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      Clinical outcome of various metformin treatments for women with polycystic ovary syndrome

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          Abstract

          Aim

          Polycystic ovary syndrome ( PCOS) is an ovulatory disorder and insulin resistance and diabetes are involved in its pathophysiology. Metformin, an anti‐diabetic agent, has been reported to be useful to induce ovulation.

          Methods

          Metformin treatment was classified into four types: (1) clomiphene–metformin combination treatment for clomiphene‐resistant patients; (2) clomiphene–metformin combination for clomiphene‐sensitive patients; (3) clomiphene–metformin combination for naïve patients; and (4) metformin monotherapy. The patients underwent physical, endocrinological, and clinical examinations for their ovulation rates, pregnancy rates, and follicular development.

          Results

          The ovulation rates, pregnancy rates, and single follicular development were not significantly different among the clomiphene–metformin combination treatment groups. In the Body Mass Index ( BMI) subanalysis, the pregnancy rate was higher in the BMI≥30 kg/m 2 group than in the other three groups with a BMI of ≤30 kg/m 2 in both cycles and cases. The ovulation rates and pregnancy rates were significantly higher in the group with a fasting insulin of ≥15 μU/ mL than in the groups with a fasting insulin of <15 μU/ mL in both cycles and cases.

          Conclusion

          Clomiphene–metformin combination treatment appears to be useful, at least for clomiphene‐resistant patients, and a BMI of >30 kg/m 2 and a fasting insulin of ≥15 μU/ mL appear to be predictors of a good result with this treatment.

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          Most cited references30

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

          The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.
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            Metformin in polycystic ovary syndrome: systematic review and meta-analysis.

            To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. Systematic review and meta-analysis. Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.
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              Lactic acidosis in patients with diabetes treated with metformin.

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                Author and article information

                Contributors
                matsuzaki.toshiya@tokushima-u.ac.jp
                Journal
                Reprod Med Biol
                Reprod. Med. Biol
                10.1111/(ISSN)1447-0578
                RMB2
                Reproductive Medicine and Biology
                John Wiley and Sons Inc. (Hoboken )
                1445-5781
                1447-0578
                04 April 2017
                April 2017
                : 16
                : 2 ( doiID: 10.1111/rmb2.2017.16.issue-2 )
                : 179-187
                Affiliations
                [ 1 ] Department of Obstetrics and Gynecology Graduate School of Biomedical Sciences Tokushima University Kuramoto Japan
                Author notes
                [*] [* ] Correspondence

                Toshiya Matsuzaki, Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.

                Email: matsuzaki.toshiya@ 123456tokushima-u.ac.jp

                Article
                RMB212026
                10.1002/rmb2.12026
                5661811
                44e71bfd-0f41-49e3-9e16-50d7c1530fb1
                © 2017 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 December 2016
                : 19 January 2017
                Page count
                Figures: 4, Tables: 5, Pages: 9, Words: 5944
                Funding
                Funded by: Chugoku and Shikoku Society of Obstetrics and Gynecology
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                rmb212026
                April 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:04.12.2017

                clomiphene,metformin,ovulation induction,polycystic ovary syndrome

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