Should insulin-sensitizing drugs be used in the treatment of polycystic ovary syndrome?

Insulin resistance is a central feature of polycystic ovary syndrome (PCOS). Hyperinsulinaemia contributes to anovulation, hyperandrogenism, infertility and early pregnancy loss in women with PCOS. Chronic hyperinsulinaemia also predisposes women with PCOS to increased risks of diabetes and cardiovascular events. Current data indicate that metformin, either as monotherapy or in combination with clomiphene in clomiphene-resistant patients, is an effective treatment for anovulation in PCOS. Initial evidence also suggests that insulin sensitizers may have a role in preventing early pregnancy loss. Of the available insulin-sensitizing agents, metformin has been the agent most frequently studied in PCOS, and has the least undesirable pregnancy safety profile. Ameliorating the metabolic syndrome associated with insulin resistance in PCOS with metformin may also prevent long-term cardiovascular and diabetes complications, pending further evidence. Based on these data, metformin should be a first-line therapy for women with PCOS.     

Pregnancy complications in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. There is an increasing body of evidence indicating that PCOS may have significant implications for pregnancy outcomes and long-term health of a woman and her offspring. Whether or not PCOS itself or the symptoms that coincide with PCOS, like obesity and fertility treatment, are responsible for these increased risks is a continuing matter of debate. Miscarriage rates among women with PCOS are believed to be increased compared with normal fertile women, although supporting evidence is limited. Pregnant women with PCOS experience a higher incidence of perinatal morbidity from gestational diabetes, pregnancy-induced hypertension, and preeclampsia. Their babies are at an increased risk of neonatal complications, such as preterm birth and admission at a neonatal intensive care unit. Pre-pregnancy, antenatal, and intrapartum care should be aimed at reducing these risks. The use of insulin sensitizing drugs to decrease hyperinsulinemic insulin resistance has been proposed during pregnancy to reduce the risk of developing preeclampsia or gestational diabetes. Although metformin appears to be safe, there are too few data from prospective, randomized controlled trials to support treatment during pregnancy.     

Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview

This article is a review of the literature assessing pregnancy outcomes and the effect of metformin treatment among women with polycystic ovary syndrome (PCOS). A review of research published in English was undertaken using PubMed and MEDLINE databases. The weight of the available evidence suggests that pregnant women with PCOS are at an increased risk of developing gestational diabetes, hypertensive disorders of pregnancy, preterm birth and early pregnancy loss. Obesity is a contributory factor for the increased risk of gestational diabetes in this group of women and is estimated to affect 5-40% of pregnant women with PCOS. The prevalence of other obstetric complications is estimated at 10-30% for gestational hypertension, 8-15% for pre-eclampsia and 6-15% for preterm birth. The association between PCOS and early pregnancy loss may not be direct, wherein the presence of PCOS-associated hyperinsulinemia, leading to hyperandrogenemia, has been implicated in the pathophysiology of early pregnancy loss. Apart from the role of metformin in improving the metabolic consequences accompanying PCOS, it has been shown to improve pregnancy rates in women with PCOS who are resistant to clomiphene citrate. In conclusion, pregnancy in women with PCOS is associated with adverse obstetric outcomes (multiple adverse obstetric risk). Whether metformin should be administered throughout pregnancy still remains controversial. Further prospective studies that foster a larger number of participants and adjust for all potentially confounding factors are needed.     

Medical therapy in women with polycystic ovarian syndrome before and during pregnancy and lactation

Polycystic ovary syndrome (PCOS) is probably the most common endocrinopathy in women of childbearing age, and is particularly common in African-American and Hispanic ethnic groups. It is characterized by oligo-amenorrhea, clinical and/or biochemical hyperandrogenism, polycystic ovaries, and, often, morbid obesity. PCOS is associated with infertility and frequent 1st trimester miscarriage, and with an increased risk of gestational diabetes. Insulin resistance with compensatory hyperinsulinemia plays an important role in the pathogenesis of PCOS. Reduction of hyperinsulinemia with metformin-diet is associated not only with improvement of the biochemical endocrinopathy, but, commonly, with restoration of menstrual cycles and fertility. The combination of metformin and clomiphene citrate (CC) in CC resistant patients provides additional benefit to a subset of patients, not responsive to metformin alone. Metformin appears to be safe for mothers and neonates (non-teratogenic) during pregnancy, though the results of double-blinded placebo-controlled studies are not yet available. Benefits from metformin therapy during pregnancy include reduction of miscarriage, reduction in likelihood of developing gestational diabetes, reduction in fetal macrosomia, and prevention of excessive maternal weight gain during pregnancy. Rosiglitazone and pioglitazone are effective therapy for ovulation induction, but pregnancy class C and should not be used during pregnancy.     

Can metformin reduce the incidence of gestational diabetes mellitus in pregnant women with polycystic ovary syndrome? Prospective cohort study

Background.?Women with polycystic ovary syndrome (PCOS) are at a high risk to develop Gestational Diabetes mellitus (GDM). We hypothesized that metformin due to its metabolic, endocrine, vascular, and anti-inflammatory effects may reduce the incidence of GDM in PCOS women.

Patient and method.?We carried out a prospective cohort study to determine the beneficial effects of metformin on PCOS patients during pregnancy. Three-hundred and sixty non-diabetic PCOS patients were included who were conceived on metformin by different treatment modalities. Two-hundred pregnant women continued on metformin at a dose of 1000–2000?mg daily throughout pregnancy (study group) and 160 women discontinued metformin use at the time of conception (control group).

Results.?There is a statistically significant reduction in the incidence of GDM in favor of metformin group (OR: 0.17, 95% CI: 0.07–0.37). There is a statistically significant reduction in the incidence of pre-eclampsia in favor of metformin group (OR: 0.35, 95% CI: 0.13–0.94).

Conclusion.?Metformin is a promising medication for the prevention or reduction of the incidence of GDM and pre-eclampsia in PCOS women.     

Metformin reduces abortion in pregnant women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are considered to be at increased risk of miscarriage. Since metformin has beneficial effects on the risk factors contributing to first-trimester abortion in PCOS patients, we hypothesized that metformin - owing to its metabolic, endocrine, vascular and anti-inflammatory effects - may reduce the incidence of first-trimester abortion in PCOS women. MATERIALS AND METHODS: A prospective cohort study was set up to determine the beneficial effects of metformin on PCOS patients during pregnancy. Two hundred non-diabetic PCOS patients were evaluated while undergoing assisted reproduction. One hundred and twenty patients became pregnant while taking metformin, and continued taking metformin at a dose of 1000-2000 mg daily throughout pregnancy. Eighty women who discontinued metformin use at the time of conception or during pregnancy comprised the control group. RESULTS: Both groups were similar with respect to all background characteristics (age, body mass index, waist/hip ratio, follicle-stimulating hormone, luteinizing hormone, estradiol and dehydroepiandrosterone sulfate levels). Rates of early pregnancy loss in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11-0.42). CONCLUSIONS: Administration of metformin throughout pregnancy to women with PCOS was associated with a marked and significant reduction in the rate of early pregnancy loss.     

Outcome of clinical pregnancies after ovulation induction using metformin.

The objective of this study was to review the first 50 clinical pregnancies of women with polycystic ovarian syndrome (PCOS) who had ovulation induced either with metformin alone, or in combination with clomifene. The study was confined to women with PCOS attending our infertility service. A register of clinical pregnancies was maintained of women who conceived after metformin therapy. The metformin was continued throughout the first trimester. The outcome of pregnancy was determined by individual chart review. Of the 50 women, 21 conceived with a combination of clomifene and metformin, and 29 with metformin alone. Seven women had a first trimester loss and 43 had a live birth. There were no perinatal deaths, no neonatal seizures and no congenital malformations. There were also no multiple pregnancies. The overall caesarean rate was 37%, and none of the babies had an Apgar score less than 7, at 5 min. This study found no evidence of any adverse clinical effects when metformin is continued in the first trimester of women with PCOS following ovulation induction. There was also no evidence of an increase in the rate of miscarriage or multiple pregnancy.     

Metformin reduces abortion in pregnant women with polycystic ovary syndrome

Background.?Women with polycystic ovary syndrome (PCOS) are considered to be at increased risk of miscarriage. Since metformin has beneficial effects on the risk factors contributing to first-trimester abortion in PCOS patients, we hypothesized that metformin – owing to its metabolic, endocrine, vascular and anti-inflammatory effects – may reduce the incidence of first-trimester abortion in PCOS women.

Materials and methods.?A prospective cohort study was set up to determine the beneficial effects of metformin on PCOS patients during pregnancy. Two hundred non-diabetic PCOS patients were evaluated while undergoing assisted reproduction. One hundred and twenty patients became pregnant while taking metformin, and continued taking metformin at a dose of 1000–2000 mg daily throughout pregnancy. Eighty women who discontinued metformin use at the time of conception or during pregnancy comprised the control group.

Results.?Both groups were similar with respect to all background characteristics (age, body mass index, waist/hip ratio, follicle-stimulating hormone, luteinizing hormone, estradiol and dehydroepiandrosterone sulfate levels). Rates of early pregnancy loss in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11–0.42).

Conclusions.?Administration of metformin throughout pregnancy to women with PCOS was associated with a marked and significant reduction in the rate of early pregnancy loss.     

Neonatal outcome in polycystic ovarian syndrome patients treated with metformin during pregnancy.

OBJECTIVE: The present study aimed to evaluate the effect of metformin exposure during pregnancy on neonates of polycystic ovarian syndrome (PCOS) patients. METHOD: Neonatal outcomes of 33 women with PCOS treated with metformin during pregnancy were compared to neonatal outcomes of 66 normal healthy women in a retrospective case-control study. RESULTS: The mean birth weight percentile of neonates exposed to metformin in utero during the first trimester was significantly lower than that of neonates delivered to normal healthy matched controls. After controlling for pregnancy complications, this observation became only marginally statistically significant. CONCLUSION: Although metformin is an attractive option for induction of ovulation in PCOS patients, there is a need for more evidence related to its safety during pregnancy.     

Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome?

AIM: Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies in women of reproductive age. It is associated with hyperinsulinemia and insulin resistance which is further aggravated during pregnancy. This mechanism has a pivotal role in the development of various complications during pregnancy. In the past few years, metformin, an insulin sensitizer, has been extensively evaluated for induction of ovulation. Its therapeutic use during pregnancy is, however, a recent strategy and is a debatable issue. At present, evidence is inadequate to support the long-term use of insulin-sensitizing agents during pregnancy. It is a challenge for both clinicians and researchers to provide good evidence of the safety of metformin for long-term use and during pregnancy. This study aimed to evaluate pregnancy outcomes in women with PCOS who conceived while on metformin treatment, and continued the medication for a variable length of time during pregnancy. METHODS: This case-control study was conducted from January 2005 to December 2006 at the antenatal clinics of the Department of Obstetrics and Gynecology, Aga Khan University, Karachi, Pakistan. The sample included 137 infertile women with PCOS; of these, 105 conceived while taking metformin (cases), while 32 conceived spontaneously without metformin (controls). Outcomes were measured in three groups of cases which were formed according to the duration of use of metformin during pregnancy. Comparison was made between these groups and women with PCOS who conceived spontaneously. RESULTS: All 137 women in this study had a confirmed diagnosis of PCOS (Rotterdam criteria). These women were followed up during their course of pregnancy; data forms were completed once they had delivered. Cases were divided into three groups: group A, 40 women who stopped metformin between 4-16 weeks of pregnancy; group B, 20 women who received metformin up until 32 weeks of gestation; and group C; 45 women who continued metformin throughout pregnancy. All the groups were matched by age, height and weight. Comparison was in terms of early and late pregnancy complications, intrauterine growth restriction and live birth rates. In groups A, B and C the rate of pregnancy-induced hypertension/pre-eclampsia was 43.7%, 33% and 13.9% respectively (P<0.020). Rates of gestational diabetes requiring insulin treatment in groups A and B were 18.7% and 33.3% compared to 2.5% in group C (P<0.004). The rate of intrauterine growth restriction was significantly low in group C: 2.5% compared to 19.2% and 16.6% in groups A and B respectively (P<0.046). Frequency of preterm labor and live birth rate was significantly better in group C compared to groups A and B. Overall rate of miscarriages was 7.8%. Controls were comparable to group A in terms of early and late pregnancy complications. CONCLUSION: In women with PCOS, continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction. No congenital anomaly, intrauterine death or stillbirth was reported in this study.     

Metformin and Polycystic Ovary Syndrome: A Literature Review

Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. Anovulation, menstrual irregularities, hirsutism, and infertility are common clinical presentations. Long-term health concerns such as type II diabetes mellitus and, possibly, cardiovascular disease, have been linked to PCOS. Metformin, an oral hypoglycemic agent, has been recently advocated as treatment for some women with PCOS due to the association of PCOS with hyperinsulinemia. Metformin is utilized as sole therapy for ovulation induction as well as in combination with traditional ovulation-induction therapies. This review identified 23 prospective studies addressing the effects of metformin on PCOS. Because of the heterogeneity of the published reports, only a qualitative assessment of the data was possible. Review of this literature confirms a beneficial role of metformin in reducing insulin resistance in some women with PCOS. Other favourable biochemical effects include reduced free testosterone levels and increased sex hormone-binding globulin (SHBG). Metformin may improve menstrual regularity, leading to spontaneous ovulation, and improve ovarian response to conventional ovulation-induction therapies. There is, however, little evidence supporting the use of metformin to facilitate weight reduction, or improve serum lipids or hirsutism. Further evaluation is required to define the long-term effectiveness of metformin, who will benefit from metformin treatment, and the optimal duration of metformin therapy.     

Is metformin a primary ovulatory agent in patients with polycystic ovary syndrome?

Insulin resistance is an important pathophysiological feature of the polycystic ovary syndrome (PCOS). Insulin resistance and its compensatory hyperinsulinemia contribute to the anovulation, hyperandrogenism, infertility and early pregnancy loss suffered by women with PCOS. Current evidence supports the role of metformin in the treatment of anovulation in PCOS, both in monotherapy and concomitantly with clomiphene in clomiphene-resistant patients. In addition, novel evidence suggests that insulin sensitizers may also play a role in reducing the risk of early pregnancy loss. The insulin-sensitizing agents available commercially include metformin, rosiglitazone and pioglitazone. Compared with the thiozolidinediones, metformin is the agent that has been most frequently studied in PCOS, and has the most favorable pregnancy safety profile. In conclusion, there is strong evidence supporting the use of metformin as a primary ovulatory agent in women with PCOS.     

Is metformin a primary ovulatory agent in patients with polycystic ovary syndrome?

Insulin resistance is an important pathophysiological feature of the polycystic ovary syndrome (PCOS). Insulin resistance and its compensatory hyperinsulinemia contribute to the anovulation, hyperandrogenism, infertility and early pregnancy loss suffered by women with PCOS. Current evidence supports the role of metformin in the treatment of anovulation in PCOS, both in monotherapy and concomitantly with clomiphene in clomiphene-resistant patients. In addition, novel evidence suggests that insulin sensitizers may also play a role in reducing the risk of early pregnancy loss. The insulin-sensitizing agents available commercially include metformin, rosiglitazone and pioglitazone. Compared with the thiozolidinediones, metformin is the agent that has been most frequently studied in PCOS, and has the most favorable pregnancy safety profile. In conclusion, there is strong evidence supporting the use of metformin as a primary ovulatory agent in women with PCOS.     

胰岛素增敏剂治疗多囊卵巢综合征疗效与安全性

多囊卵巢综合征（PCOS）导致生殖和代谢功能紊乱的同时也增加罹患2型糖尿病及代谢综合征的危险。认识到胰岛素抵抗在PCOS发病中起到的作用后,以二甲双胍为代表的胰岛素增敏剂在临床广泛应用。最近一个以胎儿活产率（live-birth rate）为终点的随机对照试验（RCT）表明,单用二甲双胍治疗由PCOS引起的不孕症,其效果不及氯米芬。无证据证明应用二甲双胍能防止PCOS的妊娠妇女发生自然流产和妊娠期糖尿病。有研究噻唑烷二酮（TZD）类药物可能会增加心血管事件发生率。长期用药安全性的问题重新引起关注。     

Ultra-short metformin pretreatment for clomiphene citrate-resistant polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of ultra-short (12 days) metformin pretreatment in clomiphene-citrate (CC) resistant polycystic ovary syndrome (PCOS). METHOD: Eighty women with CC-resistant PCOS were randomly allocated to metformin pretreatment or usual treatment. Forty women received 1500 mg metformin daily for 12 days, followed by clomiphene 150 mg daily for 5 days along with metformin. Forty women (control group) received the same dose of clomiphene but no metformin pretreatment. RESULTS: In the metformin group, 17 (42.5%) women ovulated, and 6 (15%) conceived. In the control group, 5 (12.5%) women ovulated but none conceived. Compared with the control group, the metformin group had significantly higher ovulation (P = 0.03) and pregnancy rates (P = 0.026). CONCLUSION: Twelve days of metformin pretreatment improves ovulation and pregnancy rates in women with CC-resistant PCOS.     

Review of nonsurgical and surgical treatment and the role of insulin-sensitizing agents in the management of infertile women with polycystic ovary syndrome

OBJECTIVES: To review the nonsurgical and surgical treatment and the role of insulin-sensitizing agents in the management of anovulatory infertile women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: The search term of subfertile women with anovulation and PCOS was used for identification of randomized controlled trials. Nonrandomized controlled studies were identified through computer MEDLINE and EMBASE searches for the years 1980-2002. RESULTS: For obese PCOS women weight loss of > 5% of pretreatment weight restores menstrual regularity in 89%, of whom 30% achieved spontaneous pregnancy. It was estimated that 75-80% of anovulatory PCOS women will respond to clomiphene citrate (CC) and 35-50% will achieve pregnancy. For CC-resistant PCOS women (20-25%), CC + metformin (1.5 g/day) for 3-6 months has a 70% chance of restoration of regular menses and ovulation, and a 23% chance of pregnancy. Laparoscopic ovarian drilling (LOD) can be offered to CC-resistant PCOS women. There was no statistically significant difference in the ovulation rate following LOD with electrocoagulation and laser [83% vs. 77.5%; odds ratio (OR) 1.4; 95% CI 0.9-2.1], while there was a significantly higher cumulative pregnancy rate at 12 months after surgery (65% vs. 54.5%; OR 1.5; 95% CI 1.1-2.1). CONCLUSION: Diet and exercise followed by CC should be used for nonsurgical ovulation induction. For CC-resistant PCOS women, metformin may be included in a stepwise approach before a surgical approach. LOD with electrocautery is superior to laser drilling and gonadotropin therapy.     

Effects of metformin on body mass index,menstrual cyclicity,and ovulation induction in women with polycystic ovary syndrome

OBJECTIVE: Metformin has been used as a treatment in many studies of the infertility associated with polycystic ovary syndrome (PCOS). We will review the literature on this topic as it specifically relates to changes in body mass index (BMI), improvement in menstrual cyclicity, and effects on ovulation and pregnancy rates. DESIGN: Review of studies addressing biochemical and clinical changes in women with PCOS on metformin. MAIN OUTCOME MEASURE(S): Changes in BMI, menstrual cyclicity, ovulation rate, and pregnancy rate. RESULT(S): Metformin has been shown to produce small but significant reductions in BMI. Multiple observational studies have confirmed an improvement in menstrual cyclicity with metformin therapy. The studies addressing the concomitant use of metformin with clomiphene citrate initially predicted great success, but these have been followed by more modest results. There is little data in the literature concerning the use of metformin and hMGs. CONCLUSION(S): Some (but not all) women with PCOS have improvements in their menstrual cycles while on metformin. The data supporting the use of metformin in ovulation induction with clomiphene citrate and hMG remain to be confirmed by large, randomized, prospective studies.     

Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective

Given the above observations, I suggest that metformin remains an important therapeutic option in the pharmacological treatment of infertility in PCOS, and its use should not be restricted to women with glucose intolerance, as recommended by the ESHRE/ASRM consensus statement. Taking into consideration the different time lines for achieving pregnancy among women with PCOS, I would suggest the following:

• In women with PCOS for whom time is of the essence and rapid establishment of pregnancy is desired, clomiphene should be the first-line agent. The addition of metformin to clomiphene has been shown to increase the cumulative ovulation rate, but it remains unclear whether it increases the odds of a live birth.

• In women with PCOS for whom pregnancy is a goal at a more distant time (>6 months), initial treatment with metformin, combined with diet and exercise, is an option to induce ovulation. An advantage of achieving pregnancy with metformin versus clomiphene in this situation may be a decrease in the risk of multiparity.

Infertility treatment needs to be individualized, and these recommendations attempt to take into account the needs and preferences of patients with PCOS, who may differ with respect to the urgency of achieving pregnancy and the willingness to risk multiparity. These recommendations also recognize continuing uncertainties in the field that warrant continued investigation.     

Neonatal outcome in polycystic ovarian syndrome patients treated with metformin during pregnancy

Objective.?The present study aimed to evaluate the effect of metformin exposure during pregnancy on neonates of polycystic ovarian syndrome (PCOS) patients.

Method.?Neonatal outcomes of 33 women with PCOS treated with metformin during pregnancy were compared to neonatal outcomes of 66 normal healthy women in a retrospective case–control study.

Results.?The mean birth weight percentile of neonates exposed to metformin in utero during the first trimester was significantly lower than that of neonates delivered to normal healthy matched controls. After controlling for pregnancy complications, this observation became only marginally statistically significant.

Conclusion.?Although metformin is an attractive option for induction of ovulation in PCOS patients, there is a need for more evidence related to its safety during pregnancy.