mechanismsDirect mechanismsDirect mechanismsGranulosa cellsGranulosa cells•• ↓glucose metabolism ↓energy mobilization ↓glucose metabolism ↓energy mobilization •• worsening of the signal worsening of the signal

Insulin resistance andInsulin resistance and

g gg g(androgen receptor polymorphism?) (androgen receptor polymorphism?)

Tecal cellsTecal cells•• ↑androgen production↑androgen production

Insulin resistance and Insulin resistance and hyperinsulinemiahyperinsulinemia

↑ free androgens↑ free androgensFOLLICULAR FOLLICULAR

ARRESTARREST

Indirect mechanismsIndirect mechanisms↓SHBG production↓SHBG production

Indirect mechanismsIndirect mechanisms

↑ serum LH↑ serum LH

Insulin sensitizers in infertile PCOS patients: Insulin sensitizers in infertile PCOS patients: questions to be answeredquestions to be answered

■■ Which is the role of insulin sensitizers in the Which is the role of insulin sensitizers in the firstfirst--step treatment for ovulatory infertility?step treatment for ovulatory infertility?firstfirst step treatment for ovulatory infertility?step treatment for ovulatory infertility?

■■ Which is the role of insulin sensitizers in the Which is the role of insulin sensitizers in the secondsecond--step treatment for ovulatory infertility?step treatment for ovulatory infertility?

■■ Which is the role of insulin sensitizers in Which is the role of insulin sensitizers in patients who receive gonadotropins?patients who receive gonadotropins?

EvidenceEvidence--based medicine (EBM) approach as strategy based medicine (EBM) approach as strategy for providing clinical answersfor providing clinical answers

S t ti i ith d t tS t ti i ith d t t llSystematic reviews with data metaSystematic reviews with data meta--analysesanalysesRCTs (as update)RCTs (as update)

Level of evidenceLevel of evidence Grade of recommendationGrade of recommendation

EBMEBM involvesinvolves integratingintegrating thethe currentcurrent bestbest evidenceevidence withwith clinicalclinical expertiseexpertise andand patientpatient preferencepreferencetoto makemake optimaloptimal decisionsdecisions aboutabout patientpatient carecare..

Sackett,Sackett, 19961996

44 %% ofof decisionsdecisions strongstrong evidenceevidence fromfrom researchresearch studiesstudies44 %% ofof decisionsdecisions strongstrong evidenceevidence fromfrom researchresearch studiesstudies4545 %% nono evidenceevidence oror strongstrong consensusconsensus5151 %% littlelittle evidenceevidence andand consensusconsensus

Field,Field, 19921992

Insulin sensitizers in infertile PCOS patients: Insulin sensitizers in infertile PCOS patients: an overviewan overview

Search strategySearch strategy: Pubmed: PubmedKey wordsKey words: “insulin sensitizers”, insulin sensitizing drugs,”: “insulin sensitizers”, insulin sensitizing drugs,”“biaguanides”, “metformin”, “thiazolidinediones”, “troglitazone”, “biaguanides”, “metformin”, “thiazolidinediones”, “troglitazone”, “rosiglitazone”, “pioglitazone”, “D“rosiglitazone”, “pioglitazone”, “D--chirochiro--inositolinositol” and “PCOS”” and “PCOS”Li itLi itLimits:Limits: none none Clinical trialsClinical trials: 646: 646RCTsRCTs: 107: 107M tM t ll 1010

120RCTs

MetaMeta--analysesanalyses: 10: 10

80

100 Meta-analysesClinical trials

n (%

)n

(%)

40

60

ropo

rtio

nro

port

ion

0

20PrPr

0Before1994

1996 1999 2002 2005 2007

Which insulin sensitizers for infertile PCOS patients?Which insulin sensitizers for infertile PCOS patients?

■ Metformin■ Troglitazone

MetforminTroglitazoneD-chiro-inositolOthers

■ Troglitazone■ D-chiro-inositol■ Rosiglitazone 88%88%■ Pioglitazone

Systematic reviews with data metaSystematic reviews with data meta--analysesanalysesRCTs (as update)RCTs (as update)

400

500 RCTsMeta-analysesClinical trials

ount

(n.)

ount

(n.)

50

60

70

80 RCTsMeta-analysesClinical trials

n (%

)n

(%)

100

200

300

bsol

ute

amo

bsol

ute

amo

20

30

40

50

Prop

ortio

nPr

opor

tion

0Metformin Other insulin

sensitizers

Ab

Ab

0

10

Metformin Other insulinsentitizers


■■ Which is the role of insulin sensitizers in the Which is the role of insulin sensitizers in the firstfirst--step treatment for ovulatory infertility?step treatment for ovulatory infertility?firstfirst step treatment for ovulatory infertility?step treatment for ovulatory infertility?

■■ Which is the role of insulin sensitizersWhich is the role of insulin sensitizers in the in the secondsecond--step treatment for ovulatory infertility?step treatment for ovulatory infertility?

■■ Which is the role of insulin sensitizersWhich is the role of insulin sensitizers in in patients who receive gonadotropins?patients who receive gonadotropins?

Which is the role of insulin sensitizers in the firstWhich is the role of insulin sensitizers in the first--step treatment for ovulatory infertility?step treatment for ovulatory infertility?p y yp y y

CLINICAL ISSUESCLINICAL ISSUES SCIENTIFIC DATASCIENTIFIC DATA

Is metformin effective for Is metformin effective for treating ovulatory treating ovulatory

i f tilit ?i f tilit ?

Is metformin better Is metformin better than placebo or no than placebo or no

treatment?treatment?infertility?infertility?

Is metformin the goldIs metformin the gold I f iI f i

treatment?treatment?

Is metformin the gold Is metformin the gold standard for anovulatory standard for anovulatory

PCOS patients?PCOS patients?

Is metformin more Is metformin more effective than effective than clomiphene?clomiphene?

Does metformin improveDoes metformin improve

pp

Is metformin plus Is metformin plus Does metformin improve Does metformin improve the standard first step the standard first step approach for treating approach for treating anovulation in PCOSanovulation in PCOS

ppclomiphene more clomiphene more

effective than effective than clomiphene alone (orclomiphene alone (oranovulation in PCOS anovulation in PCOS

patients?patients?clomiphene alone (or clomiphene alone (or

plus placebo)?plus placebo)?







Is metformin the goldIs metformin the gold


I f iI f iIs metformin the gold Is metformin the gold standard for anovulatory standard for anovulatory




pp







Lord et al., BMJ 2003Lord et al., BMJ 2003

Kashyap et al., Hum Reprod 2004Kashyap et al., Hum Reprod 2004


Th i ifi t ff t fTh i ifi t ff t fThere was a significant effect of There was a significant effect of metformin compared with metformin compared with placebo on ovulation rate (OR placebo on ovulation rate (OR 3.88, 95%CI 2.25 to 6.69, 3.88, 95%CI 2.25 to 6.69, PP<0.0001).<0.0001).

The clinical pregnancy rate reported by five trials comparing metformin with The clinical pregnancy rate reported by five trials comparing metformin with placebo did not show evidence of benefit (OR 2.76, 95%CI 0.85 to 8.98, placebo did not show evidence of benefit (OR 2.76, 95%CI 0.85 to 8.98, PP=0.09).=0.09).

Lord et al., BMJ 2003Lord et al., BMJ 2003


Metformin was 50% better than Metformin was 50% better than placebo for ovulation induction in placebo for ovulation induction in infertile PCOS patients [RR 1 50;infertile PCOS patients [RR 1 50;infertile PCOS patients [RR 1.50; infertile PCOS patients [RR 1.50;

95%CI 1.13 to 1.99, 95%CI 1.13 to 1.99, PP=0.004]. =0.004].

Metformin was not of confirmed Metformin was not of confirmed benefit versus placebo for benefit versus placebo for

achievement of pregnancy (RR achievement of pregnancy (RR 1.07; 95%CI 0.20 to 5.74, 1.07; 95%CI 0.20 to 5.74, PP=0.9).=0.9).














pp







Ovulation rateOvulation rateOvulation rateOvulation rate

Review:Comparison:Outcome:

Metformin or CC or both as first-step treatment in PCOSCC versus metforminOvulation rate

Study or sub-category

CCn/N

Metforminn/N

OR (random effect) 95% CI Weight % OR (random effect) 95% CI

Palomba 2005 31/47 42/45 33.7 0.14 (0.02 to 0.55)

Legro 2007 157/209 115/208 66.3 2.44 (1.58 to 3.79)

Total (95% CI) 188/256 157/253 100.0 0.62 (0.04 to 10.67)

0,01 0,1 0,2 0,5 1 2 5 10 100

Metformin is not better than clomiphene Metformin is not better than clomiphene (RR 0 62 95%CI 0 04 t 10 67(RR 0 62 95%CI 0 04 t 10 67 PP 0 7440 744

Cochran Q= 16.94, df = 1, P < 0.0001Test for overall effect: Chi²= 0.11, P= 0.744 Favours metformin Favours CC

Palomba et al., Hum Reprod Update 2007 (in press)Palomba et al., Hum Reprod Update 2007 (in press)

(RR 0.62, 95%CI 0.04 to 10.67, (RR 0.62, 95%CI 0.04 to 10.67, PP=0.744 =0.744


Pregnancy ratePregnancy ratePregnancy ratePregnancy rate


Metformin or CC or both as first-step treatment in PCOSCC versus metforminPregnancy rate


CCn/N

Metforminn/N


Palomba 2005 16/47 31/45 42.1 0.23 (0.09 to 0.61)

Legro 2007 62/209 25/208 57.9 3.09 (1.80 to 5.38)

Total (95% CI) 78/256 56/253 100.0 0.87 (0.07 to 10.95)

0,01 0,1 0,2 0,5 1 2 5 10 100

Metformin is not better than clomiphene Metformin is not better than clomiphene (RR 0 87 95%CI 0 07 t 10 95(RR 0 87 95%CI 0 07 t 10 95 PP 0 9140 914

Cochran Q= 25.04, df = 1, P < 0.0001Test for overall effect: Chi²= 0.01, P= 0.914 Favours metformin Favours CC

Palomba et al., Hum Reprod Update 2007 (in press)Palomba et al., Hum Reprod Update 2007 (in press)(RR 0.87, 95%CI 0.07 to 10.95, (RR 0.87, 95%CI 0.07 to 10.95, PP=0.914=0.914


Live birth rateLive birth rateLive birth rateLive birth rate


Metformin or CC or both as first-step treatment in PCOSCC versus metforminLive birth rate


CCn/N

Metforminn/N


Palomba 2005 9/47 26/45 22.2 0.17 (0.06 to 0.48)

Legro 2007 47/209 15/208 77.8 3.73 (1.96 to 7.44)

Total (95% CI) 188/256 157/253 100.0 0.82 (0.04 to 16.66)0,01 0,1 0,2 0,5 1 2 5 10 100

Metformin is not better than clomipheneMetformin is not better than clomiphene(RR 0 82 95%CI 0 04 t 16 66(RR 0 82 95%CI 0 04 t 16 66 PP 0 2310 231

Favours metformin Favours CCCochran Q= 28.79, df = 1, P < 0.0001Test for overall effect: Chi²= 1.43, P= 0.231

Palomba et al., Hum Reprod Update 2007 (in press)Palomba et al., Hum Reprod Update 2007 (in press)(RR 0.82, 95%CI 0.04 to 16.66, (RR 0.82, 95%CI 0.04 to 16.66, PP=0.231 =0.231













pp







Ovulation rateOvulation rateOvulation rateOvulation rate


Metformin or CC or both as first-step treatment in PCOSCC plus placebo versus CC plus metforminOvulation rate


CC alonen/N

Metformin plus CCn/N


Moll 2006 82/114 71/111 31.8 1.44 (0.79 to 2.64)

Legro 2007 157/209 174/209 68.2 0.61 (0.36 to 1.01)

Total (95% CI) 188/256 157/253 100.0 0.92 (0.40 to 2.16)

Metformin plus clomiphene is not better than clomiphene aloneMetformin plus clomiphene is not better than clomiphene alone(RR 0 92 95%CI 0 40 to 2 16(RR 0 92 95%CI 0 40 to 2 16 PP=0 856)=0 856)

Favours CC aloneFavours

CC plus metforminCochran Q= 5.26, df = 1, P=0.022Test for overall effect: Chi²= 0.03, P= 0.856

0,2 0,5 1 2 5

Palomba et al., Hum Reprod Update 2007 (in press)Palomba et al., Hum Reprod Update 2007 (in press)(RR 0.92, 95%CI 0.40 to 2.16, (RR 0.92, 95%CI 0.40 to 2.16, PP=0.856) =0.856)


Pregnancy ratePregnancy ratePregnancy ratePregnancy rate


Metformin or CC or both as first-step treatment in PCOSCC plus placebo versus CC plus metforminPregnancy rate


CC alonen/N


OR (fixed effect) 95% CI Weight % OR (fixed effect) 95% CI

Moll 2006 52/114 44/111 30.1 1.28 (0.73 to 2.25)

Legro 2007 62/209 80/209 69.9 0.68 (0.44 to 1.04)

Total (95% CI) 188/256 157/253 100.0 0.86 (0.62 to 1.19)

0,2 0,5 1 2 5

Metformin plus clomiphene is not better than clomiphene aloneMetformin plus clomiphene is not better than clomiphene alone(RR 0 86 95%CI 0 62 to 1 19(RR 0 86 95%CI 0 62 to 1 19 PP=0 765)=0 765)

Cochran Q= 3.42, df = 1, P=0.065Test for overall effect: Chi²= 0.09, P= 0.765 Favours CC alone

FavoursCC plus metformin

Palomba et al., Hum Reprod Update 2007 (in press)Palomba et al., Hum Reprod Update 2007 (in press)(RR 0.86, 95%CI 0.62 to 1.19, (RR 0.86, 95%CI 0.62 to 1.19, PP=0.765) =0.765)


Live birth rateLive birth rateLive birth rateLive birth rate


Metformin or CC or both as first-step treatment in PCOSCC plus placebo versus CC plus metforminLive birth rate


CC alonen/N


OR (fixed effect) 95% CI Weight % OR (fixed) 95% CI

Moll 2006 30/114 21/111 26.3 1.6 (0.43 to 2.24)

Legro 2007 47/209 56/209 73.7 0.79 (0.49 to 1.27)

Total (95% CI) 188/256 157/253 100.0 1.01 (0.70 to 1.44)

Metformin plus clomiphene is not better than clomiphene aloneMetformin plus clomiphene is not better than clomiphene alone(RR 1 01 95%CI 0 70 to 1 44(RR 1 01 95%CI 0 70 to 1 44 PP=0 949=0 949

Cochran Q= 3.19, df = 1, P=0.074Test for overall effect: Chi²= 0.004, P= 0.949

0,2 0,5 1 2 5

Favours CC aloneFavours

CC plus metformin

Palomba et al., Hum Reprod Update 2007 (in press)Palomba et al., Hum Reprod Update 2007 (in press)

(RR 1.01, 95%CI 0.70 to 1.44, (RR 1.01, 95%CI 0.70 to 1.44, PP=0.949 =0.949


■■ Which is the role of insulin sensitizersWhich is the role of insulin sensitizers in the in the firstfirst--step treatment for ovulatory infertility?step treatment for ovulatory infertility?firstfirst step treatment for ovulatory infertility?step treatment for ovulatory infertility?

■■ Which is the role of insulin sensitizers in the Which is the role of insulin sensitizers in the secondsecond--step treatment for ovulatory infertility?step treatment for ovulatory infertility?

■■ Which is the role of insulin sensitizersWhich is the role of insulin sensitizers in in patients who receive gonadotropins?patients who receive gonadotropins?

Which is the role of insulin sensitizers in the Which is the role of insulin sensitizers in the secondsecond--step treatment for ovulatory infertility?step treatment for ovulatory infertility?p y yp y y

Clomiphene resistant PCOSClomiphene-resistant PCOS patients

Insulin sensitizers aloneInsulin sensitizers combined with clomiphenep

I li iti b fInsulin sensitizers before clomiphene






The effect of metformin and The effect of metformin and clomiphene compared with clomiphene compared with l i h ll i h lclomiphene alone on clomiphene alone on

ovulation rate was ovulation rate was significant (OR 4.41, 95%CI significant (OR 4.41, 95%CI 2.37 to 8.22, 2.37 to 8.22, PP<0.0001) based <0.0001) based on the results of three trials. on the results of three trials.

In the three trials comparing clomiphene with metformin compared with In the three trials comparing clomiphene with metformin compared with clomiphene alone, we found a significant effect for metformin with clomiphene clomiphene alone, we found a significant effect for metformin with clomiphene

Lord et al., BMJ 2003Lord et al., BMJ 2003on pregnacy rate (OR 4.40, 95%CI 1.96 to 9.85, on pregnacy rate (OR 4.40, 95%CI 1.96 to 9.85, PP=0.0003).=0.0003).


Metformin plus clomiphene isMetformin plus clomiphene isMetformin plus clomiphene is Metformin plus clomiphene is superior to clomiphene alone or superior to clomiphene alone or with placebo with regards to with placebo with regards to

l ti (RR 3 04 95%CI 1 77l ti (RR 3 04 95%CI 1 77ovulation (RR 3.04, 95%CI 1.77 ovulation (RR 3.04, 95%CI 1.77 to 5.24, to 5.24, PP=0.0005) and =0.0005) and pregnancy (RR 3.65, 95%CI 1.11 pregnancy (RR 3.65, 95%CI 1.11 to 11.99, to 11.99, PP=0.03).=0.03).



In clomipheneIn clomiphene--resistant PCOS women metformin addiction is effective in resistant PCOS women metformin addiction is effective in inducing ovulationinducing ovulation

Siebert et al., Fertil Steril 2006Siebert et al., Fertil Steril 2006

inducing ovulationinducing ovulation(OR 6.82, 95%CI 3.59 to 12.96, (OR 6.82, 95%CI 3.59 to 12.96, PP<0.00001).<0.00001).

Which is the role of insulin sensitizers in the secondWhich is the role of insulin sensitizers in the second--step step treatment for ovulatory infertility?: an update of the RCTstreatment for ovulatory infertility?: an update of the RCTs

In obese PCOS patients, 2 weeks of metformin (from progesterone induced In obese PCOS patients, 2 weeks of metformin (from progesterone induced bleedings) significantly improves ovulation rate in clomiphenebleedings) significantly improves ovulation rate in clomiphene--resistant resistant PCOS patients who receive clomiphene [7/16 (44%) vs 1/15 (6 7%)PCOS patients who receive clomiphene [7/16 (44%) vs 1/15 (6 7%) PP=0 037]=0 037]PCOS patients who receive clomiphene [7/16 (44%) vs. 1/15 (6.7%), PCOS patients who receive clomiphene [7/16 (44%) vs. 1/15 (6.7%), PP=0.037].=0.037].

Khorram et al., Fertil Steril 2006Khorram et al., Fertil Steril 2006

ShortShort--term use of rosiglitazone and clomiphene is more efficacious than term use of rosiglitazone and clomiphene is more efficacious than metformin and clomiphene for inducing ovulation [18/28 (64.3%) vs. 12/33 metformin and clomiphene for inducing ovulation [18/28 (64.3%) vs. 12/33 (36.4%), (36.4%), PP=0.035] but not for improving fertility [6/12 (50%) vs. 5/13 (38.5%), =0.035] but not for improving fertility [6/12 (50%) vs. 5/13 (38.5%), PP=0.58]=0.58] in clomiphenein clomiphene--resistant PCOS patients.resistant PCOS patients.

Rouzi & Ardawi Fertil Steril 2006Rouzi & Ardawi Fertil Steril 2006Rouzi & Ardawi, Fertil Steril 2006Rouzi & Ardawi, Fertil Steril 2006





Insulin sensitizers as single treatment in CCInsulin sensitizers as single treatment in CC--resistant resistant PCOS patientsPCOS patientspp

Ovulation rate Ovulation rate 108/197 (54.8)108/197 (54.8) 123/231 (53.2)123/231 (53.2)Reproductive outcomesReproductive outcomes Diagnostic laparoscopy Diagnostic laparoscopy

followed by metforminfollowed by metforminLaparoscopic ovarian diathermy Laparoscopic ovarian diathermy followed by placebofollowed by placebo

PP

0.740.74(n. ovulating cycles/n. cycles, %)(n. ovulating cycles/n. cycles, %)

108/197 (54.8)108/197 (54.8) 123/231 (53.2)123/231 (53.2)

Pregnancy ratePregnancy rate(n. pregnancies/n. cycles, %)(n. pregnancies/n. cycles, %)

43/197 (21.8)43/197 (21.8) 31/231 (13.4)31/231 (13.4)

0.740.74

0.020.02

LiveLive--birth rate birth rate ( b bi /( b bi / ii %)%)

Abortion rateAbortion rate(n. abortions/n. pregnancies, %)(n. abortions/n. pregnancies, %)

4/43 (9.3)4/43 (9.3) 9/31 (29.0)9/31 (29.0)

37/43 (86.0)37/43 (86.0) 20/31 (64.5)20/31 (64.5)

0.030.03

0.030.03(n. babies/n.(n. babies/n. pregnanciespregnancies, %), %)

DayDay surgery fee = 400surgery fee = 400 €€LODLOD Metformin cloridrate treatment (850 mg twice daily)Metformin cloridrate treatment (850 mg twice daily)

One pack of metformin (30 cps of 850 mg each) = 4 18One pack of metformin (30 cps of 850 mg each) = 4 18 €€DayDay--surgery fee = 400 surgery fee = 400 €€Surgeon’s fee = 350 Surgeon’s fee = 350 €€Assistant’s fee = 100 Assistant’s fee = 100 €€Anesthetist’s fee = 200 Anesthetist’s fee = 200 €€

One pack of metformin (30 cps of 850 mg each) = 4.18 One pack of metformin (30 cps of 850 mg each) = 4.18 €€One month of treatment = 4.18 One month of treatment = 4.18 €€ x 2 = 8.36 x 2 = 8.36 €€Six months of treatment = 8.36 Six months of treatment = 8.36 €€ x 6 = 50.16 x 6 = 50.16 €€

Palomba et al., J Clin Endocrinol Metab 2004

Total = 1050 Total = 1050 €€ Total = 50.16 Total = 50.16 €€


CC-resistant PCOS patients



Insulin sensitizers preInsulin sensitizers pre--treatment before clomiphene treatment before clomiphene in clomiphenein clomiphene--resistant PCOS patients: RCTsresistant PCOS patients: RCTspp pp

Metformin preMetformin pre--treatment significantly treatment significantly increases the ovulatory response to increases the ovulatory response to clomiphene in PCOS patients byclomiphene in PCOS patients byclomiphene in PCOS patients by clomiphene in PCOS patients by decreasing insulin secretiondecreasing insulin secretion

Nestler et al., New Engl J Med 1998Nestler et al., New Engl J Med 1998

Metformin improves the ovarianMetformin improves the ovarianMetformin improves the ovarian Metformin improves the ovarian responsiveness to clomipheneresponsiveness to clomiphene

Palomba et al., Clin Endocrinol 2005Palomba et al., Clin Endocrinol 2005

Twelve days of metformin preTwelve days of metformin pre--treatment improves ovulationtreatment improves ovulation

MMetformin preetformin pre--treatment treatment improves insulin resistance improves insulin resistance and reduces androgens and reduces androgens treatment improves ovulation treatment improves ovulation

and pregnancy rates in women and pregnancy rates in women with clomiphenewith clomiphene--resistant PCOSresistant PCOS

Hwu et al., Int J Obstet Gynecol 2005Hwu et al., Int J Obstet Gynecol 2005

gglevels, but did not increase levels, but did not increase significantly the ovulation significantly the ovulation and pregnancy ratesand pregnancy rates

St k t l B J Cli Ph l 2002St k t l B J Cli Ph l 2002

Sequential treatment with metformin plus Sequential treatment with metformin plus clomiphene was effective as clomiphene was effective as

Sturrock et al., Br J Clin Pharmacol 2002Sturrock et al., Br J Clin Pharmacol 2002Sahin et al., Eur J Obstet Gynecol Reprod Biol 2004Sahin et al., Eur J Obstet Gynecol Reprod Biol 2004

ppgonadotropins in inducing ovulation with gonadotropins in inducing ovulation with significant lower dropsignificant lower drop--out rate and less out rate and less expensive costsexpensive costs

George et al., Hum Reprod 2003George et al., Hum Reprod 2003


■■ Which is the role of metformin in the firstWhich is the role of metformin in the first--step step treatment for ovulatory infertility?treatment for ovulatory infertility?treatment for ovulatory infertility?treatment for ovulatory infertility?

■■ Which is the role of metformin in the secondWhich is the role of metformin in the second--step treatment for ovulatory infertility?step treatment for ovulatory infertility?

■■ Which is the role of metformin in patients who Which is the role of metformin in patients who ppreceive gonadotropins?receive gonadotropins?

Insulin sensitizers as coInsulin sensitizers as co--treatment in infertile PCOS treatment in infertile PCOS patients who receive gonadotropinspatients who receive gonadotropinsp g pp g p

■■ Controlled ovarian stimulation for inducing Controlled ovarian stimulation for inducing l t l l t th til t l l t th timonomono--ovulatory cycles as last therapeutic ovulatory cycles as last therapeutic

step for treating ovulatory infertilitystep for treating ovulatory infertility

■■ Controlled ovarian hyperstimulation for IVF Controlled ovarian hyperstimulation for IVF cycles for treating male, tubal or unexplained cycles for treating male, tubal or unexplained infertilityinfertility





Metformin plus gonadotropins versus placebo/no treatment Metformin plus gonadotropins versus placebo/no treatment plus gonadotropins for monoplus gonadotropins for mono--ovulation inductionovulation induction

Ovulation rateOvulation rate

M tf i d t i th l ti t d i iM tf i d t i th l ti t d i iMetformin does not improve the ovulation rate during ovarian Metformin does not improve the ovulation rate during ovarian stimulation with gonadotropins stimulation with gonadotropins

(90% vs. 73.3%; OR 3.27, 95%CI 0.31to 34.72; (90% vs. 73.3%; OR 3.27, 95%CI 0.31to 34.72; PP=0.33)=0.33)

Costello et al., Hum Reprod 2006


Pregnancy ratePregnancy rate

Metformin increase nonMetformin increase non--significantly the pregnancy rate during significantly the pregnancy rate during ovarian stimulation with gonadotropins ovarian stimulation with gonadotropins

(28% vs. 10%; OR 3.46, 95%CI 0.98 to 12.2; (28% vs. 10%; OR 3.46, 95%CI 0.98 to 12.2; PP=0.05)=0.05)

Costello et al., Hum Reprod 2006Costello et al., Hum Reprod 2006


Live birth rateLive birth rate

No trial identified comparing metformin combined with No trial identified comparing metformin combined with gonadotropins vs. gonadotropins and placebo or no gonadotropins vs. gonadotropins and placebo or no g p g p pg p g p p

treatment reporting live birth as an outcome measure.treatment reporting live birth as an outcome measure.

Costello et al., Hum Reprod 2006


Length of stimulationLength of stimulation

Metformin significantly reduces the length of ovarian Metformin significantly reduces the length of ovarian stimulation at gonadotropinstimulation at gonadotropinstimulation at gonadotropin stimulation at gonadotropin

(WMD (WMD ––4.14 days, 95%CI 4.14 days, 95%CI ––6.36 to 6.36 to ––1.93, 1.93, PP=0.0002).=0.0002).



Total FSH dosesTotal FSH doses

Metformin significantly decreases the total doseMetformin significantly decreases the total doseof FSH used during the treatment cycleof FSH used during the treatment cycleof FSH used during the treatment cycleof FSH used during the treatment cycle

(WMD (WMD ––425.05 IU, 95%CI 425.05 IU, 95%CI ––507.08 to 507.08 to ––343.03, 343.03, PP<0.00001).<0.00001).



Serum estradiol levels on day of HCG Serum estradiol levels on day of HCG administrationadministration

Metformin significantly reduces the serum EMetformin significantly reduces the serum E level on thelevel on theMetformin significantly reduces the serum EMetformin significantly reduces the serum E22 level on the level on the day of HCG triggerday of HCG trigger

(WMD (WMD ––1.24 nmol/l, 95%CI 1.24 nmol/l, 95%CI ––1.5 to 1.5 to ––0.98, 0.98, PP<0.00001).<0.00001).



OHSS rateOHSS rate

No trial identified comparing metformin combined with No trial identified comparing metformin combined with gonadotropin vs. gonadotropin and placebo or no gonadotropin vs. gonadotropin and placebo or no

treatment reporting OHSS rate as an outcome measuretreatment reporting OHSS rate as an outcome measuretreatment reporting OHSS rate as an outcome measure.treatment reporting OHSS rate as an outcome measure.


Metformin as coMetformin as co--treatment in infertile PCOS patients who treatment in infertile PCOS patients who receive gonadotropins: an update of the RCTsreceive gonadotropins: an update of the RCTsg p pg p p

ff l ti i d til ti i d ti…for mono…for mono--ovulation inductionovulation induction

Palomba et al., Hum Reprod 2005Palomba et al., Hum Reprod 2005

Van Santbrik et al., Eur J Endocrinol 2005Van Santbrik et al., Eur J Endocrinol 2005

Metformin as preMetformin as pre--treatment and cotreatment and co--administration in administration in infertile PCOS patients who receive gonadotropins plus infertile PCOS patients who receive gonadotropins plus

timed intercourse or intrauterine inseminationtimed intercourse or intrauterine insemination

Note: Group A= metformin plus gonadotropins, Group B= placebo plus gonadotropins. Insulin resistant Note: Group A= metformin plus gonadotropins, Group B= placebo plus gonadotropins. Insulin resistant patients were selected measuring fasting glucose:insulin ratio and using a threshold value <4.5 mg/10patients were selected measuring fasting glucose:insulin ratio and using a threshold value <4.5 mg/10––4 IU (SI: <582 mmol/pmol) (Legro4 IU (SI: <582 mmol/pmol) (Legro et al.et al., 1998; Ducluzeau, 1998; Ducluzeau et al.et al., 2003), 2003)

Palomba et al., Hum Reprod 2005Palomba et al., Hum Reprod 2005

4 IU (SI: 582 mmol/pmol) (Legro 4 IU (SI: 582 mmol/pmol) (Legro et al.et al., 1998; Ducluzeau , 1998; Ducluzeau et al.et al., 2003), 2003)





Metformin plus gonadotropins versus placebo/no treatment Metformin plus gonadotropins versus placebo/no treatment plus gonadotropins in IVF cyclesplus gonadotropins in IVF cycles

Pregnancy ratePregnancy rate

Metformin coMetformin co--administration does not improve pregnancy rates at IVF administration does not improve pregnancy rates at IVF (34 vs. 29%; OR 1.29, 95%CI 0.84 to 1.98, (34 vs. 29%; OR 1.29, 95%CI 0.84 to 1.98, PP=0.25).=0.25).

Only one trial showed an improvement (Tang Only one trial showed an improvement (Tang et alet al., 2005).., 2005).y p ( gy p ( g , ), )



Live birth rateLive birth rate

Metformin does not improve significantly the live birth rateMetformin does not improve significantly the live birth rateMetformin does not improve significantly the live birth rateMetformin does not improve significantly the live birth rate(36 vs. 22%; OR 2.02, 95%CI 0.98 to 4.14, (36 vs. 22%; OR 2.02, 95%CI 0.98 to 4.14, PP=0.06)=0.06)



Length of stimulationLength of stimulation

M tf i h ff t th l th f i ti l ti i IVF lM tf i h ff t th l th f i ti l ti i IVF lMetformin has no effect on the length of ovarian stimulation in IVF cycles Metformin has no effect on the length of ovarian stimulation in IVF cycles (WMD (WMD ––0.09 days, 95%CI 0.09 days, 95%CI ––0.49 to 0.31, 0.49 to 0.31, PP=0.66)=0.66)



Total FSH dosesTotal FSH doses

Metformin significantly decreases the total dose of FSH used duringMetformin significantly decreases the total dose of FSH used duringMetformin significantly decreases the total dose of FSH used during Metformin significantly decreases the total dose of FSH used during the IVF cyclesthe IVF cycles

(WMD (WMD ––290.42 IU, 95%CI 290.42 IU, 95%CI ––450.34 to 450.34 to ––130.51, 130.51, PP=0.0004)=0.0004)



Serum estradiol levels on day of HCG Serum estradiol levels on day of HCG administrationadministration

Metformin does not reduce the serum EMetformin does not reduce the serum E2 2 level on the day of HCG triggerlevel on the day of HCG trigger(WMD (WMD ––3.53 nmol/l, 95%CI 3.53 nmol/l, 95%CI ––9.24 to 2.18, 9.24 to 2.18, PP=0.23)=0.23)



Number of oocytes collectedNumber of oocytes collected

Metformin has no effect on the number of oocytes collected at IVFMetformin has no effect on the number of oocytes collected at IVF(WMD=0.44, 95%CI (WMD=0.44, 95%CI ––0.98 to 1.86, 0.98 to 1.86, PP=0.54)=0.54)



OHSS rateOHSS rate

Metformin significantly reduces the risk of OHSS at IVF Metformin significantly reduces the risk of OHSS at IVF (5.6 vs. 21.0%; OR 0.21, 95%CI 0.11 to 0.41, (5.6 vs. 21.0%; OR 0.21, 95%CI 0.11 to 0.41, PP<0.00001).<0.00001).


Metformin as coMetformin as co--treatment in infertile PCOS patients who treatment in infertile PCOS patients who receive gonadotropins: an update of the RCTsreceive gonadotropins: an update of the RCTsg p pg p p

…for multiple…for multiple--ovulation induction in IVF cyclesovulation induction in IVF cycles

Tang et al., Hum Reprod 2006Tang et al., Hum Reprod 2006

ConclusionsConclusionsMessages to take home!Messages to take home!gg

Whi h i th l f i li iti i th fi tWhi h i th l f i li iti i th fi t■■ Which is the role of insulin sensitizers in the firstWhich is the role of insulin sensitizers in the first--step treatment for ovulatory infertility?step treatment for ovulatory infertility?

••Metformin administration is effective for inducing ovulation Metformin administration is effective for inducing ovulation in anovulatory PCOS patients even if studies with longin anovulatory PCOS patients even if studies with long--term term followfollow--up are needed to demonstrate its efficacy in terms of up are needed to demonstrate its efficacy in terms of fertility (fertility (II--AA). ). ••Comparative data on the single best firstComparative data on the single best first--step treatment, i.e. step treatment, i.e. metformin vs. clomiphene, are inconclusive.metformin vs. clomiphene, are inconclusive.metformin vs. clomiphene, are inconclusive.metformin vs. clomiphene, are inconclusive.••Metformin does not improve the efficacy of clomiphene as Metformin does not improve the efficacy of clomiphene as first therapeutic approach (first therapeutic approach (II--AA).).


Whi h i th l f i li iti i th dWhi h i th l f i li iti i th d■■ Which is the role of insulin sensitizers in the secondWhich is the role of insulin sensitizers in the second--step treatment for ovulatory infertility?step treatment for ovulatory infertility?

••Data analysis is robust to demonstrate a beneficial effect ofData analysis is robust to demonstrate a beneficial effect ofData analysis is robust to demonstrate a beneficial effect of Data analysis is robust to demonstrate a beneficial effect of the combination of metformin with clomiphenethe combination of metformin with clomiphene in those in those patients who were known to be resistant to clomiphene patients who were known to be resistant to clomiphene previously, even if comparative data controlled with previously, even if comparative data controlled with p y, pp y, pgonadotropin arm are lacking (gonadotropin arm are lacking (II--AA).).••As single secondAs single second--line treatment, metformin is more effective line treatment, metformin is more effective and cheaper than laparoscopic ovarian diathermy (and cheaper than laparoscopic ovarian diathermy (II--BB))and cheaper than laparoscopic ovarian diathermy (and cheaper than laparoscopic ovarian diathermy (II BB).).••Data on the efficacy of metformin preData on the efficacy of metformin pre--treatment before treatment before clomiphene in clomipheneclomiphene in clomiphene--resistant patients are resistant patients are controversialcontroversialcontroversial.controversial.


Whi h i th l f i li iti i ti tWhi h i th l f i li iti i ti t■■ Which is the role of insulin sensitizers in patients Which is the role of insulin sensitizers in patients who receive gonadotropins?who receive gonadotropins?

••In PCOS patients under metformin (as second step aloneIn PCOS patients under metformin (as second step aloneIn PCOS patients under metformin (as second step alone In PCOS patients under metformin (as second step alone or in combination) who receive gonadotropins for inducing or in combination) who receive gonadotropins for inducing ovulation, metformin should be continued in order to ovulation, metformin should be continued in order to increase the rate of monoincrease the rate of mono--ovulations (ovulations (II--BB).).(( ))••Data on FSH doses and treatment length are inconclusive Data on FSH doses and treatment length are inconclusive for the extreme data heterogeneity.for the extreme data heterogeneity.I i f til PCOS ti t h i d t i fI i f til PCOS ti t h i d t i f••In infertile PCOS patients who receive gonadotropins for In infertile PCOS patients who receive gonadotropins for

IVF cycles, metformin reduces the risk of OHSS and, thus, IVF cycles, metformin reduces the risk of OHSS and, thus, its use should be planned in highits use should be planned in high--risk patients (risk patients (II--AA).).

Is metformin administrationIs metformin administration totally safe in totally safe in nonnon--diabetic patients?diabetic patients?

In anovulatory patients without In anovulatory patients without

pp

In anovulatory patients with deep In anovulatory patients with deep y py pinsulininsulin--resistance?resistance?

y p py p pinsulininsulin--resistance?resistance?

Is metformin effective inIs metformin effective inIs metformin effective inIs metformin effective in Is metformin effective in Is metformin effective in lean PCOS patients ?lean PCOS patients ?

Is metformin effective in Is metformin effective in severely obese patients ?severely obese patients ?

Which is the right dose of metformin ?Which is the right dose of metformin ?Which is the right dose of metformin ?Which is the right dose of metformin ?

How long should be the metfomin treatment (beforeHow long should be the metfomin treatment (beforeHow long should be the metfomin treatment (before How long should be the metfomin treatment (before clomiphene or gonadotropin administration)?clomiphene or gonadotropin administration)?

Thank you for your kind attention !Thank you for your kind attention !

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O l ti i d ti i PCOSOvulation induction in PCOS: regimens ... · EvidenceEvidence--based medicine (EBM) approach as strategy based medicine (EBM) approach as strategy for providing