***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: STUDY QUESTION Do different dosages of metformin account for different clinical and biochemical outcomes in women with polycystic ovary syndrome ( PCOS ) and do basal anthropometric and metabolic characteristics of the patients provide any indications regarding the dose required to reach the target effect ? SUMMARY ANSWER Different doses of metformin exerted the same effects on clinical , biochemical and metabolic parameters in patients affected by PCOS . WHAT IS KNOWN AND WHAT THIS PAPER ADDS Since the insulin-sensitizing agents came into use in the management of PCOS , metformin has shown a positive benefits -risks ratio . Nonetheless , therapeutic schedules are not well st and ardized . This is the first study which systematic ally analyses the effect of different doses of metformin on clinical , hormonal and metabolic features of PCOS . On the basis of our results , higher doses are no more effective than lower doses . DESIGN A multicentric cohort prospect i ve study . A total of 250 PCOS women were enrolled , 49 lost to follow-up . Menstrual cyclicity , hormonal assays , oral glucose tolerance test , lipid profile and ultrasonographic pelvic examination were evaluated at the baseline and after 6 months of metformin treatment at different doses ( 1000 , 1500 and 1700 mg ) . PARTICIPANTS AND SETTING A total of 201 PCOS patients completed the study without protocol violations in three university hospitals : seventy-three patients from Centre A ( treated with metformin 500 mg twice a day ) , 60 patients from Centre B ( treated with metformin 500 mg three times a day ) and 68 patients from Centre C ( treated with metformin 850 mg twice a day ) . MAIN RESULTS AND THE ROLE OF CHANCE Metformin exerted an overall positive effect on the clinical and endocrine-metabolic features of PCOS . The degree of these effects was independent of the administered dosage in every range of basal body mass index ( BMI ) . When patients were stratified according to their insulinaemic status , scattered inter-doses differences were found in some of the outcome measures . Patients who exhibited an increase of > 2 menstrual cycles/year were considered as responders to treatment . Responders had a higher basal BMI than non-responders and showed a greater reduction in plasma testosterone levels after metformin treatment , but other outcome measures did not differ significantly . Total insulin secretion in the 180 min following the glucose tolerance test before metformin treatment ( basal AUC-I ) was significantly correlated with the decrease in insulin secretion induced by metformin in both the whole group and in responders , but only correlated with the variation in the number of cycles in responders . BIAS , CONFOUNDING AND OTHER REASONS FOR CAUTION The different doses were administered in different centres , and between-centre variation is a potential confounding factor . GENERALIZABILITY TO OTHER POPULATION S The paradigm of using the minimum effective dose of metformin could be pursued in other pathological conditions characterized by insulin resistance . STUDY FUNDING /COMPETING INTEREST(S ) No funding or competing interests to declare BACKGROUND There are few data in the literature regarding the utility of metfomin before and during gonadotrophin administration in women with polycystic ovary syndrome ( PCOS ) . The aim of the present study was to assess the effect of the pre-treatment and co-administration of metformin in infertile PCOS women treated with controlled ovarian stimulation ( COS ) followed by timed intercourse ( TI ) or intrauterine insemination ( IUI ) . METHODS Seventy insulin-resistant primary infertile women with PCOS were r and omized to receive metformin cloridrate ( 850 mg twice daily ; group A ) or placebo tablets ( two tablets daily ; group B ) for 3 months . Three trials of COS using highly purified urinary FSH ( hpFSH ) plus TI/IUI were performed . Number of ampoules of gonadotrophin used , duration of the ovarian stimulation , cycle cancellation , ovulation , pregnancy , abortion , live birth , mono-ovulatory cycles , multiple pregnancies and ovarian hyperstimulation syndrome ( OHSS ) rates were assessed . RESULTS No difference between groups was detected in ovulation , cycle cancellation , pregnancy , abortion , live birth , multiple pregnancies and OHSS rates . The mono-ovulatory cycle rates were significantly ( P = 0.002 ) more frequent in group A than in group B , whereas the days of stimulation for non-cancelled cycles and the number of vials of gonadotrophins used were significantly ( P < 0.001 ) higher in group A than in group B. CONCLUSION In insulin-resistant women with PCOS  , metformin pre-treatment and co-administration with hpFSH increases the mono-ovulatory cycles BACKGROUND Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome . P450c17 alpha , which is involved in and rogen bio synthesis , has both 17 alpha-hydroxylase and 17,20-lyase activities . Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin . We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity . METHODS We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide , a gonadotrophin-releasing hormone agonist , and performed oral glucose-tolerance tests before and after oral administration of either metformin ( 500 mg three times daily ) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome . RESULTS In the 11 women given metformin , the mean ( + /- SE ) area under the serum insulin curve after oral glucose administration decreased from 9303 + /- 1603 to 4982 + /- 911 microU per milliliter per minute ( 56 + /- 10 to 30 + /- 6 nmol per liter per minute ) ( P = 0.004 ) . This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 + /- 21 to 66 + /- 7 ng per deciliter ( 4.1 + /- 0.6 to 2.0 + /- 0.2 nmol per liter ) ( P = 0.01 ) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 + /- 54 to 281 + /- 52 ng per deciliter ( 13.7 + /- 1.6 to 8.5 + /- 1.6 nmol per liter ) ( P = 0.01 ) . The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group . In the metformin group , the basal serum luteinizing hormone concentration decreased from 8.5 + /- 2.2 to 2.8 + /- 0.5 mlU per milliliter ( P = 0.01 ) , the serum free testosterone concentration decreased from 0.34 + /- 0.07 to 0.19 + /- 0.05 ng per deciliter ( 12 + /- 3 to 7 + /- 2 pmol per liter ) ( P = 0.009 ) , and the serum sex hormone-binding globulin concentration increased from 0.8 + /- 0.2 to 2.3 + /- 0.6 microgram per deciliter ( 29 + /- 7 to 80 + /- 21 nmol per liter ) ( P < 0.001 ) . None of these values changed significantly in the placebo group . CONCLUSIONS In obese women with the polycystic ovary syndrome , decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyper and rogenism BACKGROUND Metformin has been shown to improve fertility in anovulatory patients with polycystic ovary syndrome ( PCOS ) , inducing not only a high ovulation and pregnancy rate but also reducing the incidence of miscarriages . The aim of the present study was to evaluate the uterine effects of metformin in patients with PCOS who ovulated under metformin .  METHODS Thirty-seven non-obese primary infertile anovulatory patients with PCOS and another 30 age- and body mass index-matched healthy women ( control group ) were studied . PCOS patients were treated with metformin ( 850 mg twice daily ) for 6 months , whereas the control group did not receive any treatment . In these PCOS patients who ovulated whilst under metformin treatment ( PCOS group ) and in controls , uterine , sub-endometrial and endometrial blood flow , and endometrial thickness and pattern were evaluated using serial ultrasonographic assessment s. RESULTS Before treatment , uterine , sub-endometrial and endometrial blood flows were significantly lower in patients with PCOS than in the control group . All indexes of uterine vascularization were significantly improved in the PCOS group with metformin treatment and were not different from the controls . Nor was any difference in endometrial thickness and pattern detected between PCOS and control groups . After grouping the data of PCOS patients who ovulated under metformin for cycles with favourable/unfavourable reproductive outcome , no difference in any parameter was observed . CONCLUSIONS Metformin improves all surrogate markers of endometrial receptivity in PCOS patients , without difference between patients who had favourable or unfavourable reproductive outcome BACKGROUND This study aims to evaluate the impact of metformin on ovarian response when co-administered during recombinant (r)FSH using the low-dose step-up protocol in clomiphene citrate-resistant polycystic ovarian syndrome ( PCOS ) patients with normal glucose tolerance . METHODS AND RESULTS Thirty-two patients were r and omized to metformin  ( n = 16 ) and placebo  ( n = 16 ) groups . Hormonal assessment , a 75 g oral glucose tolerance test ( OGTT ) and a frequently sample d i.v . glucose tolerance test ( FSIGTT ) were performed before and after oral administration of metformin ( 850 mg twice daily ) or placebo for 6 weeks . Recombinant FSH treatment was undertaken , thereafter , in women who did not ovulate on metformin ( n = 10 ) or placebo ( n = 15 ) . There was no significant change in all insulin sensitivity indices in both groups . The only change noted was a decline in mean serum free testosterone concentration in the metformin group ( P = 0.049 ) . One patient on placebo and six patients on metformin  ovulated spontaneously ( P < 0.05 ) . All parameters of ovarian response were comparable between the two groups during rFSH treatment . Combining the 6 week placebo or metformin-only period with a single rFSH treatment cycle , the overall ovulation rates were 75 and 94 % in the placebo and metformin groups respectively ( P > 0.05 ) . The respective figures for pregnancy were 6.3 and 31.3 % ( P > 0.05 ) . CONCLUSIONS Metformin may restore ovulation with no improvement on insulin resistance in clomiphene citrate-resistant PCOS patients with normal glucose tolerance , but has no significant effect on ovarian response during rFSH treatment OBJECTIVE To evaluate whether pretreatment with metformin improves FSH-induced ovulation in women with clomiphene-resistant polycystic ovary syndrome ( PCOS ) . DESIGN R and omized prospect i ve trial . SETTING Department of Obstetrics and Gynecology , University of Siena . PATIENT(S ) Twenty women with clomiphene citrate-resistant PCOS . INTERVENTION(S ) The women were divided r and omly into groups A and B ( 10 subjects each ) . Group B received 1,500 mg of metformin for at least a month before a single cycle of FSH stimulation . Group A underwent two cycles of FSH stimulation and then received metformin for a month before undergoing a third cycle . MAIN OUTCOME MEASURE(S ) The number of FSH ampules , days of treatment , E2 level on the day of hCG , number of follicles > 15 mm , number of hyperstimulation , and the number of cycles with hCG withheld . RESULT ( S ) The number of follicles > 15 mm in diameter on the day of hCG administration was significantly lower in cycles performed after metformin treatment . The percentage of cycles with hCG withheld because of excessive follicular development was significantly lower in cycles treated with metformin . Plasma levels of E2 were significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin . CONCLUSION ( S ) By reducing hyperinsulinism , metformin determines a reduction in intraovarian and rogens . This leads to a reduction in E2 levels and favors orderly follicular growth in response to exogenous gonadotropins This pilot study evaluated the effects of coadministration of metformin with clomiphene citrate ( CC ) and human men 
    Output:
    
Metformin administration influenced or did not influence other secondary endpoints assessed with a significant heterogeneity .
In conclusion , metformin administration increases the live-birth and pregnancy rate in PCOS patients who receive gonadotropins for ovulation induction .