Homocysteine levels in women with polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study

Kılıçdağ, Esra Bulgan; Bağış, Tayfun; Zeyneloglu, Hulusi Bulent; Tarım, Ebru; Aslan, Erdoğan; Haydardedeoğlu, Bülent; Erkanli, Serkan

doi:10.1093/humrep/deh700

Cited by 65 publications

(91 citation statements)

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“…Considering that homocysteine increases the rate of synthesis of tissue factor, which in turn activates the extrinsic coagulation pathway (27), the finding of an increase in plasma homocysteine concentrations during treatment with metformin suggests that this mechanism may contribute to the parallel changes in prothrombin time and activity observed in our patients. In conceptual agreement, an increase in circulating homocystein levels during metformin administration to PCOS patients has been previously reported (40,41), although this finding is not universal (42).…”

Section: Discussionsupporting

confidence: 85%

“…However, because we did not find any effect of obesity on baseline homocysteine levels, this hypothesis remains merely speculative. Nevertheless, considering that increased homocysteine concentrations appear to mediate the effects of metformin on prothrombin time and activity, this undesirable effect could be prevented by the concurrent administration of calcium, vitamin B or folic acid supplements (41,44), whereas the undesirable effects of oral contraceptives on coagulation cannot be avoided. Furthermore, despite the small magnitude of the changes in blood clotting tests observed here as a result of PCOS treatment that, with a few individual exceptions, occurred within the normal range, it must be highlighted that even mild reductions of activated partial thromboplastin time increased the risk for thrombotic events in large population studies (45).…”

Section: Discussionmentioning

confidence: 99%

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Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking

Luque‐Ramírez

Mendieta-Azcona²,

Sánchez³

et al. 2009

European Journal of Endocrinology

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Objective: To study the blood clotting tests and endothelial function of polycystic ovary syndrome (PCOS) patients and non-hyperandrogenic women, and their changes during PCOS treatment, as a function of the presence of obesity and smoking. Design: Case-control study followed by a randomized clinical trial. Methods: Blood clotting and endothelial function were analyzed in 40 PCOS patients and 20 nonhyperandrogenic women. Thirty-four PCOS women were randomized to an oral contraceptive containing 35 mg ethinyl-estradiol plus 2 mg cyproterone acetate (Diane 35 Diario) or metformin (850 mg twice daily), monitoring the changes on these parameters during 24 weeks of treatment. The influence of obesity and smoking was also analyzed. Results: Blood clotting and endothelial function tests were similar among PCOS patients and controls with the exception of a higher platelet count in the former. Obesity increased circulating fibrinogen levels, prothrombin activity and platelet counts, and reduced prothrombin and activated partial thromboplastin times. Smoking increased fibrinogen levels, platelet counts, and prothrombin activity, and reduced prothrombin time, in relation to the larger waist circumference of smokers. Irrespective of the treatment received, PCOS patients showed a decrease in prothrombin time and an increase in prothrombin activity, with a parallel increase in homocysteine levels in metformin users. The activated partial thromboplastin time decreased markedly in the patients treated with Diane 35 Diario. Finally, flow-mediated dilation improved in non-smokers irrespective of the drug received, but worsened in smokers. Conclusions: Oral contraceptives and metformin may exert deleterious effects on blood clotting tests of PCOS women, yet the effects of metformin appear to be milder. Because smoking potentiates some of these effects and deteriorates endothelial function, smoking cessation should be promoted in PCOS patients.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking

Luque‐Ramírez

Mendieta-Azcona²,

Sánchez³

et al. 2009

European Journal of Endocrinology

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“…The procedures of random sequence generation in seven studies [26,27,31,33,[35][36][37], of allocation concealment in nine studies [26][27][28]31,[33][34][35][36][37], and of blinding of participants and personnel in five studies [30,[32][33][34]36] were not clearly described. Selective reporting risk was unclear in one study [32].…”

Section: Quality Assessmentmentioning

confidence: 99%

“…Five studies reported that more patients in the metformin group suffered gastrointestinal side effects when compared with those in the control [27,28,30,33,35]. Also, five papers did not provide any information about adverse events [26,29,31,32,34].…”

Section: Adverse Eventsmentioning

confidence: 99%

Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Zhang

et al. 2016

Value in Health

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Abstract:The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine (Hcy) with and without simultaneous supplementation of B-group vitamins or folic acid. A literature search was conducted in PubMed, EmBase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) reporting the concentration of serum Hcy in metformin-treated adults. Meta-analysis was applied to assess the association between metformin and the changes of Hcy concentration. Twelve publications were included in this study. In the overall analysis, metformin administration was not statistically associated with the change of Hcy when compared with the control treatment (mean difference (MD), 0.40 µmol/L; 95% confidence interval (CI), −0.07~0.87 µmol/L, p = 0.10). In the subgroup analysis, metformin was significantly associated with an increased concentration of Hcy in the absence of exogenous supplementation of folic acid or B-group vitamins (MD, 2.02 µmol/L; 95% CI, 1.37~2.67 µmol/L, p < 0.00001), but with a decreased concentration of serum Hcy in the presence of these exogenous supplementations (MD, −0.74 µmol/L; 95% CI, −1.19~−0.30 µmol/L, p = 0.001). Therefore, although the overall effect of metformin on the concentration of serum Hcy was neutral, our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given.

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“…24,25 Problems associated with Metformin include gastrointestinal side effects like nausea, vomiting, abdominal discomfort, flatulence, indigestion, constipation, heartburn etc and increase in homocysteine levels in some patients which limits their long-term use. 26 Hyperhomocysteinemia is a risk for cardiovascular diseases, thromobophilia, pre-eclampsia and recurrent abortion. N-acetylcysteine (NAC) is a stable derivative of the aminoacid cysteine which has anti-oxidant properties and is required for the body's production of glutathione.…”

mentioning

confidence: 99%

Comparison of metformin and N-acetylcysteine on metabolic parameters in women with polycystic ovarian syndrome

Ali

Radhakrishnan

Singh

2017

Int J Reprod Contracept Obstet Gynecol

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INTRODUCTIONPolycystic ovary syndrome (PCOS) is a common disease that affects up to 10% of women of reproductive age, in which hyperandrogenism (HA), enlarged cystic ovaries, and chronic anovulation often coexist with obesity, dyslipidemia and insulin resistance (IR).1 The etiology of the syndrome has remained unknown although it has been revealed that IR lies at the core of its pathophysiology. 2,3 Obesity in women with PCOS is rather high, ranging from 30% to 60%, whereas hyperinsulinemia is present in more than 50% of patients with PCOS. 4,5 Furthermore, although about 70% of obese women with PCOS exhibit an exaggerated insulin secretion, this feature is also present in 20%-40% of lean PCOS. [6][7][8] Chronic hyperinsulinemia results in different pathologies such as diabetes mellitus type 2, hypertension, cardiovascular diseases and metabolic syndrome.1,9 Risk factors of cardiovascular diseases tend to accumulate in these women even at their young age and dyslipidemia in these patients is correlated with IR. [10][11][12] It has been proven ABSTRACT Background: Polycystic ovary syndrome (PCOS) is a common disease that affects up to 10% of women of reproductive age, in which hyperandrogenism (HA), enlarged cystic ovaries, and chronic anovulation often co-exist with obesity, dyslipidemia and insulin resistance (IR). There is a need for an alternative to metformin with minimal side effects to improve insulin sensitivity and correct dyslipidemia in PCOS patients. Methods: It was a prospective, Randomized controlled clinical trial. 116 PCOS patients, 58 each in two groups received either Metformin 500 mg TDS or N-acetylcysteine (NAC) 600 mg TDS for 3 months. Clinical and biochemical parameters contributing to metabolic syndrome (MS) and insulin resistance (fasting blood sugar (FBS), fasting insulin (FI), FBS:FI, HOMA-IR and QUICKI) were assessed at the start and end of the study. Results were compared between the two groups. Results: Both treatment modalities resulted in a significant reduction in number of cases with IR (p=0.001) and MS. Fasting hyperinsulinemia improved in 15 % (p=0.12) and 30% (p=0.001) of patients while 12% (p=0.23) and 18% (p=0.049) improvement was seen in FBS:FI in MET and NAC group respectively. Similarly, improvement in HOMA-IR was 12% (p=0.30) and 32% (p=0.001) in MET and NAC group which is significant with NAC. QUICKI and impaired glucose tolerance showed significant improvement in both the groups with a p-value of 0.04 and 0.006, 0.035 and 0.046 respectively. Significant reduction was seen in triglycerides (p=0.048) in NAC group. Conclusions: NAC is equally efficacious as metformin in improving parameters of insulin resistance and metabolic syndrome with minimal occasional side effects ensuring better compliance for a long-term therapy.

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Homocysteine levels in women with polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study

Abstract: Treatment with insulin sensitizers in women with PCOS may lead to increases in Hcy levels.

Cited by 65 publications

References 29 publications

Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking

Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking

Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Comparison of metformin and N-acetylcysteine on metabolic parameters in women with polycystic ovarian syndrome

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