***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Polycystic ovary syndrome ( PCOS ) affects approximately 5 % of the female population , and is a leading cause of infertility , primarily secondary to anovulation . Clomiphene citrate has been st and ard therapy for ovulation induction in patients seeking pregnancy , but recent evidence suggests that insulin sensitizing agents such as metformin may also be effective . The National Institute of Child Health and Human Development 's Reproductive Medicine Network has begun a r and omized , double-blind trial of clomiphene vs. metformin vs. clomiphene plus metformin for the induction of ovulation in patients with PCOS seeking pregnancy , with live birth rate as the primary outcome . Because the available literature was largely limited to surrogate outcomes such as ovulation and pregnancy rates , we created a Markov model to derive estimates of likely live birth rates in each arm . Using these estimates , we then constructed an algorithm that allowed only two formal comparisons between the three arms . First , we assumed that combination therapy would have to be superior to the next best single-agent therapy in order to be preferred , because of complexity , costs , increased side effects , etc . If combination therapy is not superior to the next best single agent , then the only other comparison of interest is between the two single agent therapies . Because the third possible comparison , between the best and worst of the three therapies , is not clinical ly relevant , it can be eliminated from formal statistical consideration , with subsequent reduction in sample size . Based on the opinion of the Network Steering Committee that a 15 % absolute difference in live birth rates would be clinical ly relevant , our methodology result ed in a sample size of 226 per arm , or a total of 678 subjects . The PPCOS trial should definitively answer the question of the relative efficacy of metformin , clomiphene , and combination therapy  in the treatment of infertile women with PCOS OBJECTIVE To determine the clinical , hormonal , and biochemical effects of metformin therapy in obese and nonobese patients with polycystic ovary syndrome ( PCOS ) . DESIGN Controlled clinical study . SETTING Department of Gynecology of Federal University of São Paulo , São Paulo , Brazil . PATIENT(S ) Twenty-nine patients with PCOS . INTERVENTION(S ) Patients were treated with 500 mg of p.o . metformin t.i.d . for 6 months . MAIN OUTCOME MEASURE(S ) Clinical data as well as serum concentrations of sex steroids , sex hormone-binding globulin ( SHBG ) , gonadotropins , leptin , GH , lipids , insulin , and glucose levels were assessed before and after treatment . RESULT ( S ) In the metformin group of nonobese patients , the mean fasting serum insulin concentration decreased from a pretreatment value of 12.1 + /- 2.4 to 6.3 + /- 0.6 microU/mL after treatment , and the area under the curve of insulin decreased from 5,189.1 + /- 517.4 to 3,035.6 + /- 208.9 microU/mL per minute . Also in the metformin group of nonobese patients , the mean basal serum total testosterone , free testosterone , and and rostenedione concentrations decreased by 38 % , 58 % , and 30 % , respectively . In the obese patients treated with metformin , only free testosterone showed a statistically significant decrease ( 1.7 + /- 0.2 ) . CONCLUSION ( S ) Our data suggest that nonobese patients respond better than obese patients to a 1.5 g/day metformin regimen 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 OBJECTIVE To determine the first-line medication to be used in anovulatory patients with polycystic ovary syndrome ( PCOS ) for ovulation induction and pregnancy achievement . DESIGN R and omized controlled trial . SETTING Infertility unit of a public hospital . PATIENT(S ) One hundred fifteen newly diagnosed patients with PCOS based on ESHRE/ASRM criteria . INTERVENTION(S ) These patients were assigned to three groups : group 1 ( 38 patients ) received 500 mg of metformin three times a day ; group 2 ( 39 patients ) received clomiphene citrate ( CC ) at an incremental dose ; group 3 ( 38 patients ) received both medications . MAIN OUTCOME MEASURE(S ) Rates of ovulation , pregnancy ( PR ) , and live birth . RESULT ( S ) The ovulation rate was 23.7 % in the metformin group , 59 % in the CC group , and 68.4 % in the combination treatment group . This was translated into a similar PR and live birth rate , which were higher in the CC and combination groups compared to the metformin group ( PR : 7.9 % , 15.4 % , and 21.1 % ; live birth rate : 7.9 % , 15.4 % , and 18.4 % in metformin , CC , and combination treatment groups , respectively ) , although statistically the differences were not significant . There were no multiple pregnancies and the rate of spontaneous first trimester loss was similar to the general population . CONCLUSION ( S ) Clomiphene citrate should be the first-line treatment for ovulation induction in anovulatory patients with PCOS We hypothesized that hyperinsulinemia contributes to early pregnancy loss in the polycystic ovary syndrome by adversely affecting endometrial function and environment . Serum glycodelin , a putative biomarker of endometrial function , is decreased in women with early pregnancy loss . Insulin-like growth factor-binding protein-1 may also play an important role in pregnancy by facilitating adhesion processes at the feto-maternal interface . We studied 48 women with polycystic ovary syndrome before and after 4 weeks of administration of 500 mg metformin ( n = 26 ) or placebo ( n = 22 ) 3 times daily . Oral glucose tolerance tests were performed , and serum glycodelin and insulin-like growth factor-binding protein-1 were measured during the follicular and clomiphene-induced luteal phases of menses . In the metformin group , the mean ( + /-SE ) area under the serum insulin curve after glucose administration decreased from 62 + /- 6 to 19 + /- 2 nmol/L.min ( P < 0.001 ) . Follicular phase serum glycodelin concentrations increased 20-fold from 150 + /- 46 to 2813 + /- 1192 pmol/L ( P < 0.001 ) , and serum insulin-like-growth factor-binding protein-1 concentrations increased from 936 + /- 152 to 2396 + /- 300 pmol/L ( P < 0.001 ) . Similarly , luteal phase serum glycodelin concentrations increased 3-fold from 3434 + /- 1299 to 10624 + /- 1803 pmol/L ( P < 0.001 ) , and serum insulin-like growth factor-binding protein-1 concentrations increased from 1220 + /- 136 to 4916 + /- 596 pmol/L ( P < 0.001 ) . Uterine vascular penetration also increased in the metformin group , as did blood flow of spiral arteries , as demonstrated by a 20 % decrease in the resistance index from 0.71 + /- 0.02 to 0.57 + /- 0.03 ( P < 0.001 ) . These variables did not change in the placebo group . We conclude that insulin reduction with metformin increases follicular and luteal phase serum glycodelin and insulin-like growth factor-binding protein-1 concentrations and enhances luteal phase uterine vascularity and blood flow in the polycystic ovary syndrome . These changes may reflect an improved endometrial milieu for the establishment and maintenance of pregnancy OBJECTIVE Recent reports have indicated that a number of individual patient characteristics are responsible for the success or failure of  clomiphene citrate treatment . However , a priori individualization of doses in different patients has not been investigated . We examined the thesis that wide variability in the metabolism of the active component ( zuclomiphene ) contributes to variability in response . METHODS The dose-response relationship of clomiphene was established from a meta- analysis of data from 13 published reports . Limited data relating plasma drug concentrations to treatment outcome were examined to determine whether insufficient systemic exposure at a fixed dosage might contribute to therapeutic failure . RESULTS A fixed-dosage regimen of 50 mg clomiphene per day is likely to cause ovulation in only 46 % of patients ; subsequent increment in dosage increases the number of responders but at the expense of considerable delay in individualization of treatment . Case reports indicated that dosage based on plasma drug concentration monitoring could improve patient management , and an algorithm is proposed to facilitate treatment . CONCLUSIONS Prospect i ve studies of clomiphene citrate should be performed to confirm the hypothesis that the monitoring of plasma zuclomiphene concentrations can significantly accelerate dose individualization and improve the therapeutic outcome with this " orphan " drug BACKGROUND Minimal or mild endometriosis is frequently diagnosed in infertile women . It is often treated by resection or ablation of the lesions , but whether this improves fertility has not been established . We carried out a r and omized , controlled trial to determine whether laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis . METHODS We studied 341 infertile women 20 to 39 years of age with minimal or mild endometriosis . During diagnostic laparoscopy the women were r and omly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only . They were followed for 36 weeks after the laparoscopy or , for those who became pregnant during that interval , for up to 20 weeks of pregnancy . RESULTS Among the 172 women who had resection or ablation of endometriosis , 50 became pregnant and had pregnancies that continued for 20 weeks or longer , as compared with 29 of the 169 women in the diagnostic-laparoscopy group ( cumulative probabilities , 30.7 percent and 17.7 percent , respectively ; P=0.006 by the log-rank test ) . The corresponding rates of fecundity were 4.7 and 2.4 per 100 person-months ( rate ratio , 1.9 ; 95 percent confidence interval , 1.2 to 3.1 ) . Fetal losses occurred in 20.6 percent of all the recognized pregnancies in the laparoscopic-surgery group and in 21.6 percent of all those in the diagnostic-laparoscopy group ( P=0.91 ) . Four minor operative complications ( intestinal contusion , slight tear of the tubal serosa , difficult pneumoperitoneum , and vascular trauma ) were reported ( three in the surgery group and one in the control group ) . CONCLUSIONS Laparoscopic resection or ablation of minimal and mild endometriosis enhances fecundity in infertile women The diagnostic criteria used to identify patients suffering from polycystic ovary syndrome remain controversial . The present prospect i ve longitudinal follow-up study was design ed to identify whether certain criteria assessed during st and ardized initial screening could predict the response to ovulation induction with clomiphene citrate ( CC ) in 201 patients presenting with oligomenorrhea or amenorrhea and infertility .  Serum FSH levels were within the normal range ( 1 - 10 IU/L ) , and all patients underwent spontaneous or progestin-induced withdrawal bleeding . Initial CC doses were 50 mg daily for 5 days starting on cycle day 3 . In the case of an absent response , doses were increased to 100 and 150 mg daily in subsequent cycles . First ovulation with CC was used as the end point . After a complete follow-up ( in the case of a nonresponse , at least 3 treatment cycles with daily CC doses up to 150 mg ) 
    Output:
    
In PCOS patients with anovulatory infertility and not previously treated , the administration of metformin plus CC is not better than monotherapy ( metformin alone or CC alone ) , whereas to date no specific recommendation can be given regarding the use of CC or metformin as first-step drug