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The effect of metformin on uteroplacental circulation and pregnancy outcomes in pregnant women with Polycystic Ovary Syndrome
Jamal A,Aleyasin A,Shabani P,Khodaverdi S
Tehran University Medical Journal , 2010,
Abstract: "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Some complications of pregnancy such as abortion, gestational diabetes mellitus, preeclampsia, and preterm delivery are more common among women with polycystic ovary syndrome (PCOS). Recently it has been reported that metformin treatment during pregnancy reduces pregnancy complications, so this study was conducted to demonstrate the possible effects of metformin on the uteroplacental circulation and pregnancy complications. "n"nMethods: Seventy pregnant women with polycystic ovary syndrome (PCOS) from 1386 to 1388 were enrolled in a randomized, double-blind, placebo-controlled trial of metformin during pregnancy in Shariati hospital. Doppler ultrasound examinations of the uterine arteries and umbilical artery were performed at 12th and 20th weeks of gestation. All patients were followed up to the end of pregnancy, then the effect of metformin on the uteroplacental circulation was evaluated by the comparison of the pulsatility index (PI) of uterine arteries and prevalence of obstetric complications between two groups. "n"nResults: The mean reduction of PI in metformin group from 12th to 20th weeks of gestation was 0.38 versus 0.16 in placebo group (p=0.016). Gestational diabetes mellitus, pre-eclampsia and preterm delivery, were more common in pregnant women in placebo group but the difference was not statistically significant. "n"nConclusions: Metformin treatment in pregnancy accompanied with reduced uterine artery impedance between 12 and 20 weeks of gestation but this reduction showed no effect on the pregnancy complications such as preterm delivery, preeclampsia and gestational diabetes.
Pregnancy outcome in women with polycystic ovary syndrome comparing the effects of laparoscopic ovarian drilling and clomiphene citrate stimulation in women pre-treated with metformin: a retrospective study
Johannes Ott, Christine Kurz, Kazem Nouri, Stefan Wirth, Elisabeth Vytiska-Binstorfer, Johannes C Huber, Klaus Mayerhofer
Reproductive Biology and Endocrinology , 2010, DOI: 10.1186/1477-7827-8-45
Abstract: Setting: Academic research institution. We retrospectively analyzed the courses of 40 spontaneous pregnancies after LOD for CC-resistance, 40 pregnancies after CC stimulation, and 40 pregnancies after metformin treatment alone. Patients in the LOD and the CC groups had been pre-treated with Metformin. Primary outcome parameters were: the rate of multiple pregnancies; the rate of early pregnancy losses/miscarriages; the development of gestational diabetes, pregnancy-induced hypertension, and preeclampsia/HELLP-syndrome; premature delivery; and birth weight.The rate of twin pregnancies did not differ between the CC group (12.5%), the LOD group (7.5%), and the metformin only group (2.5%, p = 0.239). Seventeen women suffered an early miscarriage. There were no differences with regard to the rates of gestational diabetes, pregnancy-induced hypertension, preeclampsia, and preterm delivery. By analyzing all pregnancy complications together, the overall pregnancy complication rate was highest in the CC group (70.0%, 28/40), followed by the LOD group (45.0%, 18/40), and the metformin only group (47.5%, 19/40; p = 0.047).CC, but not LOD, increases the complication rate in pregnant patients who received metformin.Despite the fact that polycystic ovary syndrome (PCOS) remains one of the most common female endocrinopathies, with an incidence of 5-10% in women of reproductive age, the etiology, pathogenesis, and even treatment of infertile women who suffer from PCOS are still the subject of much controversy [1,2]. Clomiphene citrate (CC) is presumed to be the first-line therapy, since it is known to result in higher ovulation, conception, pregnancy, and live-birth rates when compared with metformin; the combination of both drugs did not result in a significant benefit [3,4].As second- and third-line therapies, gonadotropin stimulation and laparoscopic ovarian drilling (LOD) are recommended for CC-resistant anovulatory PCOS patients. To date, five randomized controlled trials have
The Role of Metformin in Metabolic Disturbances during Pregnancy: Polycystic Ovary Syndrome and Gestational Diabetes Mellitus  [PDF]
Joselyn Rojas,Mervin Chávez-Castillo,Valmore Bermúdez
International Journal of Reproductive Medicine , 2014, DOI: 10.1155/2014/797681
Abstract: Maintenance of gestation implicates complex function of multiple endocrine mechanisms, and disruptions of the global metabolic environment prompt profound consequences on fetomaternal well-being during pregnancy and postpartum. Polycystic Ovary Syndrome (PCOS) and gestational diabetes mellitus (GDM) are very frequent conditions which increase risk for pregnancy complications, including early pregnancy loss, pregnancy-induced hypertensive disorders, and preterm labor, among many others. Insulin resistance (IR) plays a pivotal role in the pathogenesis of both PCOS and GDM, representing an important therapeutic target, with metformin being the most widely prescribed insulin-sensitizing antidiabetic drug. Although traditional views neglect use of oral antidiabetic agents during pregnancy, increasing evidence of safety during gestation has led to metformin now being recognized as a valuable tool in prevention of IR-related pregnancy complications and management of GDM. Metformin has been demonstrated to reduce rates of early pregnancy loss and onset of GDM in women with PCOS, and it appears to offer better metabolic control than insulin and other oral antidiabetic drugs during pregnancy. This review aims to summarize key aspects of current evidence concerning molecular and epidemiological knowledge on metformin use during pregnancy in the setting of PCOS and GDM. 1. Introduction Infertility currently affects approximately 48.5 million of women aged 20–44 years around the world [1], with severe implications in their physical and mental well-being [2]. Female fertility entails a complex array of endocrine mechanisms surrounding the integrity of the hypothalamus-pituitary-ovary (HPO) axis, which are especially important in maintenance of a healthy pregnancy, particularly due to the demands of the growing fetus [3]. Many conditions may disrupt this environment, and Polycystic Ovary Syndrome (PCOS)—an endocrine-metabolic disease that encompasses multiple hormonal alterations related to female infertility—stands out mainly due to its high prevalence, affecting 6-7% of women aged 12–45 years [4], with a worrisome 70% of women estimated to remain undiagnosed [5]. The hallmarks of this gynecoendocrine disease are disruption of ovarian steroidogenesis, giving rise to hyperandrogenemia and insulin resistance (IR) [6]. A complex IR-hyperinsulinemia-hyperandrogenemia cycle involved in the endocrine disruptions in PCOS [7] leads not only to the typical clinical picture of PCOS—featuring oligoanovulation and hyperandrogenic manifestations—but also to diverse
Comparison of pregnant and non-pregnant women with clomiphene resistant polycystic ovary syndrome in treatment with metformin and letrozole
Azam Azargoon,Jafar Alavi Toussy
Koomesh , 2011,
Abstract: Introduction: Polycystic ovary syndrome (PCOS) is one of the most common causes of anovulatory infertility. Clomiphen citrate (CC) is the first line therapy for women with infertility and PCOS. These patients usually respond to clomiphene citrate in doses between 50-100 mg/day. However, fialure of the patient to respond to a dosage of 150 mg/day of clomiphene citrate is considered as clomiphene resistant. The aim of this study was to compare between pregnant and non-pregnant women in cases of PCOS patients with CC resistant. Meanwhile, we evaluated ovulatory rate, pregnancy rate and live birth rates. Materials and Methods: We studied 106 CC-resistant PCOS patients who attended to Amir-Al- Momenin Hospital (Semnan, Iran) during the years 2005-2008. After an initial 6-8 weeks of metformin (1500mg daily: 500mg q8h), they received 2.5mg letrozole for 5 days starting on cycle day 3. If they failed to show ovluation with 2.5mg letrozole, doses were increased to 5 and 7.5 mg daily in the subsequent cycles. Results: One patient developed generalized rash with metformin and excluded from the study. 14 of 105 patients (13.33%) conceived with metformin alone. Overall, ovulation rate was 83.91(91.2%). Overall, pregnancy rate was 60/105 (57.14%) with 45 (74.9%) full term pregnancies, 10 (16.7%) abortions and 5 (8.3%) preterm births. The only significant difference between the responder and non-responder was found in the age of patients (P=0.008) . No significant differences were found in BMI, period of infertility, menstrual pattern, hirsutism, pictures of PCO in one or two ovaries in sonography, LH, and FSH or LH/FSH ratio. Conclusion: Combination of metformin with incremental doses of letrozole associated with a good pregnancy rate in CC-resistant PCOS patients. The treatment seems especially more effective in young weman.
Polycystic Ovary Syndrome and the Role of Metformin in Ovulation Induction  [PDF]
Fabiana Fraga, Gabriel Azeredo César Salgado Romeiro, Larissa Bianca Paiva Cunha de Sá, Alberto Krayyem Arbex
Health (Health) , 2018, DOI: 10.4236/health.2018.105045
Abstract: The Polycystic Ovary Syndrome (PCOS) is frequently associated with comorbidities such as obesity, reduced glucose tolerance, hypertension, macrovascular disease and dyslipidemia. The Metabolic syndrome occurs in 30% of women with PCOS. Metformin has increasingly been used in this therapy due to its effects in reducing insulin resistance. Treatment of PCOS aims to reduce the symptoms of hyperandrogenism, regularize the menstrual cycle, reduce metabolic abnormalities, and lower the risk of type 2 diabetes mellitus and of cardiovascular disease. Additionally it is important to prevent hyperplasia and endometrial cancer, and to offer contraception to those who do not wish pregnancy, and to help to induce ovulation to those who do. The effectiveness of metformin in this treatment is assessed in the light of the current best evidence.
Effects of Metformin on Ovulation and Pregnancy Rate in Women with Clomiphene Resistant Poly Cystic Ovary Syndrome  [PDF]
Mahnaz Ashrafi,Fatemeh Zafarani,Ahmad Reza Baghestani
International Journal of Fertility & Sterility , 2007,
Abstract: Background: To evaluate the effect of metformin on ovulation and pregnancy rate in clomiphene citrateresistant women with polycystic ovary syndrome (PCOS).Material & Methods: In this clinical trial each patient, regarding her previous resistance to Clomiphene,served as her own control. A total of 35 clomiphene citrate resistant PCOS patients, referring to Royan institutewere studied. Clomiphene citrate resistance was defined as having failure of ovulation during at least threecycles using clomiphene citrate doses up to 200 mg/day on cycle days 3-7 after a withdrawal bleeding withprogesterone. Metformin was used alone or in combination with clomiphene citrate. First, the patients receivedmetformin up to 1500 mg/day for 8 weeks. During the next 2-3 cycle if the patients did not become pregnant,clomiphene was added with increments of 100 mg (up to 150 mg/day). Follicular development and ovulationwere monitored by ultrasound scans and mid-luteal progesterone level. Menstrual pattern, ovulation, andpregnancy rate were evaluated during the two stages of treatment.Results: After 8 weeks of meformin monotherapy, ovulation occurred in 23 cases (65.7%) and 7 patients (20%)became pregnant. Among other patients (28/35) who were treated with Clomiphene Ci rate and metformin for64 cycles, 19 patients (67.8%) had proper ovulation and five of them (17.8%) became pregnant. Totally,metformin induced ovulation in 31 of 35 patients (88.6%) and twelve (34.3%) of them achieved pregnancy.Conclusion: Metformin alone or in combination with clomiphene is a very effective treatment in inducingovulation and pregnancy in clomiphene resistant women with PCOS.
Metformin Therapy Decreases Hyperandrogenism and Ovarian Volume in Women with Polycystic Ovary Syndrome
Marzieh Farimani Sanoee,Nosrat Neghab,Soghra Rabiee,Iraj Amir
Iranian Journal of Medical Sciences , 2011,
Abstract: Background: It is well known that there is a close relationship between elevated androgen plasma levels and the ultrasound findings of stromal hypertrophy in polycystic ovary syndrome (PCOS). The objective of this study was to investigate the effects metformin on the hyperandrogenism and ovarian volume in PCOS. Methods: The study is an unrandomized clinical trial with before–after design. Twenty eight patients with infertility (male or female factor) meeting the Rotterdam ESHRE/ASRM criteria for PCOS were studied during the 2008-2009. The anthropometric characteristics of the patients, mean bilateral ovarian volume, and morphology by trans vaginal sonography as well as the plasma levels of leutinizing hormone, follicle stimulating hormone, estradiol, testosterone, 17-α-hydroxyprogesterone, and dehydroepianderosterone sulfate were obtained before and after treatment with metformin (500 mg three times a day) for three months. Paired t, Pearson's Correlation Coefficient, or Partial Correlation test was used to analyze the findings. Results: The patients had a mean age of 25.67 years. A significant reduction in mean ovarian volume (11.70±4.31 ml vs 8.27±3.71 ml P=0.001), body mass index (BMI, 28.11±4.55 kg/m2 vs 26.84±4.55 kg/m2 P=0.000) and serum androgen levels was seen after three months of treatment with metformin. There was positive correlations between the ovarian volume and serum testosterone level (r=0.589, P=0.001) or BMI (r=0.663, P=0.000). Conclusion: Metformin therapy may lead to a reduction in ovarian volume. It is likely that the reduction of ovarian volume reflect a decrease in the mass of androgen producing tissues
Metformin Lowers Serum Cobalamin without Changing Other Markers of Cobalamin Status: A Study on Women with Polycystic Ovary Syndrome  [PDF]
Eva Greibe,Birgitta Trolle,Mustafa V. Bor,Finn F. Lauszus,Ebba Nexo
Nutrients , 2013, DOI: 10.3390/nu5072475
Abstract: Treatment with the anti-diabetic drug metformin is followed by a decline in plasma cobalamin, but it is unsettled whether this denotes an impaired cobalamin status. This study has explored changes in the markers of cobalamin status in women with Polycystic Ovary Syndrome treated with metformin (1.5–2.5 g per day) ( n = 29) or placebo ( n = 23) for six months. Serum samples were collected before and after two, four, and six months of treatment. We found serum cobalamin to decline and reach significant lower levels after six months of treatment ( p = 0.003). Despite the decline in serum cobalamin, we observed no reductions in the physiological active part of cobalamin bound to transcobalamin (holotranscobalamin), or increase in the metabolic marker of cobalamin status, methylmalonic acid. Instead, the non-functional part of circulating cobalamin bound to haptocorrin declined ( p = 0.0009). Our results have two implications: The data questions whether metformin treatment induces an impaired cobalamin status in PCOS patients, and further suggests that serum cobalamin is a futile marker for judging cobalamin status in metformin-treated patients.
Metabolomics Reveals Reduction of Metabolic Oxidation in Women with Polycystic Ovary Syndrome after Pioglitazone-Flutamide-Metformin Polytherapy  [PDF]
Maria Vinaixa, Miguel Angel Rodriguez, Sara Samino, Marta Díaz, Antoni Beltran, Roger Mallol, Cinta Bladé, Lourdes Iba?ez, Xavier Correig, Oscar Yanes
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029052
Abstract: Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients.
Síndrome de ovario poliquístico y embarazo Polycystic ovary syndrome and pregnancy  [cached]
Teresa Sir-Petermann,Amanda Ladrón de Guevara,Ana Claudia Villarroel,Jessica Preisler
Revista médica de Chile , 2012,
Abstract: Background: Polycystic ovary syndrome (PCOS) is a common endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications and prenatal programming of the offspring. The aim of this review is to report our experience in PCOS patients who became pregnant and were followed during the whole pregnancy. Firstly, we analyzed the effect of pregnancy on PCOS pathophysiology and secondly the role of PCOS in pregnancy outcomes. Regarding the firstpoint, during normal pregnancy a progressive insulin resistance, serum lipid changes and an increase in androgen levels is observed, which is exacerbated in the PCOS condition. This adverse intrauterine environment could have a prenatal programming effect with detrimental consequences for female or male fetuses. Regarding the second point, PCOS is associated with an increased risk for maternal complications such as gestational diabetes (GDM) and pregnancy-induced hypertension. Moreover, these adverse pregnancy outcomes are more frequently associated with an increase in low birth weight and high birth weight newborns. According to our clinical experience, PCOS patients who became pregnant and were not treated with metformin during the whole pregnancy, showed a higher prevalence of gestational diabetes and SGA newborns, which was improved with metformin treatment. In summary, pregnancy may constitute a period in which an abnormal condition is established or aggravated in the fetus of a PCOS mother. Moreover, PCOS enhanced adverse obstetric and neonatal outcomes.
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