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Metformin in polycystic ovary syndrome

Moll, E.

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35

Chapter 3

The role of metformin in polycystic ovary syndrome. A systematic review.

Etelka Moll, Fulco van der Veen, Madelon van Wely

Human Reproduction Update 2007; 13(6):527-537

36

Abstract

This meta-analysis evaluated the effectiveness of metformin in subfertile

women with polycystic ovary syndrome (PCOS). Only randomised trials investigating

the effectiveness of metformin and PCOS definition consistent with the Rotterdam

consensus criteria were eligible. Primary outcome was live birth rate. A literature

search identified 27 trials. In therapy naive women, we found no evidence of a

difference in live birth rate when comparing metformin with clomifene citrate (CC)

[relative risk (RR) 0.73; 95% confidence interval (CI) 0.51 - 1.1] or comparing

metformin plus CC with CC (RR 1.0; 95% CI 0.82 - 1.3). In CC-resistant women,

metformin plus CC led to higher live birth rates than CC alone (RR 6.4; 95% CI 1.2 -

35); metformin also led to higher live birth rates than laparoscopic ovarian drilling

(LOD) (RR 1.6; 95% CI 1.1 - 2.5). We found no evidence for a positive effect of

metformin on live birth when added to LOD (RR 1.3; 95% CI 0.39 - 4.0) or FSH (RR

1.6; 95% CI 0.95 - 2.9), or when co-administered in IVF (RR 1.5; 95% CI 0.92 - 2.5).

In IVF, metformin led to fewer cases of ovarian hyperstimulation syndrome (OHSS)

(RR: 0.33; 95% CI: 0.13 - 0.80). This meta-analysis demonstrates that CC is still first

choice therapy for women with therapy naïve PCOS. In CC-resistant women, the

combination of CC plus metformin is the preferred treatment option before starting

with LOD or FSH. At present, there is no evidence of an improvement in live birth

when adding metformin to LOD or FSH. In IVF, metformin leads to a reduced risk of

OHSS.

37

Introduction

The polycystic ovary syndrome (PCOS) affects 5% to 10% of women of

reproductive age.1 PCOS is characterised by oligo-anovulation, clinical or

biochemical hyperandrogenism and / or polycystic ovaries.2-4 Insulin resistance

accompanied by compensatory hyperinsulinemia constitutes another major

biochemical feature of PCOS.

In 1994, more than 70 years after the first description of a patient with insulin

resistance and hyperandrogenism, the first study on the insulin sensitizer metformin

in women with PCOS was published.5 Originally, this trial was meant to study

metabolic and endocrinological parameters, but the authors noticed that some (12%)

of the women conceived spontaneously.

From that moment on many trials were set up to test insulin sensitizers (mainly

metformin) for ovulation induction in women with PCOS. These studies have been

summarized in several reviews and meta-analyses.6-11 These meta-analyses were

based on trials all consisting of a very small number of patients. In the analyses no

consistent distinction between therapy naïve and clomifene citrate (CC)-resistant

women was made. The reviews separately did not overview the total spectrum of

treatment possibilities.

In addition, two large trials were recently published.12;13 The total number of

patients in each separate trial exceeded the total number of patients in the existing

reviews. Both trials found - in contrast to the previously published trials - that

metformin does not lead to higher pregnancy rates when combined with CC and the

same was true for metformin alone when compared with CC.

In view of this, we felt that updating our knowledge on metformin in subfertility

and a critical appraisal of all existing studies might be helpful to guide clinical

practice. In this review, we will therefore concentrate on the effect of metformin on

live birth rate in women with PCOS for all comparisons studied so far.

38

Materials and Methods

Search Strategy

We searched the Cochrane Menstrual Disorders & Subfertility Group trials

register, the Cochrane Central Register of Controlled Trials (both searched February

2007), MEDLINE (January 1966 to February 2007), the website for registration of

controlled trials (controlled-trials.com) and several personal contacts with experts in

this field (Balen, Nestler, Palomba). All electronic databases were searched using the

following keywords: assisted reproduction, clomifene citrate, gonadotrophins, IVF,

IUI, metformin, ovulation induction, PCOS, pregnancy. We handsearched the

reference lists of selected trials and of recent reviews concerning this subject. No

restrictions were held concerning publication year or language. All retrieved articles

were of English language and published from 1996 till February 2007.

Study selection and data extraction

Studies were selected if the target population were women with PCOS. The

definition of PCOS had to follow the standards of the ESHRE/ASRM 2003

consensus, or the criteria used in the article had to be, in retrospect, in consensus

with the definition.4 If included patients did not meet the definition of ESHRE/ASRM,

the study was not included in this review. Furthermore, the studies had to be of

randomised design comparing the effect of metformin with placebo or no treatment,

metformin with another ovulation induction agent or method or comparing the effect

of metformin as co-treatment in IVF with no co-treatment.

The primary outcome of interest was live birth rate per randomised woman.

Secondary outcomes were clinical pregnancy, multiple pregnancy and ovarian

hyperstimulation syndrome (OHSS). It appeared that if live birth rate was not given in

a manuscript, data on ongoing pregnancy were also not presented. Therefore,

clinical pregnancy rate was chosen as a secondary outcome.

The review was undertaken by two reviewers (E.M., M.v.W.). The search

strategy was employed to obtain titles and, where possible, abstracts of studies that

were potentially relevant to the review. Both reviewers independently assessed

whether the studies met the inclusion criteria, with disagreements resolved by

discussion and final arbitration by F.V.

For each included trial, information was collected regarding the location of the

study, methods of the study (as per quality assessment checklist), the participants

39

(age range, eligibility criteria), the nature of the interventions and data relating to the

outcomes specified above. When possible, missing data were sought from the

authors. The trial specific characteristics are expressed in Table 1.

We distinguished three indications: metformin as first-line treatment in therapy

naive women; metformin as second-line treatment in CC-resistant women and

metformin as co-treatment in women undergoing IVF. We subdivided first-line and

second-line treatment into metformin monotherapy or co-treatment in combination

with CC, FSH or laparoscopic ovarian drilling (LOD).

Statistical analysis

Relative risks (RR) with 95% confidence intervals (95% CI) were calculated for

every study. Pooled RR were calculated using fixed effects models.14 If there was

statistical heterogeneity, we performed a sensitivity analysis by pooling using a

‘random effects’-method.15

Statistical heterogeneity was assessed using forest plots, the I2 statistic and

chi-square test. Clinical heterogeneity was assessed by reviewing differences across

trials in characteristics of randomized patients.

Data from cross-over trials were only used from the first phase (i.e. before

crossover). Any such trials that did not provide results at this point were excluded

from the analysis. Review Manager-software (RevMan 4.2.7, Cochrane

Collaboration, Oxford, UK) was used for the statistical analysis. We analysed the

data on intention to treat basis.

Results of search

Our search selected 443 articles. After reading the titles, 296 articles did not

answer our question. From the remaining 147 articles, 94 articles were discarded

while they were non-original papers (reviews, letters). The 53 remaining articles were

read. Thirty articles did not meet our inclusion criteria for not having a proper control

group,5;16-24 for not using randomisation,25-27 for not providing clear information on live

birth or clinical pregnancy rates,28-40 for using a cross-over design without clear rates

of pregnancy before the cross-over,41-43 or because of selection bias.44 Furthermore,

in one trial women were included that did not intend to get pregnant and had been

advised to take contraception (J.Nestler, personal communication).45

40

By handsearching reference lists, we came across four articles we did not find

in the initial search.46-49 In total 27 studies were included in the analysis (Fig. 1).

Three studies compared metformin with placebo,46;50;51 two compared

metformin with CC,13;52 12 compared metformin plus CC with CC,12;13;41;47;49;53-59 one

compared metformin with LOD,60 one compared metformin plus LOD with LOD,61 one

compared metformin plus CC with HMG,62 four compared metformin plus FSH with

FSH48;63-65 and four compared metformin added in IVF versus IVF without

metformin.34;66-68

Results

The quality and the main characteristics of the 27 trials included in this review

are presented in Table 1. Most trials were of poor quality. Seventeen of 27 trials used

an appropriate method of randomization, with 17 out of 27 having adequate

concealment of allocation. A power calculation was only reported in eight trials. Trial

size varied from 17 to 626 women.

Eight studies excluded women over the age of 35 years. Most studies did not

have restrictions considering BMI. One study included women with BMI <25 kg/m2.

Two studies included women with BMI <30 and <35 kg/ m2, respectively. Two studies

included women with BMI >29 and 30 kg/m2, respectively.

Metformin in CC naïve women

Metformin monotherapy

We retrieved two randomised controlled trials in which metformin was

compared with placebo for as first line treatment in 185 therapy naïve infertile women

with PCOS (Table 1).46;51 None used HCG for triggering ovulation. Both trials

reported clinical pregnancy rate. The pooled RR was 3.3 (95% CI: 0.92-11) (Fig. 2a).

Visual examination of the forest plot and the I2 statistic (0%) suggested no

heterogeneity in treatment effect across trials.

Live birth rate was not reported, nor multiple pregnancy rates. One study gave

life style modification before starting drug therapy.51 The median weight loss was 2.8

versus 1.5%.

We found two double-blinded randomised controlled trials in which metformin

was directly compared with CC as first line treatment in 509 infertile women with

41

PCOS (Table 1).13;52 HCG was not used for triggering ovulation. The pooled clinical

pregnancy rate after six months of treatment was significantly lower after metformin

(RR: 0.72; 95% CI: 0.54-0.97) (Fig. 2a). The pooled RR for live birth was 0.73 (95%

CI: 0.51-1.1) (Fig. 2b). However, for both pregnancy outcomes there was significant

heterogeneity in treatment effect across the two trials. When the data were pooled

using a random effects model the RR was 0.88 (95% CI: 0.19 – 4.1) and 0.96 (95%

CI: 0.11-8.2) for clinical pregnancy rate and live birth rate respectively. Furthermore,

there was no evidence of a difference in multiple pregnancy rate between the two

groups (RR: 0.38; 95% CI: 0.02-7.1).

Metformin as co-treatment in combination with CC

Seven randomised controlled trials compared CC plus metformin with CC in

985 infertile women with PCOS (Table 1).12;13;47;49;53-55 Two studies used HCG to

trigger ovulation.47;55 After combining the data, there was a significantly higher clinical

pregnancy rate in the metformin plus CC group (RR 1.5; 95% CI 1.2 - 1.8) (Fig. 2a).

However, there was significant heterogeneity in treatment effect across the trials.

When the data were pooled using a random effects model the difference in clinical

pregnancy was still significant (RR 1.9; 95% CI: 1.2 – 3.3). The pooled RR for live

birth was 1.0 (95% CI 0.82 - 1.3; three trials with 664 women) (Fig. 2b). For live birth,

there was no indication for heterogeneity in treatment effect across trials.

Two studies reported multiple pregnancy rates.12;13 After combining these data

no significant difference was seen (RR 0.38; 95% CI 0.09 - 1.5; 193 women).

Metformin in CC-resistant women

Metformin monotherapy

We retrieved one randomised clinical trial in which metformin was compared

with placebo in 18 infertile women with CC-resistant PCOS (Table 1).50 In this small

number of women there was no evidence of a difference in clinical pregnancy or live

birth rate (both RR: 0.50; 95% CI: 0.05-4.6) (Fig. 3a and b). No data on multiple

pregnancy rates were given.

42

Metformin as co-treatment in combination with CC

We retrieved five randomised controlled trials in which CC plus metformin was

compared with CC alone in 210 infertile women with CC-resistant PCOS (Table

1).41;56-59 Two trials used HCG to trigger ovulation.56;57

Combining the results showed that metformin plus CC led to a significantly

higher clinical pregnancy rate than CC alone (RR: 5.6; 95% CI: 2.3-13) (Fig. 3a). Live

birth rate was also in favour of metformin plus CC compared with the CC group (RR:

6.4; 95% CI: 1.2-34; 2 trials with 107 women) (Fig. 3b). For both pregnancy

outcomes, visual examination of the forest plot and the I2 statistic (0%) suggested no

heterogeneity in treatment effect across trials.

In the only trial that reported on multiple pregnancy no multiple pregnancies

were observed in both groups.59

Metformin as opposed to LOD

Only one randomised trial was retrieved in which metformin treatment was

compared with LOD (Table 1).60 There was no evidence of a difference in clinical

pregnancy rate (RR: 1.3; 95% CI: 0.96-1.7) (Fig 3a). Live birth rate however was

higher in the metformin group (RR: 1.6; 95% CI: 1.1-2.5) (Fig 3b). Multiple

pregnancies were not observed.

Metformin as co-treatment in combination with LOD

One trial randomised 42 PCOS patients between LOD followed by metformin

or LOD alone (Table 1).61 There were no significant differences in clinical pregnancy

rate (RR: 2.3; 95% CI: 0.82-6.2) or live birth rate (RR: 1.3; 95% CI: 0.39-4.0) (Fig. 3a

and 3b).

Metformin plus CC compared with gonadotrophins

In one randomised clinical trial, metformin plus CC was compared with

gonadotrophins in 60 CC- resistant women (Table 1).62 Both groups were triggered

for ovulation with HCG. There was no evidence of a difference in clinical pregnancy

rate (RR: 0.71; 95% CI: 0.26-2.0) (Fig. 3a). There were no data on live birth, multiple

pregnancy or OHSS.

43

Metformin plus FSH compared with FSH alone

In four randomised controlled trials FSH plus metformin was compared with

FSH alone in 154 infertile women with PCOS (Table 1).48;63-65 All studies used HCG

to trigger ovulation. The pooled clinical pregnancy rate was significantly higher in the

FSH plus metformin group compared with FSH only group (RR: 1.7; 95% CI: 1.1-2.8)

(Fig. 3a). A difference in live birth rate could however not be proven (RR: 1.6; 95%

CI: 1.0-2.9) (Fig. 3b). For both pregnancy outcomes, visual examination of the forest

plot and the I2 statistic (0%) suggested no heterogeneity in treatment effect across

trials. Metformin led to less multiple pregnancies (RR: 0.26; 95% CI: 0.07-0.96).

There was no evidence of a difference in OHSS (RR: 0.59; 95% CI: 0.17-2.1).

Metformin as additional treatment in controlled ovarian hyperstimulation in IVF

Four trials studied the effect of metformin during ovarian hyperstimulation in

IVF/ICSI in 283 women with PCOS (Table 1)34;66-68 (T.Tang, personal

communication).

In the first study, reasons for IVF treatment were not specified.34 In the second

study, women received IVF or ICSI because of other fertility problems like tubal

pathology, endometriosis or male subfertility.66 In the third study women with PCOS

in whom conventional therapy had not lead to pregnancy, were included.67 In the

fourth study, reasons for IVF were failure of conventional therapy and other fertility

problems.68

All studies presented data in clinical pregnancy rate. Combining the results did

not show a significant difference between the women treated with metformin or

placebo (RR: 1.2; 95% CI: 0.85-1.6) (Fig. 4). Visual examination of the forest plot and

the I2 statistic (0%) suggested no heterogeneity in treatment effect across trials. Live

birth rate was reported in two studies.66;68 There was no evidence of a significant

difference between the two groups (RR: 1.5; 95% CI: 0.92-2.5) (Fig. 4). Pooling the

data of the two trials that reported multiple pregnancy gave no evidence of a

significant difference between the two groups on multiple pregnancy rate66;68 (RR:

0.93; 95% CI: 0.42-2.1). OHSS was reported in all studies. When combining the

results, there was a significant reduced risk in favour of metformin (RR: 0.33; 95% CI:

0.13-0.80).

44

Discussion

In this review, we evaluated whether metformin leads to a more effective

fertility treatment for women with PCOS.11;69-73 From the placebo controlled trials

performed in infertile women with therapy naïve PCOS it is clear that metformin can

induce ovulation and can lead to pregnancies. The important clinical question

however is not whether metformin “works”, but whether it is better than CC in terms

of live birth in CC naïve women or whether it has additional benefit in terms of live

birth when used as co-treatment in therapy naïve or CC-resistant women.

At present, there is no evidence of a difference between metformin and CC in

therapy naïve women in favour of metformin. The two trials that studied this

comparison had conflicting results. In the study by Palomba et a 52 the live birth rate

was three times higher in the metformin group. In contrast, in the study by Legro et

al13 with quadruple the number of patients, the live birth rate was three times lower in

the metformin group. Of interest is that in the Palomba study, live birth rate in the CC

group was unusually low due to a high miscarriage rate. Legro included patients

previously treated with CC or metformin. We presumed these patients not to be CC-

resistant. Through personal communication we were informed that it is not clear how

many of these patients were CC-resistant. (R. Legro, personal communication). Still,

this particular mixture of patients can explain the low live birth rate in this study.

Meta-analysis of the studies that compared co-treatment of metformin with CC

versus CC alone did not show any benefit of metformin for live birth rate. These data,

taken together, make it highly unlikely that metformin – as monotherapy or as co-

treatment in combination with CC - is beneficial over CC in CC naïve women.

The clinical pregnancy rate in the comparison metformin plus CC versus CC in

therapy naïve women was significantly higher in the metformin group. However, there

was significant heterogeneity between studies as the small studies all favoured

metformin plus CC above CC alone while this difference was not found in the larger

studies. This difference between the larger and smaller studies may be a result of

publication bias or low study quality bias.74;75 The sensitivity analysis using pooling

with a random effects method was not helpful here as a random effects meta-

analysis will award relatively more weight to smaller studies.

In CC-resistant women, two studies showed a clear benefit of adding

metformin to CC over CC alone in terms of live birth. One should interpret these

45

results with some caution as one study was not blinded and the total number of

patients in these two studies was only 107.

Metformin appears to be superior to LOD considering live birth rate in CC-

resistant women, but these data are also based on a small number of women and

from one monocenter study. This being so, metformin is quite a different treatment

strategy than LOD and avoids the considerable risks of laparoscopic surgery,

especially in obese patients.

No differences in live birth were detected when metformin was added to LOD

compared with LOD alone and when metformin was added to FSH compared with

FSH alone, but again few studies, including few patients, have been carried out so

far.

Up till now, there is no evidence for better results on live birth rates when

metformin is added during ovarian hyperstimulation in IVF. This is based on two

studies with a limited number of patients and with probably totally different

populations of women, as in one study a mix of women after failed ovulation

induction and with other indications was included, while in the other studies only

women with other fertility problems were included. Metformin may however, reduce

the risk of OHSS.

In general, duration of metformin therapy differed substantially over the studies

and we can only speculate which effects this will have on outcome parameters.

In summary, this meta-analysis demonstrates that CC is still first choice

therapy for women with therapy naïve PCOS. In CC-resistant women, the

combination of CC plus metformin is the preferred treatment option before starting

with LOD or FSH. At present, there is no evidence of an improvement in live birth

rates when adding metformin to LOD or FSH.

46

References

(1) Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale

HF. A prospective study of the prevalence of the polycystic ovary syndrome in

unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;

85(7):2434-2438.

(2) Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R.

Prevalence of the polycystic ovary syndrome in unselected black and white

women of the southeastern United States: a prospective study. J Clin

Endocrinol Metab 1998; 83(9):3078-3082.

(3) Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333(13):853-861.

(4) Fauser BC. Revised 2003 consensus on diagnostic criteria and long-term

health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;

19(1):41-47.

(5) Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy

in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance,

hyperandrogenemia, and systolic blood pressure, while facilitating normal

menses and pregnancy. Metabolism 1994; 43(5):647-654.

(6) Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin,

troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary

syndrome. Cochrane Database Syst Rev 2003;(3):CD003053.

(7) Cheang KI, Nestler JE. Should insulin-sensitizing drugs be used in the

treatment of polycystic ovary syndrome? Reprod Biomed Online 2004;

8(4):440-447.

(8) Costello MF. Polycystic ovary syndrome--a management update. Aust Fam

Physician 2005; 34(3):127-133.

(9) Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome:

systematic review and meta-analysis. BMJ 2003; 327(7421):951-953.

47

(10) De Leo V, La Marca A, Petraglia F. Insulin-lowering agents in the

management of polycystic ovary syndrome. Endocr Rev 2003; 24(5):633-667.

(11) Norman RJ. Editorial: Metformin--comparison with other therapies in ovulation

induction in polycystic ovary syndrome. J Clin Endocrinol Metab 2004;

89(10):4797-4800.

(12) Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, Van der Veen F. Effect of

clomifene citrate plus metformin and clomifene citrate plus placebo on

induction of ovulation in women with newly diagnosed polycystic ovary

syndrome: randomised double blind clinical trial. BMJ 2006; 332(7556):1485-

1489.

(13) Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA et al.

Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.

N Engl J Med 2007; 356(6):551-566.

(14) Mantel N, Haenszel W. Statistical aspects of the analysis of data from

retrospective studies of disease. J Natl Cancer Inst 1959; 22(4):719-748.

(15) DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials

1986; 7(3):177-188.

(16) Zafar S. Role of metformin in correcting hyperinsulinemia, menstrual

irregularity and anovulation in polycystic ovary syndrome. J Ayub Med Coll

Abbottabad 2005; 17(4):54-56.

(17) Qublan HS, Malkawi HY. Metformin in the treatment of clomiphene citrate-

resistant women with high BMI and primary infertility: clinical results and

reproductive outcome. J Obstet Gynaecol 2005; 25(1):55-59.

(18) Weerakiet S, Tingthanatikul Y, Sophonsritsuk A, Choktanasiri W, Wansumrith

S, Rojanasakul A. Efficacy of metformin on ovulation induction in Asian

women with polycystic ovary syndrome. Gynecol Endocrinol 2004; 19(4):202-

207.

48

(19) Kumari AS, Haq A, Jayasundaram R, Abdel-Wareth LO, Al Haija SA, Alvares

M. Metformin monotherapy in lean women with polycystic ovary syndrome.

Reprod Biomed Online 2005; 10(1):100-104.

(20) Aruna J, Mittal S, Kumar S, Misra R, Dadhwal V, Vimala N. Metformin therapy

in women with polycystic ovary syndrome. Int J Gynaecol Obstet 2004;

87(3):237-241.

(21) Kriplani A, Agarwal N. Effects of metformin on clinical and biochemical

parameters in polycystic ovary syndrome. J Reprod Med 2004; 49(5):361-367.

(22) Vrbikova J, Hill M, Starka L, Vondra K. Prediction of the effect of metformin

treatment in patients with polycystic ovary syndrome. Gynecol Obstet Invest

2002; 53(2):100-104.

(23) Heard MJ, Pierce A, Carson SA, Buster JE. Pregnancies following use of

metformin for ovulation induction in patients with polycystic ovary syndrome.

Fertil Steril 2002; 77(4):669-673.

(24) Parsanezhad ME, Alborzi S, Zarei A, Dehbashi S, Omrani G. Insulin

resistance in clomiphene responders and non-responders with polycystic

ovarian disease and therapeutic effects of metformin. Int J Gynaecol Obstet

2001; 75(1):43-50.

(25) Zhao JZ, Ye BL, Lin JJ, Lin WQ, Chi HH. [Effects of metformin on

gonadotropin-induced ovulation in patients with polycystic ovary syndrome].

Zhonghua Fu Chan Ke Za Zhi 2003; 38(9):545-548.

(26) Stadtmauer LA, Toma SK, Riehl RM, Talbert LM. Impact of metformin therapy

on ovarian stimulation and outcome in 'coasted' patients with polycystic ovary

syndrome undergoing in-vitro fertilization. Reprod Biomed Online 2002;

5(2):112-116.

(27) Stadtmauer LA, Toma SK, Riehl RM, Talbert LM. Metformin treatment of

patients with polycystic ovary syndrome undergoing in vitro fertilization

improves outcomes and is associated with modulation of the insulin-like

growth factors. Fertil Steril 2001 Mar ;75 (3 ):505 -9 2001; 75(3):505-509.

49

(28) Doldi N, Persico P, Di Sebastiano F, Marsiglio E, Ferrari A. Gonadotropin-

releasing hormone antagonist and metformin for treatment of polycystic ovary

syndrome patients undergoing in vitro fertilization-embryo transfer. Gynecol

Endocrinol 2006; 22(5):235-238.

(29) Carmina E, Lobo RA. Does metformin induce ovulation in normoandrogenic

anovulatory women? Am J Obstet Gynecol 2004; 191(5):1580-1584.

(30) Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on

spontaneous and clomiphene-induced ovulation in the polycystic ovary

syndrome. N Engl J Med 1998; 338(26):1876-1880.

(31) Turner MJ, Walsh J, Byrne KM, Murphy C, Langan H, Farah N. Outcome of

clinical pregnancies after ovulation induction using metformin. J Obstet

Gynaecol 2006; 26(3):233-235.

(32) Eisenhardt S, Schwarzmann N, Henschel V, Germeyer A, von Wolff M,

Hamann A et al. Early effects of metformin in women with polycystic ovary

syndrome: a prospective randomized, double-blind, placebo-controlled trial. J

Clin Endocrinol Metab 2006; 91(3):946-952.

(33) Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A

randomized, 48-week, placebo-controlled trial of intensive lifestyle modification

and/or metformin therapy in overweight women with polycystic ovary

syndrome: a pilot study. Fertil Steril 2004; 82(2):421-429.

(34) Fedorcsak P, Dale PO, Storeng R, Abyholm T, Tanbo T. The effect of

metformin on ovarian stimulation and in vitro fertilization in insulin-resistant

women with polycystic ovary syndrome: an open-label randomized cross-over

trial. Gynecol Endocrinol 2003; 17(3):207-214.

(35) Chou KH, von Eye CH, Capp E, Spritzer PM. Clinical, metabolic and

endocrine parameters in response to metformin in obese women with

polycystic ovary syndrome: a randomized, double-blind and placebo-controlled

trial. Horm Metab Res 2003; 35(2):86-91.

50

(36) Loverro G, Lorusso F, De Pergola G, Nicolardi V, Mei L, Selvaggi L. Clinical

and endocrinological effects of 6 months of metformin treatment in young

hyperinsulinemic patients affected by polycystic ovary syndrome. Gynecol

Endocrinol 2002; 16(3):217-224.

(37) Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M et al. Metformin

effects on clinical features, endocrine and metabolic profiles, and insulin

sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-

controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin

Endocrinol Metab 2000; 85(1):139-146.

(38) Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced

resumption of normal menses in 39 of 43 (91%) previously amenorrheic

women with the polycystic ovary syndrome. Metabolism 1999; 48(4):511-519.

(39) Ramzy AM, Al-Inany H, Aboulmaaty Z, El-Kateb S, Abdel Badie M. The Use

Of Metformin In Overweight And Lean Infertile Patients With Polycystic

Ovarian Syndrome: A Randomized Controlled Trial. Middle East Fertility

Society Journal 2003; 8(3).

(40) Malkawi HY, Qublan HS, Hamaideh AH. Medical vs. surgical treatment for

clomiphene citrate-resistant women with polycystic ovary syndrome. J Obstet

Gynaecol 2003; 23(3):289-293.

(41) Sturrock ND, Lannon B, Fay TN. Metformin does not enhance ovulation

induction in clomiphene resistant polycystic ovary syndrome in clinical

practice. Br J Clin Pharmacol 2002; 53(5):469-473.

(42) Batukan C, Baysal B. Metformin improves ovulation and pregnancy rates in

patients with polycystic ovary syndrome. Arch Gynecol Obstet 2001 Aug ;265

(3 ):124 -7 2001; 265(3):124-127.

(43) De Leo V, La Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on

gonadotropin-induced ovulation in women with polycystic ovary syndrome.

Fertil Steril 1999; 72(2):282-285.

51

(44) Jakubowicz DJ, Seppala M, Jakubowicz S, Rodriguez-Armas O, Rivas-

Santiago A, Koistinen H et al. Insulin reduction with metformin increases luteal

phase serum glycodelin and insulin-like growth factor-binding protein 1

concentrations and enhances uterine vascularity and blood flow in the

polycystic ovary syndrome. J Clin Endocrinol Metab 2001; 86(3):1126-1133.

(45) Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha

activity and serum free testosterone after reduction of insulin secretion in

polycystic ovary syndrome. N Engl J Med 1996; 335(9):617-623.

(46) Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function

and metabolic factors in women with oligomenorrhea treated with metformin in

a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab

2002; 87(2):569-574.

(47) El-Biely MM, Habba M. The use of metformin to augment the induction of

ovulation in obese infertile patients with polycystic ovary syndrome. Middle

East Fertility Society Journal 2001; 6(1):43-49.

(48) van Santbrink EJ, Hohmann FP, Eijkemans MJ, Laven JS, Fauser BC. Does

metformin modify ovarian responsiveness during exogenous FSH ovulation

induction in normogonadotrophic anovulation? A placebo-controlled double-

blind assessment. Eur J Endocrinol 2005; 152(4):611-617.

(49) Singh I, Bedaywi MA, Hatwal A, Kumar A, Agarwal A. Increased pregnancy

rates with metformin and clomiphene citrate in non-obese patients with

polycystic ovary syndrome: prospective randomized study. Fertil Steril 76,

S94. 24-10-2001.

(50) Ng EH, Wat NM, Ho PC. Effects of metformin on ovulation rate, hormonal and

metabolic profiles in women with clomiphene-resistant polycystic ovaries: a

randomized, double-blinded placebo-controlled trial. Hum Reprod 2001;

16(8):1625-1631.

52

(51) Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined

lifestyle modification and metformin in obese patients with polycystic ovary

syndrome. A randomized, placebo-controlled, double-blind multicentre study.

Hum Reprod 2006; 21(1):80-89.

(52) Palomba S, Orio F, Jr., Falbo A, Manguso F, Russo T, Cascella T et al.

Prospective parallel randomized, double-blind, double-dummy controlled

clinical trial comparing clomiphene citrate and metformin as the first-line

treatment for ovulation induction in nonobese anovulatory women with

polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90(7):4068-4074.

(53) Khorram O, Helliwell JP, Katz S, Bonpane CM, Jaramillo L. Two weeks of

metformin improves clomiphene citrate-induced ovulation and metabolic

profiles in women with polycystic ovary syndrome. Fertil Steril 2006;

85(5):1448-1451.

(54) Raja A, Hashmi SN, Sultana N, Rashid H. Presentation of polycystic ovary

syndrome and its management with clomiphene alone and in combination with

metformin. J Ayub Med Coll Abbottabad 2005; 17(2):50-53.

(55) Sahin Y, Yirmibes U, Kelestimur F, Aygen E. The effects of metformin on

insulin resistance, clomiphene-induced ovulation and pregnancy rates in

women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol

2004; 113(2):214-220.

(56) Hwu YM, Lin SY, Huang WY, Lin MH, Lee RK. Ultra-short metformin

pretreatment for clomiphene citrate-resistant polycystic ovary syndrome. Int J

Gynaecol Obstet 2005; 90(1):39-43.

(57) Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves

ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-

resistant women with polycystic ovary syndrome. Fertil Steril 2002; 77(1):101-

106.

(58) Malkawi HY, Qublan HS. The effect of metform plus clomiphene citrate on

ovulation and pregnancy rates in clomiphene-resistant women with polycystic

ovary syndrome. Saudi Medical Journal 2002; 23(6):663-666.

53

(59) Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE.

Metformin increases the ovulatory rate and pregnancy rate from clomiphene

citrate in patients with polycystic ovary syndrome who are resistant to

clomiphene citrate alone. Fertil Steril 2001; 75(2):310-315.

(60) Palomba S, Orio F, Jr., Nardo LG, Falbo A, Russo T, Corea D et al. Metformin

administration versus laparoscopic ovarian diathermy in clomiphene citrate-

resistant women with polycystic ovary syndrome: a prospective parallel

randomized double-blind placebo-controlled trial. J Clin Endocrinol Metab

2004; 89(10):4801-4809.

(61) Kocak I, Ustun C. Effects of metformin on insulin resistance, androgen

concentration, ovulation and pregnancy rates in women with polycystic ovary

syndrome following laparoscopic ovarian drilling. J Obstet Gynaecol Res

2006; 32(3):292-298.

(62) George SS, George K, Irwin C, Job V, Selvakumar R, Jeyaseelan V et al.

Sequential treatment of metformin and clomiphene citrate in clomiphene-

resistant women with polycystic ovary syndrome: a randomized, controlled

trial. Hum Reprod 2003; 18(2):299-304.

(63) Yarali H, Yildiz BO, Demirol A, Zeyneloglu HB, Yigit N, Bukulmez O et al. Co-

administration of metformin during rFSH treatment in patients with clomiphene

citrate-resistant polycystic ovarian syndrome: a prospective randomized trial.

Hum Reprod 2002; 17(2):289-294.

(64) Tasdemir S, Ficicioglu C, Yalti S, Gurbuz B, Basaran T, Yildirim G. The effect

of metformin treatment to ovarian response in cases with PCOS. Arch

Gynecol Obstet 2004; 269(2):121-124.

54

(65) Palomba S, Falbo A, Orio F, Jr., Manguso F, Russo T, Tolino A et al. A

randomized controlled trial evaluating metformin pre-treatment and co-

administration in non-obese insulin-resistant women with polycystic ovary

syndrome treated with controlled ovarian stimulation plus timed intercourse or

intrauterine insemination. Hum Reprod 2005; 20(10):2879-2886.

(66) Kjotrod SB, Von D, V, Carlsen SM. Metformin treatment before IVF/ICSI in

women with polycystic ovary syndrome; a prospective, randomized, double

blind study. Hum Reprod 2004; 19(6):1315.

(67) Onalan G, Pabuccu R, Goktolga U, Ceyhan T, Bagis T, Cincik M. Metformin

treatment in patients with polycystic ovary syndrome undergoing in vitro

fertilization: a prospective randomized trial. Fertil Steril 2005; 84(3):798-801.

(68) Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for

women with PCOS undergoing IVF treatment. Hum Reprod 2006; 21(6):1416-

1425.

(69) Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the

evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003;

361(9372):1894-1901.

(70) Costello MF, Chapman M, Conway U. A systematic review and meta-analysis

of randomized controlled trials on metformin co-administration during

gonadotrophin ovulation induction or IVF in women with polycystic ovary

syndrome. Hum Reprod 2006; 21(6):1387-1399.

(71) Checa MA, Requena A, Salvador C, Tur R, Callejo J, Espinos JJ et al. Insulin-

sensitizing agents: use in pregnancy and as therapy in polycystic ovary

syndrome. Hum Reprod Update 2005; 11(4):375-390.

(72) Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary

therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;

19(11):2474-2483.

55

(73) Saleh AM, Khalil HS. Review of nonsurgical and surgical treatment and the

role of insulin-sensitizing agents in the management of infertile women with

polycystic ovary syndrome. Acta Obstet Gynecol Scand 2004; 83(7):614-621.

(74) Poole C, Greenland S. Random-effects meta-analyses are not always

conservative. Am J Epidemiol 1999; 150(5):469-475.

(75) Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and

discrepancies between large and small randomized trials in meta-analyses.

Ann Intern Med 2001; 135(11):982-989.

56

Tab

le 1

. Cha

ract

eris

tics

of r

ando

mis

ed tr

ials

of m

etfo

rmin

ver

sus

plac

ebo

in fe

rtili

ty tr

eatm

ent

Tri

al

(n =

nu

mb

er o

f ra

nd

om

ised

p

atie

nts

)

Par

tici

pan

ts

Inte

rven

tio

n

Co

mp

aris

on

M

ain

O

utc

om

es

Qu

alit

y fe

atu

res

El B

iely

200

1 (n

=45

ver

sus

45)

CC

-nai

ve;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd;

Age

: 26

vers

us 2

6 B

MI:

29 v

ersu

s 27

Met

form

in 5

00m

g 3/

day

+ C

C 5

0-15

0mg

6 m

onth

s

Pla

cebo

+

CC

50-

150m

g 6

mon

ths

Ovu

latio

n P

regn

ancy

O

HS

S

Ran

dom

isat

ion

with

com

pute

r-ge

nera

ted

bloc

ks;

Sin

gle

blin

ded.

Fed

orc

sak

2003

(n

=9

vers

us 8

)

PC

O u

ltras

ound

+ 2

ou

t of

hype

rand

roge

nism

, hi

rsut

ism

; In

sulin

res

ista

nce

Age

and

BM

I: no

t av

aila

ble

Met

form

in 5

00m

g 3/

day

+ IV

F/IC

SI

5 w

eeks

IVF

/ICS

I 5

wee

ks

Pre

gnan

cy

Fle

min

g 2

002

(n=

45 v

ersu

s 47

)

CC

-nai

ve;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd;

Age

: 29

vers

us 2

9 B

MI:

34 v

ersu

s 35

Met

form

in 8

50m

g 2/

day

16 w

eeks

Pla

cebo

16

wee

ks

Ovu

latio

n R

ando

mis

atio

n w

ith c

ompu

ter-

gene

rate

d bl

ocks

; D

oubl

e bl

inde

d.

Geo

rge

2003

(n

=30

ver

sus

30)

CC

-res

ista

nt;

Olig

omen

orro

ea +

hy

pera

ndro

geni

sm +

1

out o

f PC

O

ultr

asou

nd, L

H-F

SH

-ra

tio >

2;

Age

: 25

vers

us 2

6 B

MI:

26 v

ersu

s 26

Met

form

in 5

00m

g 3/

day

+ C

C 1

50-2

00m

g 6

mon

ths

+ 3

cyc

les

(CC

was

sta

rted

af

ter

6 m

onth

s tr

eatm

ent)

hMG

, ste

p-up

3

cycl

es

Ovu

latio

n P

regn

ancy

R

ando

mis

atio

n w

ith c

ompu

ter-

gene

rate

d bl

ocks

; N

ot b

linde

d.

56

57

Hw

u 2

005

(n=

40 v

ersu

s 40

)

CC

-res

ista

nt;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd +

hy

pera

ndro

geni

sm;

Age

: 29

vers

us 2

8 B

MI:

25 v

ersu

s 24

Met

form

in 5

00m

g 3/

day

+ C

C 1

50m

g 1

cycl

e

CC

150

mg

1 cy

cle

Ovu

latio

n P

regn

ancy

R

ando

mis

atio

n no

t cl

ear;

N

ot b

linde

d.

Kh

orr

am 2

006

(n=

16 v

ersu

s 15

)

CC

-nai

ve;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd +

hy

pera

ndro

geni

sm +

B

MI >

29;

A

ge: 2

8 ve

rsus

28

BM

I: 35

ver

sus

39

Met

form

in 5

00m

g 3/

day

+ C

C 1

00m

g 2

wee

ks

CC

100

mg

2 w

eeks

O

vula

tion

Car

d ou

t of b

ox

with

trea

tmen

t; N

ot b

linde

d.

Kjo

tro

d 2

004

(n=

37 v

ersu

s 36

)

Mix

ed fe

rtili

ty

prob

lem

s;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd+

te

stos

tero

ne >

2

nmol

/l +

one

of

LH-

FS

H-r

atio

> 2

, hi

rsut

ism

, SH

BG

< 3

0 nm

ol/l,

bas

elin

e in

sulin

> 1

nm

ol/l;

A

ge: 2

9 ve

rsus

30

BM

I: st

ratif

ied

< o

r �

28

Met

form

in 1

000m

g 2/

day

+ IV

F/IC

SI

trea

tmen

t 16

wee

ks

Pla

cebo

+

IVF

/ICS

I tr

eatm

ent

16 w

eeks

Pre

gnan

cy

Live

birt

h O

HS

S

Ran

dom

isat

ion

with

pha

rmac

y-ge

nera

ted

bloc

ks;

Dou

ble

blin

ded.

57

58

Ko

cak,

I 20

06

(n=

21 v

ersu

s 21

)

CC

-fai

lure

; 3

or m

ore

of:

olig

omen

orro

ea, P

CO

ul

tras

ound

, hy

pera

ndro

geni

sm,

anov

ulat

ion,

infe

rtili

ty,

hirs

utis

m, o

besi

ty;

Age

: 27

vers

us 2

8 B

MI:

27 v

ersu

s 32

LOD

+

Met

form

in 8

50m

g 2/

day

6 m

onth

s

LOD

6

mon

ths

Ovu

latio

n P

regn

ancy

R

ando

mis

atio

n no

t cl

ear;

N

ot b

linde

d.

Ko

cak,

M 2

002

(n=

28 v

ersu

s 28

)

CC

-res

ista

nt;

Olig

omen

orro

ea +

1

or m

ore

of P

CO

ul

tras

ound

, hy

pera

ndro

geni

sm;

Age

: 26

vers

us 2

7 B

MI:

32 v

ersu

s 31

Met

form

in 8

50m

g 2/

day

+ C

C 1

00m

g 2

cycl

es (

CC

was

ad

ded

if no

ov

ulat

ion

afte

r 1

cycl

e)

Pla

cebo

850

mg

bid

+ C

C 1

00m

g 2

cycl

es (

CC

was

ad

ded

if no

ov

ulat

ion

afte

r 1

cycl

e)

Ovu

latio

n P

regn

ancy

S

eale

d en

velo

pes;

D

oubl

e bl

inde

d.

Leg

ro 2

007

(n=

208

vers

us

209

vers

us 2

09)

CC

-naï

ve /

appr

oxim

atel

y 50

%

used

CC

or

met

form

in o

r co

mbi

natio

n pr

ior

to

stud

y;

Olig

omen

orro

ea +

el

evat

ed

test

oste

rone

; A

ge: 2

8 ve

rsus

28

BM

I: 36

ver

sus

36

Met

form

in 1

000m

g 2/

day

+ p

lace

bo

30 w

eeks

Pla

cebo

+

CC

50-

150m

g 30

wee

ks

Thi

rd g

roup

: M

etfo

rmin

10

00m

g bi

d +

CC

50

-150

mg

Live

birt

h In

tera

ctiv

e vo

ice

syst

em; s

trat

ified

ba

sed

on s

tudy

si

te a

nd p

revi

ous

expo

sure

to e

ither

of

the

stud

y dr

ugs;

D

oubl

e bl

inde

d.

58

59

Mal

kaw

i 200

2 (n

=16

ver

sus

12)

CC

-res

ista

nt o

r fa

ilure

; P

CO

ultr

asou

nd +

3

or m

ore

of

olig

omen

orro

ea,

hype

rand

roge

nism

, LH

-FS

H-r

atio

>2,

el

evat

ed L

H,

Fer

riman

-Gal

lwey

sc

ore

> 7

; A

ge: 2

9 ve

rsus

29

BM

I: 28

ver

sus

28

Met

form

in 8

50m

g 2/

day

+ C

C 5

0-20

0mg

6 cy

cles

Pla

cebo

+

CC

50-

200m

g 6

cycl

es

Ovu

latio

n P

regn

ancy

C

entr

alis

ed

rand

omis

atio

n pr

oces

s;

Dou

ble

blin

ded

Mo

ll 20

06

(n=

111

vers

us

114)

CC

-nai

ve;

Def

initi

on c

onfo

rm

ES

HR

E 2

003;

A

ge: 2

8 ve

rsus

28

BM

I: 29

ver

sus

28

Met

form

in 5

00m

g 4/

day

+ C

C 5

0-15

0mg

6 cy

cles

Pla

cebo

+

CC

50-

150m

g 6

cycl

es

Ovu

latio

n P

regn

ancy

R

ando

mis

atio

n w

ith c

ompu

ter-

gene

rate

d bl

ocks

; D

oubl

e bl

inde

d.

Ng

200

1 (n

=9

vers

us 9

)

CC

-res

ista

nt;

PC

O u

ltras

ound

; A

ge: 3

1 ve

rsus

32

BM

I: 24

ver

sus

24

Met

form

in 5

00m

g 3/

day

+ C

C 1

00m

g 3

mon

ths

and

1 cy

cle

(CC

was

ad

ded

if no

ov

ulat

ion

afte

r 3

mon

ths)

Pla

cebo

500

mg

3/da

y +

CC

100

mg

3 m

onth

s an

d 1

cycl

e (C

C w

as

adde

d if

no

ovul

atio

n af

ter

3 m

onth

s)

Ovu

latio

n R

ando

mis

atio

n w

ith c

ompu

ter-

gene

rate

d lis

t in

enve

lope

s;

Dou

ble

blin

ded.

On

alan

200

5 (n

=53

ver

sus

55)

Last

fert

ility

tr

eatm

ent;

O

ligom

enor

roea

+

hype

rand

roge

nism

; A

ge: 2

9 ve

rsus

30

BM

I: 25

ver

sus

24

Met

form

in 8

50m

g 2-

3/da

y (d

epen

ding

on

BM

I < o

r �

28)

+ IV

F/IC

SI

trea

tmen

t 12

wee

ks

Pla

cebo

+

IVF

/ICS

I tr

eatm

ent

12 w

eeks

Pre

gnan

cy

Abo

rtio

n O

HS

S

Ran

dom

isat

ion

with

com

pute

r-ge

nera

ted

bloc

ks;

Dou

ble

blin

ded.

59

60

Pal

om

ba

2004

(n

=54

ver

sus

55)

CC

-res

ista

nt;

Olig

omen

orro

ea +

el

evat

ed

test

oste

rone

; A

ge: 2

7 ve

rsus

28

BM

I: 28

ver

sus

28

Dia

gnos

tic

lapa

rosc

opy

+ M

etfo

rmin

850

mg

2/da

y 6

mon

ths

LOD

+

pla

cebo

6

mon

ths

Ovu

latio

n P

regn

ancy

Li

ve b

irth

Ran

dom

isat

ion

with

com

pute

r-ge

nera

ted

bloc

ks;

Dou

ble

blin

ded.

Pal

om

ba

2005

(n

=50

ver

sus

50)

CC

-nai

ve;

Olig

omen

orro

ea +

el

evat

ed

test

oste

rone

; A

ge: 2

6 ve

rsus

26

BM

I: 27

ver

sus

27

Met

form

in 8

50m

g 2/

day

+ p

lace

bo

6 m

onth

s

Pla

cebo

+

CC

150

mg

6 m

onth

s

Ovu

latio

n P

regn

ancy

Li

ve b

irth

Ran

dom

isat

ion

with

com

pute

r-ge

nera

ted

bloc

ks;

Dou

ble

blin

ded.

Pal

om

ba

2005

(n

=35

ver

sus

35)

CC

-res

ista

nt;

Olig

omen

orro

ea +

el

evat

ed

test

oste

rone

; A

ge: 2

6 ve

rsus

27

BM

I: 27

ver

sus

26

Met

form

in 8

50m

g 2/

day

+ F

SH

ste

p up

3

mon

ths

+ 3

cyc

les

(FS

H w

as s

tart

ed

afte

r 8

wee

ks

trea

tmen

t)

Pla

cebo

+

FS

H s

tep

up

3 m

onth

s +

3

cycl

es (

FS

H w

as

star

ted

afte

r 8

wee

ks tr

eatm

ent)

Pre

gnan

cy

Live

birt

h M

ultip

le

preg

nanc

y O

HS

S

Ran

dom

isat

ion

with

com

pute

r-ge

nera

ted

bloc

ks;

Dou

ble

blin

ded.

Raj

a 20

05

(n=

50 v

ersu

s 50

)

CC

-nai

ve;

PC

O u

ltras

ound

+ 2

or

mor

e of

: ol

igom

enor

roea

, hy

pera

ndro

geni

sm,

LH-F

SH

-rat

io >

2,

hirs

utis

m, e

leva

ted

LH;

Age

: 27

vers

us 2

7 B

MI:

not a

vaila

ble

Met

form

in 5

00m

g 3/

day

+ C

C 5

0mg

6 cy

cles

CC

50m

g 6

cycl

es

Ovu

latio

n P

regn

ancy

R

ando

mis

atio

n no

t cl

ear;

N

ot b

linde

d.

60

61

Sah

in 2

004

(n=

11 v

ersu

s 10

)

CC

-nai

ve;

3 or

mor

e of

ol

igom

enor

roea

, PC

O

ultr

asou

nd,

hype

rand

roge

nism

, LH

-FS

H-r

atio

>2,

hi

rsut

ism

; A

ge: 2

7 ve

rsus

25

BM

I: 30

ver

sus

26

Met

form

in 8

50m

g 2/

day

+ C

C 1

00m

g 3

mon

ths

CC

100

mg

3 m

onth

s O

vula

tion

Pre

gnan

cy

Ran

dom

isat

ion

not

clea

r;

Not

blin

ded.

Sin

gh

200

1 (n

=53

ver

sus

47)

CC

-nai

ve;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd +

LH

-FS

H-r

atio

> 2

; A

ge: 2

6 ve

rsus

28

BM

I: no

t ava

ilabl

e

Met

form

in 5

00m

g 2/

day

+ C

C 5

0mg

4 m

onth

s

CC

50m

g 4

mon

ths

Pre

gnan

cy

Ran

dom

isat

ion

not

clea

r;

Pre

sum

ed n

ot

blin

ded.

O

nly

abst

ract

av

aila

ble.

S

turr

ock

200

2 (n

=54

ver

sus

55)

CC

-res

ista

nt;

Olig

omen

orro

ea;

Age

: 29

vers

us 3

1 B

MI:

34 v

ersu

s 35

Met

form

in 5

00m

g 3/

day

+ C

C 5

0-15

0mg

3 m

onth

s +

3 c

ycle

s

Pla

cebo

+

CC

50-

150m

g 3

mon

ths

+ 3

cy

cles

Ovu

latio

n P

regn

ancy

R

ando

mis

atio

n pe

rfor

med

by

phar

mac

y;

Cro

ss-o

ver

(onl

y da

ta b

efor

e cr

oss-

over

are

use

d)

Dou

ble

blin

ded.

T

ang

200

6 (n

=56

ver

sus

66)

CC

-nai

ve;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd +

B

MI >

30;

Age

: 30

vers

us 3

0 B

MI:

38 v

ersu

s 39

Met

form

in 8

50m

g 2/

day

6 m

onth

s

Pla

cebo

6

mon

ths

Pre

gnan

cy

R

ando

mis

atio

n w

ith c

ompu

ter-

gene

rate

d bl

ocks

; D

oubl

e bl

inde

d.

61

62

Tan

g 2

006b

(n

=51

ver

sus

47);

4

patie

nts

ente

red

twic

e

Def

initi

on c

onfo

rm

ES

HR

E 2

003;

A

ge: 3

1 ve

rsus

31

BM

I: 28

ver

sus

27

Met

form

in 8

50m

g 2/

day

+ IV

F/IC

SI

trea

tmen

t 28

day

s

Pla

cebo

+

IVF

/ICS

I tr

eatm

ent

28 d

ays

Pre

gnan

cy

Live

birt

h O

HS

S

Ran

dom

isat

ion

with

com

pute

r-ge

nera

ted

bloc

ks;

Dou

ble

blin

ded.

Tas

dem

ir 2

004

(n=

16 v

ersu

s 16

)

CC

- re

sist

ant;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd +

hy

pera

ndro

geni

sm;

Age

: 32

vers

us 3

1 B

MI:

29 v

ersu

s 29

Met

form

in 8

50m

g 2/

day

+ F

SH

8

wee

ks +

1 c

ycle

(F

SH

was

sta

rted

af

ter

8 w

eeks

tr

eatm

ent)

FS

H

8 w

eeks

+ 1

cyc

le

(FS

H w

as s

tart

ed

afte

r 8

wee

ks

trea

tmen

t)

Pre

gnan

cy

Ova

rian

resp

onse

Ran

dom

isat

ion

not

clea

r;

Not

blin

ded.

van

San

tbri

nk

2005

(n

=11

ver

sus

7)

CC

-res

ista

nt o

r C

C-

failu

re;

Olig

omen

orro

ea +

in

sulin

res

ista

nce;

A

ge: 2

8 ve

rsus

28

BM

I: 38

ver

sus

34

Met

form

in 8

50m

g 2/

day

+ F

SH

ste

p-up

35

day

s an

d 1

cycl

e (F

SH

was

add

ed if

no

ovu

latio

n af

ter

35

days

)

Pla

cebo

850

mg

bid

+ F

SH

ste

p-up

35

day

s an

d 1

cycl

e (F

SH

was

ad

ded

if no

ov

ulat

ion

afte

r 35

da

ys)

Ova

rian

resp

onse

S

eale

d en

velo

pes;

D

oubl

e bl

inde

d.

Van

der

mo

len

20

01

(n=

12 v

ersu

s 15

)

CC

-res

ista

nt;

Olig

omen

orro

ea +

hy

pera

ndro

geni

sm;

Age

: 29

vers

us 3

0 B

MI:

38 v

ersu

s 38

Met

form

in 5

00m

g 3/

day

+ C

C 5

0-15

0mg

6 w

eeks

and

6

cycl

es (

CC

was

ad

ded

if no

ov

ulat

ion

afte

r 6

wee

ks)

Pla

cebo

+

CC

50-

150m

g 6

wee

ks a

nd 6

cy

cles

(C

C w

as

adde

d if

no

ovul

atio

n af

ter

6 w

eeks

)

Ovu

latio

n P

regn

ancy

R

ando

mis

atio

n w

ith c

ompu

ter-

gene

rate

d bl

ocks

; D

oubl

e bl

inde

d.

62

63

Yar

ali 2

002

(n=

16 v

ersu

s 16

)

CC

-res

ista

nt;

Olig

omen

orro

ea +

P

CO

ultr

asou

nd +

te

stos

tero

ne >

2.4

nm

ol/l;

A

ge: 3

0 ve

rsus

28

BM

I: 29

ver

sus

30

Met

form

in 8

50m

g 2/

day

+ F

SH

ste

p-up

6

wee

ks a

nd 1

cyc

le

(FS

H w

as a

dded

if

no o

vula

tion

afte

r 6

wee

ks)

Pla

cebo

850

mg

bid

+ F

SH

ste

p-up

6

wee

ks a

nd 1

cy

cle

(FS

H w

as

adde

d if

no

ovul

atio

n af

ter

6 w

eeks

)

Ova

rian

resp

onse

S

eale

d en

velo

pes;

D

oubl

e bl

inde

d.

63

64

Figure 1. Trial flow

Trials extra found in reference lists; n=4

Trials included in meta-analysis;

n=27

Potentially relevant trials; n=443

Trials retrieved for evaluation; n=147

Potentially appropriate trials; n=53

Articles excluded not meeting inclusion criteria by title;

n=296

Articles excluded not meeting inclusion criteria by abstract;

n=94

Trials withdrawn not meeting inclusion criteria; n=30 -10 no control group -3 no randomisation

-13 no pregnancy rates -3 cross-over design

-1 selection bias

F (Fig

ure

2. F

ore

(A)

Clin

ical

prees

t plo

ts fo

r cl

o

egna

ncy

rate

iomife

ne c

itrat

e

in c

lom

ifene

cie

naïv

e w

ome

itrat

e na

ïve

won om

en

65

65

6( 66

(B)

Live

birt

h rra

te in

clo

mife

ne c

itrat

e na

ïvve

wom

en

66

Figure

(A) Clin

3. Forest

nical pregn

plots for cl

nancy rate

lomifene c

in clomifen

itrate resis

ne citrate r

stant wome

resistant w

en

women

67

6 ( 68

(B)

Live

birt

h rra

te in

clo

mife

ne c

itrat

e re

sisst

ant w

omen

68

F Fig

ure

4. F

orees

t plo

ts fo

r cl

inic

al p

regn

ancy

rat

e an

d livv

e bi

rth

rate

in w

omen

trea

teed

with

IVF

.

69

69