The use of metformin for women with PCOS undergoing IVF treatment. 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. IVF/ICSI outcomes between cycles with luteal estradiol (E2) pre-treatment before GnRH antagonist protocol and standard long GnRH agonist protocol: a prospective and randomized study. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. [Indication of metformin in the management of hormonal dysfunction secondary to polycystic ovarian syndrome: prospective comparative study of 63 cases].
Metformin appears to improve reproductive function in some women with polycystic ovary syndrome (PCOS). We wished to explore the effect of metformin in women with PCOS undergoing IVF.
                A randomized, placebo-controlled, double-blind study was carried out between 2001 and 2004. Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were randomized to receive metformin (MET), 850 mg, or placebo (PLA) tablets twice daily from the start of the down-regulation process until the day of oocyte collection. The primary outcome was to be an improvement in the overall fertilization rate.
                One-hundred and one IVF/ICSI cycles were randomized to receive metformin (52) or to receive placebo (49). There was no difference in the total dose of rFSH required per cycle (median dose: MET = 1200 U, PLA = 1300 U; P = 0.937). The median number of oocytes retrieved per cycle (MET = 17.2, PLA = 16.2; P = 0.459) and the overall fertilization rates (MET = 52.9%, PLA = 54.9%; P = 0.641) did not differ. However, both the clinical pregnancy rates beyond 12 weeks gestation per cycle (MET = 38.5%, PLA = 16.3%; P = 0.023) and per embryo transfer (MET = 44.4%, PLA = 19.1%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) was observed (MET = 3.8%, PLA = 20.4%; P = 0.023), and this was still significant after adjustment for BMI, total rFSH dose and age (OR = 0.15; 95% CI: 0.03, 0.76; P = 0.022).
                Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS. Although metformin has been shown to be effective in the treatment of anovulation in women with polycystic ovary syndrome (PCOS), clomiphene citrate (CC) is still considered to be the first-line drug to induce ovulation in these patients.
                The goal of this study was to compare the effectiveness of metformin and CC administration as a first-line treatment in anovulatory women with PCOS.
                We describe a prospective parallel randomized, double-blind, double-dummy controlled clinical trial.
                The study was conducted at the University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
                One hundred nonobese primary infertile anovulatory women with PCOS participated.
                We administered metformin cloridrate (850 mg twice daily) plus placebo (group A) or placebo plus CC (150 mg for 5 d from the third day of a progesterone withdrawal bleeding) (group B) for 6 months each.
                The main outcome measures were ovulation, pregnancy, abortion, and live-birth rates.
                The subjects of groups A (n = 45) and B (n = 47) were studied for a total of 205 and 221 cycles, respectively. The ovulation rate was not statistically different between either treatment group (62.9 vs. 67.0%, P = 0.38), whereas the pregnancy rate was significantly higher in group A than group B (15.1 vs. 7.2%, P = 0.009). The difference found between groups A and B regarding the abortion rate was significant (9.7 vs. 37.5%, P = 0.045), whereas a positive trend was observed for the live-birth rate (83.9 vs. 56.3%, P = 0.07). The cumulative pregnancy rate was significantly higher in group A than group B (68.9 vs. 34.0%, P < 0.001).
                Six-month metformin administration is significantly more effective than six-cycle CC treatment in improving fertility in anovulatory nonobese PCOS women. To study if luteal E(2) pre-treatment before GnRH antagonist protocol improves IVF/ICSI outcomes compared with standard long GnRH agonist protocol.
                A prospective, randomized and controlled study.
                ART center of a state public hospital
                Two hundred twenty infertile women underwent IVF/ICSI treatments.
                Participants received oral Estradiol Valerate 4 mg/day preceding the IVF cycle from day 21 until day 2 of next cycle before GnRH antagonist protocol (E(2) pre-treatment group n=109) or received standard long GnRH agonist protocol as control group (n=111).
                Number of oocytes collected, MII oocytes, fertilization, implantation, live birth and early pregnancy rate, and hormone profiles.
                E(2) pre-treatment exerted a significant suppressive effect on FSH but not LH secretion compared with basal FSH and LH levels. In E(2) pre-treatment group serum LH level was significantly higher during COH and serum P was also significantly higher on the day of HCG injection compared with control group. Five patients from E(2) pre-treatment group had elevated LH at all time (>or= 10 IU/L) and also a concomitantly high P (>1 ng/mL). Two of the five women achieved pregnancy but had early pregnancy loss. Overall, IVF/ICSI outcomes such as implantation, clinical pregnancy and live birth rates were similar between E(2) pre-treatment and control groups.
                Luteal E(2) pre-treatment before GnRH antagonist protocol significantly increases serum LH level and incidence rate of premature LH but no significant effect is observed on implantation, clinical pregnancy, live birth and early pregnancy loss rates compared with long GnRH agonist protocol. However, more studies in large numbers of cycles are needed to confirm that increased serum LH level by E(2) pre-treatment during COH has no negative effect on the IVF/ICSI outcomes. Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome (PCOS) scheduled for IVF stimulation.
                Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria: hyperandrogenaemia, elevated LH/FSH ratio, hyperinsulinism, decreased SHBG levels or hirsutism, were studied. Normal weight and overweight patients were randomized separately in a prospective, randomized, double blind study. All patients were treated for at least 16 weeks with metformin (1000 mg bid) or placebo ending on the day of HCG injection.
                No differences were found in the primary end-points: duration of FSH stimulation 14.4 (13.1-15.7) versus 14.2 (12.6-15.7) days or estradiol on the day of HCG injection 6.8 (5.3-8.2) versus 7.6 (5.6-9.6) nmol/l in the metformin and placebo groups, respectively. The secondary end-points number of oocytes, fertilization rates, embryo quality, pregnancy rates and clinical pregnancy rates were equal. However, in the normal weight subgroup (BMI <28 kg/m(2), n = 27), pregnancy rates following IVF were 0.71 (0.63-0.79) versus 0.23 (0.15-0.31) in the metformin and placebo groups, respectively (P = 0.04). Overall clinical pregnancy rates were equal: 0.51 (0.34-0.68) versus 0.44 (0.27-0.62) in the metformin and placebo groups, respectively. However, in the normal weight subgroup, clinical pregnancy rates were 0.67 (0.43-0.91) and 0.33 (0.06-0.60), respectively (P = 0.06).
                Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome. However, among normal weight PCOS women, pre-treatment with metformin tends to improve pregnancy rates. Further studies in subgroups of PCOS women are required. To determine the first-line medication to be used in anovulatory patients with polycystic ovary syndrome (PCOS) for ovulation induction and pregnancy achievement.
                Randomized controlled trial.
                Infertility unit of a public hospital.
                One hundred fifteen newly diagnosed patients with PCOS based on ESHRE/ASRM criteria.
                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.
                Rates of ovulation, pregnancy (PR), and live birth.
                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.
                Clomiphene citrate should be the first-line treatment for ovulation induction in anovulatory patients with PCOS. Polycystic ovarian syndrome (PCOS) is the most common hormonal dysfunction in women. It's a cause of female infertility by oligoanovulation, clinical and biochemical hyperandrogenism and polycystic ovaries. Weight loss, firstly proposed in overweight or obese patient suffering from PCOS, aims to reduce hyperinsulinism and hyperandrogenism. Recently, Metformin, an insulin sensitizer, has been proposed as an alternative first line treatment for polycystic ovarian syndrome by improving hyperinsulinemia and hyperandrogenism in these women.
                The aim of our study, and through a literature review, is to demonstrate if Metformin should be used as a first-line drug for infertile women with this syndrome or as an adjunction to Clomifene Citrate, the longest established treatment already used in this syndrome.
                A prospective comparative study including 63 patients with PCOS has been done during 2 years. Women were randomly allocated to clomifene + Metformin (Metformin group, Metformin took during 8 weeks, 850 mg twice a day, plus Clomifene 100 mg per day during five days) or Clomifene only (100 mg per day during five days). All patients underwent a two- month's diet.
                The middle age was about 30.63 years and the body mass index (BMI) was about 29.88 kg/ m(2). We noticed a 6.2% weight loss in both groups (a non significant difference in p=0.04). The median of infertility period was about 2.49 years. The ovulation rate in the Metformin group was 53.12% (significant difference for inducing ovulation p=0.02) and 32.25% in Clomifene group (non-significant difference 0.07). There was also a significant difference for ongoing pregnancies (p=0.04). In fact, 11 on 32 patients (34%) achieved a full-term pregnancy in Metformin group versus only 4 ones on 31 patients (12.9%) in Clomifene group.
                Our conclusion is that Metformin is an effective addition to Clomifene Citrate in term of reestablishment of ovulation and full-term pregnancies achievement, excluding ART cycles.
This review found no evidence that metformin treatment before or during ART cycles improves live birth or pregnancy rates. The risk of OHSS in women with PCOS and undergoing IVF or ICSI cycles was reduced with metformin. Further large RCTs are necessary to definitively answer if the use of metformin in PCOS women undergoing ART improves live birth and pregnancy rates.